WO2011034971A1

WO2011034971A1 - Modified fluoroquinolone compounds and methods of using the same

Info

Publication number: WO2011034971A1
Application number: PCT/US2010/048996
Authority: WO
Inventors: David H. Peyton; Steven J. Burgess
Original assignee: Designmedix, Inc.; State Of Oregon, Acting By And Through The State Board Of Higher Education On Behalf Of Portland State University
Priority date: 2009-09-15
Filing date: 2010-09-15
Publication date: 2011-03-24

Abstract

Embodiments of the invention relate to modified fluoroquinolone (MFQ) compounds and methods of using the same in treatment of an infection in a subject.

Description

MODIFIED FLUOROQUINOLONE COMPOUNDS AND METHODS OF USING

THE SAME

FIELD OF THE INVENTION

[ 0001] The invention disclosed herein generally relates to compositions comprising modified fluoroquinolone compounds and methods of using the same for treatment of bacterial infections.

BACKGROUND

[0002 ] Drug resistance is a growing problem in the effort to contain bacterial infections. Many antibiotics have been extensively, and in some cases, inappropriately used. This has resulted in the development of resistance to commonly-used drugs in many pathogens, requiring the use of second- and third-line drugs to control infections diseases. The level of resistance ranges from low to almost 100%. The World Health Organization (WHO) currently regards the problem of drug resistance as a major threat to world health and has proposed strategies to encourage appropriate and cost-effective use of drugs to treat bacterial infections.

[0003] The updated National Institute of Allergy and Infectious Diseases (NIAID) Strategic Plan for Biodefense Research emphasizes development of broad spectrum therapeutics. With the limited resources available, it is highly desirable to have drugs that are effective against a variety of bacteria. It is also desirable to have platform technologies and approaches to be able to adapt rapidly to changing situations and evolving bacterial strains. Thus, there is a need for innovative technology to design and develop new drugs that are (1) suitable for broad spectrum antibacterial use, (2) effective on multiple species or strains of bacteria, (3) effective on drug- resistant organisms, (4) safe and (5) cost-effective and straightforward to manufacture. Effective control and treatment of such infections would have a significant impact on the burden of bacteria-caused disease, particularly diseases caused by drug-resistant strains, in the world.

SUMMARY OF THE INVENTION

[0004] Embodiments of the invention relate to modified fluoroquinolone (MFQ) compounds and methods of using the same. The MFQ compound includes a fluoroquinolone base structure of the formula (I):

in which

X₁ is nitrogen or carbon;

X₂ is hydrogen, a halogen, or an alkoxy group having 1-6 carbons in the alkyl part;

X₃ is a straight-chain or branched alkyl group with 1 to 6 carbons optionally having a substituted halogen on the terminal carbon, a phenyl, a substituted phenyl, or a cycloalkane having 1 to 6 carbons; or

X₂ and X₃ together form a 6-membered ring that can include one or more heteroatoms (such as N, O or S) at any position that valence requirements permit;

Ring 1 is a three-, four-, five-, six-, or seven-membered aliphatic ring, heterocyclic ring with one or more heteroatoms, aryl ring or heteroaryl ring, or a polycyclic ring comprising the same;

(X₄)_n is a hydrogen, an alkyl group having 1-6 carbon atoms, a halo, a haloalkyl, an amino, a hydroxyl, an alkoxy, an alkylamino, or an arylamino; n is 0 to 4 (such as 0 to 2, 1 or 2, or 1); n is 0 to 2 (all ring valences are filled by H where m and/or n is 0); and

X₅ is carbon or nitrogen,

or salts or solvates or stereoisomers or prodrugs thereof.

[0005] In some embodiments, Ring 1 has the formula of (II):

wherein G is

and wherein

X₆ is a straight chain or branched alkyl or heteroalkyl group having from 1 to 12 atoms, and

R₁ and R₂ are independently selected from a hydrogen, a straight-chain or branched alkyl having from 1 to 12 carbon atoms, a straight-chain or branched heteroalkyl group having from 1 to 12 atoms and comprising at least one heteroatom, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl, or

R₁ and R2 together with N form a monocyclic ring or a polycyclic ring system.

[0006] In some embodiments, ¾ is selected from the group of: an alkyl, an alkoxy, an alkylamino, -N-, or— O-.

[ 0007 ] In some embodiments, R₁ and R₂ independently have the structural formula of (IV):

wherein

X₇ is selected from halo, haloalkyl, amino, hydroxyl, hydroxyalkyl, alkylamino, cyano, alkoxy, sulfonamide, mercapto, keto, and carboxyl;

s is an integer from zero to 5; and

Y₂ is selected from C, S, or N.

[ 0008] In some embodiments, (X₇)_s is selected from fluoro, chloro, trifluoromethyl, methoxy, amine, carboxyl, sulfonamide, and hydroxylalkyl. In some embodiments, Y₂ is nitrogen.

[0009] In some embodiments, R₁ and R₂ are the same. In some embodiments, R₁ and R₂ are different.

[0010] In some embodiments, R₁ and R₂ together with N form a monocyclic ring.

[0011] In some embodiments, R₁ and R₂ together with N form the central ring of a polycyclic ring system. [ 0012] In some embodiments, wherein R₁ and R2 together with N form a ring structure, the central ring formed by R₁, R₂, and N is a 5-, 6-, or 7-membered ring.

[0013 ] In some embodiments, wherein R₁ and R₂ together with N form the central ring of a polycyclic ring system, the polycyclic ring system comprised of R₁, R₂ and N has the structure (V):

wherein

(X₉)_q and (Xg)_t are independently selected from H, alkyl, halo, haloalkyl, alkoxy, amino, hydroxyl, alkylamino, cyano, and mercapto;

q is an integer from zero to 4;

t is an integer from zero to 4; and

each of the peripheral rings can independently include at least one heteroatom at any position that valence requirements permit.

[00 4] In some embodiments, wherein R₁ and R₂ together with N form the central ring of a polycyclic ring system, the polycyclic ring system comprised of R₁, R₂ and N has the structure (VI):

wherein Y₂ is selected from NR₄, O, and S, and wherein R4 is selected from H, lower alkyl and acyl;

(X9>q and (Xe)t are independently selected from H, alkyl, halo, haloalkyl, alkoxy, amino, hydroxyl, alkylamino, cyano, and mercapto;

q is an integer from zero to 4;

t is an integer from zero to 4; and

[0015] In some embodiments, wherein R₁ and R₂ together with N form the central ring of a polycyclic ring system, the polycyclic ring system comprised of R₁, R₂ and N has the structure (VII):

wherein

Y2 is selected from NR4, O, and S, and wherein R4 is selected from H, lower alkyl and acyl;

R3 is selected from H, alkyl, heteroalkyl, =0, amino, amine, amide, sulfonamide, halo, cyano, hydroxy, mercapto, haloalkyl, alkoxy, alkylthio, thioalkoxy, arylalkyl, heteroaryl, alkylamino, dialkylamino, and alkylsulfano;

(Xs))q and (Xa)t are independently selected from H, alkyl, halo, haloalkyl, alkoxy, amino, hydroxyl, alkylamino, cyano, and mercapto;

q is an integer from zero to 4;

t is an integer from zero to 4; and

each of the peripheral rings can independently include at least one heteroatom at any position that valence requirements permit. [0016] In some embodiments, the piperazine group of the fluoroquinolone base structure of the formula (I) can be modified as represented by the formula (VI):

in which

R₁ and R₂ independently are a hydrogen, a straight-chain or branched alkyl having from 1 to 12 carbon atoms, a straight-chain or branched heteroalkyl group having from 1 to 12 atoms and containing one or more heteroatoms such as oxygen, nitrogen or sulfur, a cycloalkyl, a heterocyclyl, an aryl (such as a substituted or unsubstituted phenyl or benzyl), and a heteroaryl (such as a pyridyl, a pyridylalkyl, a pyrazinyl, a furyl, or an indolyl), or

R₁ and R₂ together with N form a monocyclic ring or a poly cyclic ring system, such as a bicyclic or tricyclic ring system; and

wherein u is from 0 to 2.

[0017] In some embodiments, the compound is one selected from the group of: 1- cyclopropy l-7-(4-(2-(diethy lamino)-2-oxoethy l)piperazin- 1 -yl)-6-fluoro-4-oxo- 1 ,4- dihydroquinoline-3-carboxylic acid; 1 -cyclopropyl-7-(4-(2-(cyclopropylamino)-2- oxoemyl)piperazm-1-yl)-6-fluoro-4-oxo-1,4-dmydroquinoline-3-carbox lic acid; 1-cyclopropyl- 6-fluoro-4-oxo-7-(4-(2-oxo-2-(4-(trifluoromethy l)phenyIamino)ethyl)piperazin- 1 -yl)- 1 ,4- dihydroquinoline-3-carboxylic acid; 9-fluoro-3-methyl-7-oxo-10-(4-(2-oxo-2-

(phenylamino)emyl)piperazm-1-yl)-3,7-dmydro-2H-[1,4]oxazmo[2_>3_>4-ij]qumolme-6

carboxylic acid, 1 -cyclopropyl-7-(4-(2-(adamantalamino)-2-oxoemyl)piperazin-1-yl)-6-fluoro- 4-oxo- 1 ,4-dihydroquinoIine-3-carboxy lie acid; 7-(4-(2-(cyclohexylamino)-2-oxoethyl)piperazin- 1-yl)- l-cyclopropyI-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid; l-cyclopropyl-6- fluoro-7-(4-(2-(mesitylammo 2-oxoemyl)piperazm-1-yl)-4-oxo-1,4-dmydroqumolme- carboxylic acid; l-cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(3-

(trifluoromemyl)phenylammo)emyl)pi^ acid; 1- cyclopropyl-6-fluoro-7-(4-(2-(methyl(phenethyl)amino)-2-oxoethyl)piperazin- 1 -yl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxylic acid; 1 -cyclopropyl-6-fluoro-7-(4-(2-(methyl(phenyl)amino)-2- oxoethyl)piperazin- l-yl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid; l-cyclopropyl-6-fluoro- 4-oxo-7-(4-(2-oxo-2-(phenylammo)e yl)piperazm-^^

acid; 1 -cyclopropyl-7-(4-(2-(diphenylamino)-2-oxoethyl)piperazin- l-yl)-6-fluoro-4-oxo- 1 ,4- dihydroquinoline-3-carboxylic acid; 1 -cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(9-oxoacridin- 10(9H)-yl)ethyl)piperazin-l -yl)-l ,4-dihydroquinol ne-3-carboxylic acid; l-cyclopropyl-6- fluoro-4-oxo-7-(4-(2-oxo-2-(perfluorophenylam^

3- carboxylic acid; l-cyclopropyl-7-(4-(2-(10,l l-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2- oxoethyl)piperazin- l-yI)-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid; 1 -cyclopropyl-

6- fluoro-4-oxo-7-(4-(2-oxo-2-(pyridin-4-ylaniino)ethyl)piperazin-1-yl)-1,4-d^

carboxylic acid; l-cyclopropyl-6-fluorc-4-oxo-7-(4-(2-oxo-2-(2,4,4-trimethylpentan-2- y lamino)ethy l)piperazin- 1 -y 1)- 1 ,4-dihy droquinoline-3 -carboxylic acid; 1 -cyclopropyl-6-fluoro-

4- oxc-7-(4-(2-oxo-2-(phenyl(pyridin-4-yl)amino)ethyl)piperazin- 1 -yl)- 1 ,4-dihydroquinoline-3- carboxylic acid; 1 -cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(tritylaniino)ethyl)pipei^in- 1 -yl)- 1 ,4-dihydroquinoline-3-carboxylic acid; 1 -cyclopropyl-7-(4-(2-(dicyclohexylamino)-2- oxoethyl)piperazin- 1 -yl)-6-fluoro-4-oxo- 1 ,4-dihy droquinoline-3 -carboxylic acid; 1 -cyclopropyl-

7- (4-<2-(dipyridin-2-ylamino)-2-oxoethyl)piperazin- l-yl)-6-fluoro-4-oxo- 1 ,4-dihydroquinoline- 3-carboxylic acid; 1 -cyclopropyl-6-fluoro-7-(4-(2-(octylamino)-2-oxoethyl)piperazin- 1 -yl)-4- oxo-1,4-dihydroquinoline-3-carboxylic acid; and l-cyclopropyl-7-(4-(2-(dodecylamino)-2- oxoethyl piperazin- 1 -yl)-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylic acid ("DM1086 DP116"); or salts or solvates or stereoisomers or prodrugs thereof.

[0018] In some embodiments, the salt of the compound is a pharmaceutically acceptable salt.

[0019] Embodiments of the invention also relate to a pharmaceutical composition containing a therapeutically effective emount of an MFQ compound as disclosed herein, or a prodrug or salt thereof. In some embodiments, the pharmaceutical composition includes an inert pharmaceutical carrier in admixture with the compound. In some embodiments, the pharmaceutical composition includes a sterile or physiologically isotonic aqueous solution. In some embodiments, the MFQ compound, or prodrug or salt thereof, is present in the pharmaceutical composition in an amount of from about 0.5% to about 90% (w/w).

[0020 In embodiments of the invention, a kit comprising an MFQ compound as disclosed herein, or a prodrug or salt thereof, is provided.

[0021] In embodiments of the invention, a medicament in dosage unit form is provided, wherein the medicament contains a therapeutically effective amount of an MFQ compound as disclosed herein, or a prodrug or salt thereof. In some embodiments, the dosage unit form is one selected from the group of: a tablet, a pill, a capsule, an ampule and a suppository.

[0022 ] Embodiments of the invention can relate to a method of treating an infection in a subject, wherein the method includes: administering a therapeutically effective amount of an MFQ compound as disclosed herein, or a prodrug or salt thereof, to said subject, wherein the administration of a therapeutically effective amount of compound results in a diminishment of infection.

[0023] Embodiments of the invention are also directed to the use of a therapeutically effective amount of an MFQ compound as disclosed herein, or a prodrug or salt thereof, in the manufacture of a medicament for treatment of a bacterial infection.

[0024] In addition, embodiments of the invention are directed to a method of preventing or reducing the likelihood of developing an infection in a subject, wherein the method includes: administration of a therapeutically-effective amount of an MFQ compound, or a prodrug or salt thereof, to said subject, wherein the administration of a therapeutically effective amount of compound results in a reduced likelihood of infection relative to that of a subject who has not received an administration of compound.

[0025] Embodiments of the invention are also directed to the use of a therapeutically effective emount of an MFQ compound as disclosed herein, or a prodrug or salt thereof, in the manufacture of a medicament for treatment of an infection.

[0026] In some embodiments, the infection is caused by Acinetobacter spp.

[0027 ] In some embodiments, the infection is caused by Actinomycetes spp.

[0028] In some embodiments, the infection is caused by Arthrobacter spp.

[0029] In some embodiments, the infection is caused by Bacillus spp.

[0030 ] In some embodiments, the infection is caused by Bacteroides spp.

[0031] In some embodiments, the infection is caused by Bordetella spp.

[0032 ] In some embodiments, the infection is caused by Borrelia spp.

[0033] In some embodiments, the infection is caused by Branhamella spp.

[0034] In some embodiments, the infection is caused by Brucella spp.

[ 0035 ] In some embodiments, the infection is caused by Burkholderia spp.

[0036] In some embodiments, the infection is caused by Buttlauxella spp.

[0037] In some embodiments, the infection is caused by Cedecea spp.

[0038 ] In some embodiments, the infection is caused by Cepacia spp.

[0039 ] In some embodiments, the infection is caused by Chlamydia spp.

[ 0040 ] In some embodiments, the infection is caused by Citrobacter spp. [00 1] In some embodiments, the infection is caused by Clostridium spp.

[ 0042 ] In some embodiments, the infection is caused by Coxiella spp.

[0043 ] In some embodiments, the infection is caused by Edwardsiell spp.

[0044] In some embodiments, the infection is caused by Enterobacter spp.

[ 0045 ] In some embodiments, the infection is caused by Enterobacteriaceae spp.

[ 0046] In some embodiments, the infection is caused by Enterococcus spp.

[0047 ] In some embodiments, the infection is caused by Erwinia spp.

[0048] In some embodiments, the infection is caused by Escherichia spp.

[ 0049] In some embodiments, the infection is caused by Erysipelothrix spp.

[0050] In some embodiments, the infection is caused by Ewingella spp.

[0051] In some embodiments, the infection is caused by Francisella spp.

[0052 ] In some embodiments, the infection is caused by Fusospirocheta spp.

[ 0053 ] In some embodiments, the infection is caused by Gardenerella spp.

[0054] In some embodiments, the infection is caused by Haemophilus spp.

[0055] In some embodiments, the infection is caused by Hafnia spp.

[ 0056] In some embodiments, the infection is caused by Klebsiella spp.

[0057] In some embodiments, the infection is caused by Kluyvera spp.

[0058] In some embodiments, the infection is caused by Legionella spp.

[ 0059 ] In some embodiments, the infection is caused by Listeria spp.

[0060 ] In some embodiments, the infection is caused by Micrococcus spp.

[0061] In some embodiments, the infection is caused by Morganella spp.

[ 0062 ] In some embodiments, the infection is caused by Mycobacteria spp.

[ 0063 ] In some embodiments, the infection is caused by Mycoplasma spp.

[0064] In some embodiments, the infection is caused by Neisseria spp.

[0065] In some embodiments, the infection is caused by Pasteurella spp.

[0066] In some embodiments, the infection is caused by Peptostreptococcus spp .

[0067] In some embodiments, the infection is caused by Proteus spp.

[ 0068 ] In some embodiments, the infection is caused by Providencia spp.

[006 ] In some embodiments, the infection is caused by Pseudomonas spp.

[ 0070] In some embodiments, the infection is caused by Rahnella spp.

[0071] In some embodiments, the infection is caused by Rickettsia spp.

[0072] In some embodiments, the infection is caused by Salmonella spp.

[ 0073] h some embodiments, the infection is caused by Serratia spp.

[007 In some embodiments, the infection is caused by Shigella spp.

[ 0075] In some embodiments, the infection is caused by Spirillum spp. [0076] In some embodiments, the infection is caused by Spirochaeta spp.

[0077 ] In some embodiments, the infection is caused by Staphylococcus spp.

[ 0078 ] In some embodiments, the infection is caused by Streptobacillus spp.

[0079] In some embodiments, the infection is caused by Streptococcus spp.

[0080] In some embodiments, the infection is caused by Streptomyces spp.

[0081] In some embodiments, the infection is caused by Tatumella spp.

[0082] In some embodiments, the infection is caused by Treponema spp.

[0083 ] In some embodiments, the infection is caused by Trichomonas spp.

[0084] In some embodiments, the infection is caused by Ureaplasma spp.

[0085] In some embodiments, the infection is caused by Vaginalis spp.

[0086] In some embodiments, the infection is caused by Vibrio spp.

[0087] In some embodiments, the infection is caused by Xanthomonas spp.

[ 0088] In some embodiments, the infection is caused by Yersinia spp.

[0089] In some embodiments, the infection is caused by Acinetobacter baumannii

[0090] In some embodiments, the infection is caused by Bacillus anthracis.

[00 1] In some embodiments, the infection is caused by Bacillus cereus.

[ 0092 ] In some embodiments, the infection is caused by Bacillus subtilis.

[0093 ] In some embodiments, the infection is caused by Bacteroides fragilis.

[009 ] In some embodiments, the infection is caused by Branhamella catarrhalis.

[0095] In some embodiments, the infection is caused by Brucella melitensis.

[00 6] In some embodiments, the infection is caused by B rkholderia mallei.

[0097 ] In some embodiments, the infection is caused by Burkholderia pseudomallei.

[0098 ] In some embodiments, the infection is caused by Chlamydia psittaci.

[0099] In some embodiments, the infection is caused by Citrobacter diversu .

[ 0100 ] In some embodiments, the infection is caused by Citrobacter freundii.

[0101] In some embodiments, the infection is caused by Clostridium Botulinum.

[ 0102 ] In some embodiments, the infection is caused by Clostridium difficile.

[ 0103 ] In some embodiments, the infection is caused by Clostridium perfringens.

[ 0104 ] In some embodiments, the infection is caused by Clostridium tetani.

[0105] In some embodiments, the infection is caused by Coxiella burnetii.

[ 010 ] In some embodiments, the infection is caused by Enterobacter aerogenes.

[0107 ] In some embodiments, the infection is caused by Enterobacter cloacae.

[0108 ] In some embodiments, the infection is caused by Enterococcus faecalis.

[ 0109 ] In some embodiments, the infection is caused by Enterococcus faecium.

[0110] In some embodiments , the infection is caused by Escherichia coli. [0111] In some embodiments, the infection is caused by Francisella tularensis.

[0112] In some embodiments, the infection is caused by Haemophilus influenzae.

[0113 ] In some embodiments, the infection is caused by Klebsiella oxytoca.

[0114] In some embodiments, the infection is caused by Klebsiella pneumoniae.

[0115] In some embodiments, the infection is caused by Listeria monocytogenes.

[0116] In some embodiments, the infection is caused by Morganella morganii.

[0117] In some embodiments, the infection is caused by Mycobacterium tuberculosis.

[0118] In some embodiments, the infection s caused by Neisseria gonorrhea.

[0119] In some embodiments, the infection s caused by Neisseria meningitidis.

[0120] In some embodiments, the infection s caused by Proteus mirabilis.

[0121] In some embodiments, the infection ,s caused by Proteus vulgaris.

[ 0122] In some embodiments, the infection s caused by Providencia rettgeri.

[0123] In some embodiments, the infection s caused by Providencia stuartii.

[0124] In some embodiments, the infection s caused by Pseudomonas aeruginosa.

[ 0125] In some embodiments, the infection s caused by Rickettsia prowazekii.

[0126] In some embodiments, the infection s caused by Salmonella bongori.

[0127 ] In some embodiments, the infection s caused by Salmonella choleraesuis.

[0128 ] In some embodiments, the infection s caused by Salmonella enterica.

[0129] In some embodiments, the infection s caused by Serratia marcescens.

[0130] In some embodiments, the infection s caused by Shigella boydii.

[0131] In some embodiments, the infection s caused by Shigella dysenteriae.

[0132 ] In some embodiments, the infection s caused by Shigella flexneri.

[0133 ] In some embodiments, the infection s caused by Shigella sonnet.

[0134] In some embodiments, the infection s caused by Staphylococcus aureus.

[0135] In some embodiments, the infection s caused by Staphylococcus epidermis.

[0136] In some embodiments, the infection is caused by Staphylococcus haemolyticus.

[0137 ] In some embodiments, the infection is caused by Staphylococcus hominis.

[0138] In some embodiments, the infection is caused by Staphylococcus saprophyticus.

[0139] In some embodiments, the infection is caused by coagulese-negative staphylococci.

[0140] In some embodiments, the infection is caused by Stenotrophomonas maltophilia. [01 1] In some embodiments, the infection is caused by Streptococcus agalactia .

[0142] In some embodiments, the infection is caused by Streptococcus mutans.

[0143] In some embodiments, the infection is caused by Streptococcus pneumoniae.

[0144] In some embodiments, the infection is caused by Streptococcus pyogenes.

[0145] In some embodiments, the infection is caused by Vibrio cholerae.

[0146] In some embodiments, the infection is caused by V. vulnificus.

[0147] In some embodiments, the infection is caused by Xanthomonas maltophilia.

[0148] In some embodiments, the infection is caused by Yersinia pestis.

BRIEF DESCRIPTION OF THE DRAWINGS

[0149] Those of skill in the art will understand that the drawings, described below, are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

[0150] Figure 1 includes chemical structures that illustrate embodiments of the modified fluoroquinone compounds (MFQs) as disclosed herein.

[0151] Figures 2-11 include chemical structures that illustrate embodiments of modifications to the fluoroquinolone base structure as disclosed herein.

[0152] Figure 12 is a bar graph illustrating the inhibitory concentration that inhibits the growth of 50% of organisms (IC₅0) for various MFQ compounds on Gram-positive bacteria.

[0153] Figure 13 is a three-dimensional bar graph illustrating the inhibitory concentration that inhibits the growth of 50% of organisms (ICso) for various MFQ compounds on several different strains of methicillin-resistant Staphylococcus aureus (MRSA).

[0154] Figure 14 is a three-dimensional bar graph illustrating the inhibitory concentration that inhibits the growth of 50% of organisms (IC50) for various MFQ compounds on several different strains of Escherichia coli.

[0155] Figure 15 is a three-dimensional bar graph illustrating the inhibitory concentration that inhibits the growth of 50% of organisms (IC50) for various MFQ compounds on Gram-negative bacteria.

[0156] Figure 16 is a bar graph illustrating the measured cytotoxicity for various MFQ compounds on HepG2 cells.

DETAILED DESCRIPTION OF THE INVENTION

[0157] Embodiments of the invention are directed to modified fluoroquinolone (MFQ) compounds that are effective at inhibiting bacterial growth and are useful in the treatment and prevention of bacterial infections. Also disclosed herein are methods of preparing the MFQ compounds in a pharmaceutical composition and methods of using the same to treat an infection caused by one or more bacteria species.

Definitions

[0158] Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art. For example, definitions of common terms in chemistry terms may be found in The McGraw-Hill Dictionary of Chemical Terms, 1985, and The Condensed Chemical Dictionary, 1981.

[0159] As used herein, the term "treating" or "treatment," with respect to disease, encompasses relieving the disease, e.g., causing regression of the disease or its clinical symptoms.

[0160] As used herein, the term "preventing" or "prevention," with respect to a disease or particular condition, encompasses reducing the likelihood of acquiring or developing the disease or particular condition, including in cases where prevention is sought but is ultimately unsuccessful.

[016 ] As used herein, the term "subject" includes all animals, including humans and other animals, including, but not limited to, companion animals, farm animals and zoo animals. The term "animal" can include any living multi-cellular vertebrate organisms, a category that includes, for example, a mammal, a bird, a simian, a dog, a cat, a horse, a cow, a rodent, and the like. Likewise, the term "mammal" includes both human and non-human mammals.

[0162] As used herein, the term "optional" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, '¾eterocyclo group optionally mono- or di-substituted with an alkyl group" means that the alkyl may but need not be present, and the description includes situations where the heterocyclo group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.

[0163] It is further to be understood that any molecular weight or molecular mass values are approximate and are provided only for description.

[0164] Except as otherwise noted, the methods and techniques of the present invention are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New YorkrOxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley- Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New YorkrLongman, 1978.

Fluoroquinolone base structure

[0165] Fluoroquinolones were first developed in the early 1960s. The first fluoroquinolone, nalidixic acid, was approved by the FDA in 1963 for the treatment of urinary tract infections and is considered the parent of the fluoroquinolone class of compounds. The development of other fluoroquinolones by chemically altering the base structure of nalidixic acid has led to the synthesis of a wide variety of fluoroquinolones that populate this class of structures.

[0166] The fluoroquinolone base structure that is modified as herein disclosed can be any fluoroquinolone known to those skilled in the art. Exemplary fluoroquinolones useful in the compositions and methods of embodiments of the invention include, but are not limited to, those described in BE 870,576, U.S. Patent No. 4,448,962, DE 3,142,854, EP 047,005, EP 206,283, BE 887,574, EP 221,463, EP 140,116, EP 131,839, EP 154,780, EP 078,362, EP 310,849, EP 520,240, U.S. Patent No. 4,499,091, U.S. Patent No. 4,704,459, U.S. Patent No. 4,795,751, U.S. Patent No. 4,668,784, and U.S. Patent No. 5,532,239, each of the foregoing which is incorporated herein by reference in its entirety.

[0167] Exemplary fluoroquinolone compounds that can be modified include, but are not limited to, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, sparfioxacin, trovafloxacin, tosufloxacin, temafloxacin, and sarafloxacin.

[0168] Generally, a fluoroquinolone compound having the structure (I) can be modified as disclosed herein:

in which Xi is nitrogen or carbon;

X2 is hydrogen, a halogen, or an alkoxy group having 1-6 carbons in the alkyl part;

X3 is a straight-chain or branched alkyl group with 1 to 6 carbons optionally having a substituted halogen on the tenninal carbon, a phenyl, a substituted phenyl, or a cycloalkane having 1 to 6 carbons; or

X₂ and X3 together form a 6-membered ring that can include one or more heteroatoms (such as N, O or S) at any position that valence requirements permit;

(X _n is a hydrogen, an alkyl group having 1-6 carbon atoms, a halo, a haloalkyl, an amino, a hydroxyl, an alkoxy, an alkylamino, or an arylamino; n is 0 to 4 (such as 0 to 2, 1 or 2, or 1); n is 0 to 2 (all ring valences are filled by H where m and/or n is 0); and

X5 is carbon or nitrogen.

Modifications to fluoroquinolone base structure

[0169] In embodiments of the invention, the fluoroquinolone base structure can be modified at any position in Ring 1 of structure (Γ). For example, in some embodiments, a modified fluoroquinolone (MFQ) compound can have a chemical structure in which the nitrogen at position 4 of the piperazine group is modified as follows:

[0170] With reference to the general structure above, G represents a fluoroquinolone-resistance reversal agent moiety. Suitable G groups include derivatives of reversal agents having one or more cyclic groups. In some embodiments, G has the structure as follows:

in which

Χδ is a straight chain or branched alkyl or heteroalkyl group having from 1 to 12 atoms, and

R₁ and R₂ together with N form a monocyclic ring or a polycyclic ring system, such as a bicyclic or tricyclic ring system.

[0171] In some embodiments, ¾ is alkyl (such as methyl, ethyl, propyl, i-propyl, or butyl), alkoxy (such as methoxy or ethoxy), alkylamino (such as methylamino or ethylamino), -N-, or -0-.

[0172 ] Exemplary R₁ and R₂ groups include aryl groups and substituted alkyl groups, such as cyclohexyl, methylcyclohexyl (-CFfcCeHu), adamantyl, methyl adamantyl and ethyl adamantyl. In some embodiments, at least one of R₁ and R₂ is a sterically bulky group. Suitable sterically bulky groups for incorporation as R₁ and/or R₂ will be readily apparent to those of ordinary skill in the art upon consideration of the present disclosure.

[0173] In some embodiments, R₁ and R₂ independently have a chemical structure as follows:

wherein X7 is independently halo, haloalkyl (such as trifluoromethyl), amino, hydroxyl, hydroxyalkyl, alkylamino, cyano, alkoxy, sulfonamide, mercapto, keto, or carboxyl; s is 0 to 5 as valence requirements permit (for example, when Y₂ is nitrogen, s is from 0 to 4); Y2 is C, S, or N.

[0174] In some embodiments, (X₇)_s is independently fluoro, chloro, trifluoromethyl, methoxy, amine (e.g., -NH2), carboxyl {e.g., -COOH), sulfonamide (e.g., -SO2NH₂), hydroxylalkyl (e.g., -(CH2)„-OH, where n is 1, 2, 3, or 4), and/or s is 0 to 3, 0 to 2, or 1. For example, X₇ can be independently fluoro, chloro, trifluoromethyl, or methoxy. In some embodiments, X₇ can be independently selected from these groups for each occurrence "s."

[ 0175] In some embodiments, Y2 is nitrogen.

[0176] In some embodiments, R₁ and R₂ are the same (referred to as, symmetric). In some embodiments, R₁ and R₂ are different, such compounds are referred to herein as being asymmetric.

[0177] In some embodiments, R₁ and R₂ together with N form a monocyclic ring. For example, R₁ and R₂ together with N can form a monocyclic ring that is a 5-, 6- or 7-membered ring. In some embodiments, R₁ and R₂ together with N can form a monocyclic ring with greater than 7 members.

[0178] In some embodiments, R₁ and R₂ together with N form the central ring of a polycyclic ring system, such as a bicyclic or tricyclic ring system. In some embodiments, the central ring formed by R|, R₂, and N is a 5-, 6-, or 7-membered ring. Exemplary structures for a tricyclic ring system formed by R₁, R₂, and N include, without limitation:

where Y₂ is C, NR , O, or S; R3 is H, alkyl, heteroalkyl, =0, amino, amine, amide, sulfonamide, halo (such as F, CI), cyano, hydroxy, mercapto, haloalkyl (such as trifluoromethyl), alkoxy (such as methoxy), alkylthio, thioalkoxy, arylalkyl, heteroaryl, alkylamino, dialkylamino, or alkylsulfano; (X^_q and (Xg)t are independently H, alkyl, halo (such as F, CI), haloalkyl (such as trifluoromethyl), alkoxy (such methoxy), amino, hydroxyl, alkylamino, cyano, or mercapto; R is H, lower alkyl or acyl; q and t are independently 0 to 4 as valence requirements permit (such as 0 to 2, 1 or 2, or 1); and each of the peripheral rings can independently include at least one heteroatom (such as N) at any position that valence requirements permit. In some examples, (Χ<>)₄ and (Xs)_t are independently H, methyl, fluoro, chloro, trifluoromethyl, methoxy, or cyano. In other examples, Y2 is N or S. In particular examples, R3 is H or =0 (and the ring carbon, which is double bonded to oxygen is otherwise single bonded to adjacent atoms).

[0179] Exemplary modifications to the fluoroquinolone base at the nitrogen at position 4 of the piperazine group include, but are not limited to, the specific structures illustrated in Figure 2.

[ 0180 ] In some embodiments, the piperazine group of the fluoroquinolone base can be modified as represented by the formula:

wherein u is from 0 to 2. Exemplary compounds having this structure are as recited in Figures 1-11:

Additional fluoroquinolone modifications

[0181] Fluoroquinolone resistance reversal agents suitable for incorporation as, for example "G" in the general structures presented above, can be based upon knowledge of chloroquine resistance reversal agents found in the art (for example, Bhattacharjee et al. 2002. J. Chem. Inf. Comput. Sci. 42:1212-1220; Guan et al. 2002. J. Med. Chem. 45(13):2741-2748, each of the foregoing which is incorporated herein by reference in its entirety). Without being bound to one theory, reversal agents are believed to exert their biological effect, at least in part, by decreasing the efflux of fluoroquinolone (or fluoroquinolone-like drugs) from the pathogen, which efflux is thought to be mediated by a membrane pump. Exemplary reversal agents include, without limitation, amitriptyline, amlodipine, azatadine, chlc^heniramine, citalopram, cyclosporine, cyproheptadine, cyproheptadine, desipramine, dibenzosuberanylpiperazine derivatives (Osa et al. 2003. /. Med. Chem. 46(10): 1948- 1956), diethyl-! 3-[3-(4-methoxy- benzylidene)-pyrrolidm-1-yl]-propyl}-amme, erythromycin, fantofarone (Adovelande et al. 1998. J. Biochem. Pharmacol. 55(4):433-440), fluoxetine, haloperidol, icajine, imiprarnine, isoretuline, ivermectin, ketotefin, ketotifen, nomifensine, nonylphenolethoxylates (including, for example, NP30: C₉Hi₉-Phenyl-(0-CH₂CH₂)₃oOH; Crandall et al. 2000. Antimicrob. Agents Chemother. 44(9):2431-2434), oxaprotiline, probenecid, progesterone, promethazine, strychnobrasiline, BG958 (a 9,10-dihydroethanoanthracene derivative; Millet et al. 2004. Antimicrob. Agents Chemother. 48(12):4869-4872), trifluoperazine, verapamil, and WR 268954 (De et al. 1993. Am. J. Trop. Med. Hyg. 49(1):113-120).

[ 0182] A fluoroquinolone-resistance reversal agent moiety as described herein includes any known reversal agent or derivative thereof that retains fluoroquinolone resistance reversal function, or any chemical structure that satisfies a fluoroquinolone resistance reversal agent pharmacophore (such as one based on the Bhattacharjee et al. pharmacophore described above) and confers fluoroquinolone resistance reversal function. A fluoroquinolone resistance reversal function is the ability of a compound (or moiety) to sensitize at least one fluoroquinolone-resistant target species to a modified fluoroquinolone (MFQ) compound when the MFQ compound is modified with a reversal function. A fluoroquinolone-resistant target species is sensitized to an MFQ compound if a an MFQ compound inhibits target pathogen growth as compared to pathogen growth in the presence of fluoroquinolone compound alone. For example, pathogen growth in the presence of a an MFQ compound) can be at least about 10%, at least about 25%, at least about 40%, at least about 50%, at least about 75%, at least about 80%, at least about 90%, or at least about 95% less than pathogen growth in the presence of fluoroquinolone compound only.

[0183] A fluoroquinolone compound (such as, for example, ciprofloxacin) can be covalently linked to a fluoroquinolone-resistant reversal agent moiety via commonly known chemical syntheses.

Exemplary compounds

[0184] Exemplary MFQ compounds include, but are not limited to, l-cyclopropyl-7- (4-(2-(diethylamino)-2-oxoethyl)piperazin- 1 -yl)-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3- carboxylic acid ("DM1050 DP102"); l-cyclopropyl-7-(4-(2-(cyclopropylamino)-2- oxoethyl)piperazin- l-yl)-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid ("DM1051/DP103"); l-cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(4- (trifluoromethyl)phenylamino)ethyl)piperazin- 1 -y \y 1 ,4-dihydroquinoline-3 -carboxylic acid ("DM1052/DP104"); 9-fluoro-3-memyl-7-oxo-10-(4-(2-oxo-2-(phenylan^o)emyl)piperazin-1- yl)-3,7-dmydro-2H-[1,4]oxazmo[2,3,4-ij]qumoline-6-carboxylic acid ("DM1054/DP105"), l-cyclopropyl-7-(4-(2-(adamantalamino)-2-oxoethyl)piperazin- 1 -yl)-6-fluoro-4-oxo- 1 ,4- dihydroquinoline-3-carboxylic acid ("DM1063/DP106"); 7-(4-(2-(cyclohexylamino)-2- oxoethy l)piperazin- 1 -yl)- 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid ("DM1064/DP110"); l-cyclopropyl-6-fluoro-7-(4-(2-(mesitylamino)-2-oxoethyl)piperazin- 1- yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ("DM1065/DP107"); l-cyclopropyl-6-fluoro- 4-oxo-7-(4-(2-oxo-2-(3-(trifluoromethyl)phenylamino)ethyl)piperazin-1-yI)-1,4- dihydroquinoline-3-carboxylic acid ("DM1066 DP108"); l-cyclopropyl-6-fluoro-7-(4-(2- (methyl(phenethyl)amino)-2-oxoethyl)piperazin- 1 -yl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid ("DM1067 DP109"); l-cyclopropyl-6-fluoro-7-(4-(2-(methyl(phenyl)amino)-2- oxoethyl)piperazin-1-yl)^oxo-1,4-dihydroquinoline-3-carboxylic acid ("DM1068/DP111"); 1- cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(phenylamino)ethy l)piperazin- 1 -yl)- 1 ,4- dihydroquinoline-3-carboxylic acid ("DM1021 DP100"); l-cyclopropyl-7-(4-(2- (diphenylammo)-2-oxoemyl)piperazm-1-yl)-6-fluoro-4-^

acid C 'DM 1023/TDP101 ") ; 1 -cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(9-oxoacridin- 10(9H)- yl)ethyl)piperazin-1-yl)- 1,4-dihydroquinoline-3-carboxylic acid; l-cyclopropyl-6-fluoro-4-oxo- 7-(4-(2-oxo-2-(perfluorophenylamino)ethyl)piperazin-1-yl)-1,4-dihydroquinolm^

acid; 1 -cyclopropyl-7-(4-(2-( 10,11 -dihydro-5H-dibenzo[b,f] azepin-5-y l)-2-oxoethyl)piperazin- l-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxyIic acid ("DM1084 DP112"); 1- cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(pyridin-4-ylamino)ethyl)piperazin-1-yl)-1,4- dihydroquinoline-3-carboxylic acid ("DM1094/DM118"); l-cyclopropyl-6-fluoro-4-oxo-7-(4- (2-oxo-2-(2,4,4-trimethylpentan-2-ylamino)ethyl)piperazin- 1 -yl)- 1 ,4-dihydroquinoline-3- carboxylic acid; l-cyclopropyl-6-fluorc^4-oxo-7-(4-(2-oxo-2-^henyl(pyridin-4- yl)amino)ethyl)piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid; l-cyclopropyl-6-fluoro- 4-oxo-7-(4-(2-oxo-2-(tritylamino)ethy l)piperazin- 1 -yl)- 1 ,4-dihydroquinoline-3-carboxylic acid ("DM1088 DP117"); l-cyclopropyl-7 4-(2-(dicyclohexylamino)-2-oxoctliyl)piperazin-1-yl)-6- fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ("DM1091 DP114"); l-cyclopropyl-7-(4- (2-(dipyridin-2-ylamino)-2-oxoethyl)piperazin- 1 -yl)-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3- carboxylic acid; l-cyclopropyl-6-fluoro-7-(4-(2-(c<¾ylamino)-2-oxoethyl)piperazin-1-yl)-4-oxo- 1,4-dihydroquinoline-3-carboxylic acid ("DM1085 DP113"); and l-cyclopropyl-7-(4-(2- (dodecylam o)-2-oxoemyl)piperazin-1-yl)-6-fluoro-4-^

acid ("DM1086 DP116").

[0185] Exemplary compounds also include, but are not limited to, those disclosed herein, including those illustrated in Figures 1-11. Methods of MFQ compound synthesis

[0186] The disclosed MFQ compounds can be synthesized by any method known in the art. Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York:Longman, 1978).

[0187] Compounds as described herein may be purified by any of the means known in the art, including chromatographic means, such as HPLC, preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L.R. Snyder and J.J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, ed E. Stahl, Springer- Verlag, New York, 1969.

[0 88] Exemplary syntheses of MFQ compounds are provided as herein disclosed in the Examples.

Pharmaceutical formulations

[0189] Formulations for pharmaceutical compositions are well known in the art For example, Remington's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 15^th Edition, 1975, describes exemplary formulations (and components thereof) suitable for pharmaceutical delivery of disclosed RCQ compounds. Pharmaceutical compositions comprising at least one MFQ compound as disclosed herein can be formulated for use in human or veterinary medicine. Particular formulations of a disclosed pharmaceutical composition can depend, for example, on the mode of administration (e.g., oral or parenteral) and/or on the location of the infection to be treated (e.g., liver-stage and/or blood-stage for parasites). In some embodiments, formulations include a pharmaceutically acceptable carrier in addition to at least one active ingredient, such as a MFQ compound. In other embodiments, other medicinal or pharmaceutical agents, for example, with similar, related or complementary effects on the affliction being treated can also be included as active ingredients in a pharmaceutical composition.

[01 0] Pharmaceutically acceptable carriers useful for the disclosed methods and compositions are conventional in the art. The nature of a pharmaceutical carrier will depend on the particular mode of administration being employed. For example, parenteral formulations typically comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (e.g., powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, pharmaceutical compositions to be administered can optionally contain minor amounts of non-toxic auxiliary substances (e.g., excipients), such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like; for example, sodium acetate or sorbitan monolaurate. Other non-limiting excipients include, nonionic solubilizers, such as cremophor, or proteins, such as human serum albumin or plasma preparations.

[0191] The disclosed pharmaceutical compositions can be formulated as a pharmaceutically acceptable salt of a disclosed MFQ compound. Pharmaceutically acceptable salts are non-toxic salts of a free base form of a compound that possesses the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids. Non-limiting examples of suitable inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydriodic acid, and phosphoric acid. Non-limiting examples of suitable organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, methyl sulfonic acid, salicylic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, asparagic acid, aspartic acid, benzenesulfonic acid, p- toluenesulfonic acid, naphthalenesulfonic acid, and the like. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17^th Edition, Mack Publishing Company, Easton, PA, 1985. A pharmaceutically acceptable salt can also serve to adjust the osmotic pressure of the composition.

[0192 ] In addition, in some embodiments, the disclosed pharmaceutical compositions can be formulated as a pro-drug of a disclosed MFQ compound. Pro-drug forms of the MFQ compound include carboxylic acid ester forms, forms that incorporate amidic functions on a free nitrogen of the 7-piperazinyl group of the MFQ compound, and forms that incorporate sulfur moieties at the C-2 position of the fluoroquinolone base structure of an MFQ compound.

[0193] The dosage form of a disclosed pharmaceutical composition will be determined by the mode of administration chosen. For example, in addition to injectable fluids, topical or oral dosage forms can be employed. Topical preparations can include eye drops, ointments, sprays and the like. Oral formulations can be liquid (e.g., syrups, solutions or suspensions), or solid (e.g., powders, pills, tablets, or capsules). Methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art.

[0194] Certain embodiments of the pharmaceutical compositions comprising a disclosed MFQ compound can be formulated in unit dosage form suitable for individual administration of precise dosages. The amount of active ingredient (e.g., MFQ compound) administered will depend on the subject being treated, the severity of the affliction, and the manner of administration, and is known to those skilled in the art. Within these bounds, the formulation to be administered will contain a quantity of the extracts or compounds disclosed herein in an amount effective to achieve the desired effect in the subject being treated.

[0195] In some embodiments, at least one modified fluoroquinolone (MFQ) compound, or prodrug or salt thereof, is present in the pharmaceutical composition in an amount ranging from about 0.5 percent to about 90 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 1 percent to about 85 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 5 percent to about 80 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 10 percent to about 75 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 15 percent to about 50 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 25 percent to about 35 percent by weight of the pharmaceutical composition.

[0196] In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 2 percent to about 25 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 2 percent to about 20 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 2 percent to about 10 percent by weight of the pharmaceutical composition.

[ 0197] In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 5 percent to about 15 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount ranging from about 5 percent to about 10 percent by weight of the pharmaceutical composition.

[0198] In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount greater than about 20 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount greater than about 30 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount greater than about 35 percent by weight of the pharmaceutical composition. In some embodiments, the at least one MFQ compound is present in the pharmaceutical composition in an amount greater than about 40 percent by weight of the pharmaceutical composition.

[ 0199 ] In some embodiments, the pharmaceutical composition is a solution.

[0200] In some embodiments, the pharmaceutical composition is injectable.

[0201] In some embodiments, the pharmaceutical composition can be administered parenterally.

[0202] In some embodiments, the pharmaceutical composition can be administered subcutaneously.

[0203 ] In some embodiments, the pharmaceutical composition can be administered intravenously.

[0204] In some embodiments, the pharmaceutical composition can be administered orally.

[0205] The pharmaceutical composition can further comprise one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, sweeteners, flavoring agents, preservatives, and coloring agents. Such excipients are known in the art. Examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences at pages 1447-1676 (Alfonso R. Gennaro ed., 19* ed. 1995), which is incorporated herein by reference in its entirety.

[0206] Examples of preservatives include, but are not limited to, potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, and quaternary ammonium compounds such as benzalkonium chloride.

Methods of treatment

[ 0207] Embodiments of the invention relate to methods of treating or preventing a condition in a subject comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition as disclosed herein. In some embodiments, the method comprises administering a pharmaceutical composition comprising a disclosed MFQ compound, or prodrug or salt thereof (and, optionally, one or more other pharmaceutical agents) to a subject in a pharmaceutically acceptable carrier and in an amount effective to treat the condition. The treatment can also be used prophylactically in any subject

[0208 ] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.

[0209] In some embodiments, the subject is one selected from the group of: a companion animal, a farm animal and a zoo animal. In some embodiments, the animal is one selected from the group of: a bird, a simian, a dog, a cat, a horse, a cow, and a rodent.

[0210] In some embodiments, the condition to be treated or prevented is an infection. In some embodiments, the condition to be treated or prevented is a bacterial infection. In some embodiments, the condition is an infection caused by bacteria from a variety of genera, including, but not limited to, Acinetobacter spp., Actinomycetes spp., Arthrobacter spp., Bacillus spp., Bacteroides spp., Bordetella spp., Borrelia spp., Branhamell spp., Brucella spp., Burkkolderia spp.s, Buttlauxella spp., Cedecea spp., Chlamydia spp., Citrobacter spp., Clostridium spp., Coxiella spp., Edwardsiella spp., Enterobacter spp., Enterobacteriaceae spp., Enterococcus spp., Erwinia spp., Escherichia spp., Erysipelothrix spp., Ewingella spp., Francisella spp., Fusospirocheta spp., Haemophilus spp., Hafhia spp., Klebsiella spp., Kluyvera spp., Legionella spp., Listeria spp., Micrococcus spp., Morganella spp., Mycobacteria spp., Mycoplasma spp., Neisseria spp., Pasteur ella spp., Peptostreptococcus spp., Proteus spp., Providencia spp., Pseudomonas spp., Rahnella spp., Rickettsia spp., Salmonella spp., Serratia spp., Shigella spp., Spirillum spp., Spirochaeta spp., Staphylococcus spp., Streptobacillus spp., Streptococcus spp., Streptomyces spp., Tatumella spp., Treponema spp., Trichomonas spp., Ureaplasma spp., Vibrio spp., Xanthomonas spp., and Yersinia spp. Accordingly, embodiments of the invention feature a method of treating infections by a bacteria belonging to the genera above, among others. For example, the condition can be a bacterial infection caused by bacteria including, but not limited to, Acinetobacter baumannii, Bacillus anthracis, Bacteroides fragilis, Branhamella catarrhalis, Brucella melitensis, Burkholderia mallei, Burkholderia pseudomallei, Chlamydia psittaci, Citrobacter diversus, Citrobacter freundii, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Coxiella burnetii, Enterobacter aerogenes, Enterobacter cloacae, Enterococcus faecium, Escherichia coli, Francisella tularensis, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Listeria monocytogenes, Morganella morganii, Mycobacterium tuberculosis. Neisseria gonorrhea, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Rickettsia prowazekii, Salmonella bongori, Salmonella choleraesuis, Salmonella enterica, Serratia marcescens, Shigella boydii. Shigella dysenteriae. Shigella flexneri, Shigella sonnei, Staphylococcus aureus. Staphylococcus epidermis, Staphylococcus haemolyticus. Staphylococcus hominis, Staphylococcus saprophyticus, coagulese-negative staphylococci. Streptococcus pneumoniae, Streptococcus pyogenes, Vibrio choleraue, V. vulnificus, Xanthomonas maltophilia, and Yersinia pestis.

[0211] Embodiments of the invention are also directed to a method of treating or preventing a condition or infection caused by a Gram-positive bacteria. Gram- positive bacteria have a thick cell membrane consisting of multiple layers of peptidoglycan and an outside layer of teichoic acid. Exemplary gram-positive organisms include, but are not limited to, coagulase- negative staphylococci, streptococci, enterococci, corynebacteria, and Bacillus species. For example, exemplary gram-positive bacterial infections that can be treated according to embodiments of the invention include, but are not limited to, infections by Bacillus anthracis, Bacillus cereus. Bacillus subtilis, Clostridium perfringens, Clostridium tetani, Clostridium botulinum, Clostridium difficile Enterococcus faecalis, Enterococcus faecium, Mycobacterium tuberculosis, Staphylococcus aureus, Staphylococcus epidermidis. Streptococcus agalactiae. Streptococcus mutans, Streptococcus pneumoniae and Streptococcus pyogenes,.

[0212] In embodiments of the invention, a method of treating or preventing a condition or infection caused by a Gram-negative bacteria is provided. Exemplary gram- negative organisms include, but are not limited to, Acinetobacter spp., Burkholderia spp., Cepacia spp., Gardenerella spp., Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella enterica, Shigella sonnei, Stenotrophomonas maltophilia, Vaginalis spp, and Vibrio cholerae.

[ 0213 ] In addition, multi-drug resistant strains of bacteria can be treated according to embodiments of the invention. Resistant strains of bacteria include penicillin-resistant, methicillin-resistant, quinolone-resistant, macrolide-resistant, and or vancomycin-resistant bacterial strains. Multi-drug resistant bacterial infections to be treated using embodiments of the invention include infections by penicillin-, methicillin-, macrolide-, vancomycin-, and/or quinolone-resistant Streptococcus pneumoniae', penicillin-, methicillin-, macrolide-, vancomycin-, and/or quinolone-resistant Staphylococcus aureus; penicillin-, methicillin-, macrolide-, vancomycin-, and or quinolone-resistant Streptococcus pyogenes; and penicillin-, methicillin-, macrolide-, vancomycin-, and or quinolone-resistant Enterococcus spp.

[0214] In addition, embodiments of the invention are directed to treatment or prevention of infections caused by the following bacteria: SHIGELLA SPECIES

[ 0215] Shigella species are aerobic, non-motile, glucose-fermenting, gram-negative bacterial rods that are highly contagious, causing diarrhea after ingestion of less than 100 organisms. Exemplary pathogenic species include, but are not limited to, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Shigella boydii. S. sonnei is primarily responsible for the 450,000 cases of shigellosis that occur in the U.S. each year, while S. flexneri causes the majority of the 1.8 million cases that occur globally.

[ 0216 ] Fluoroquinolone resistance in Shigella spp. is linked to efflux-mediated resistance although individual resistance-components have not yet been identified (Zhang, L. et al. 2000. Antimicrobial Agents & Chemotherapy 44(2):287-283, which is incorporated herein by reference in its entirety). Preliminary results show that modified fluoroquinolone (MFQ) drug candidates as disclosed herein are effective at inhibiting growth of Shigella spp. at concentrations of less than 1 micromolar.

DlARRHEAGENIC E. COLI SPECIES

[ 0217 ] Diarrheagenic Escherichia coli (E. coli) causes watery or bloody diarrhea, including traveler's diarrhea and food borne disease. Exemplary Escherichia coli include many different serotypes, categorized into four major groups according to virulence mechanisms: enterotoxigenic (ETEC) (primary cause of traveler's disease); enteropathogenic (EPEC) and enteroinvasive (EIEC) (two common causes of children's disease in developing countries); and enteroaggregative (Eagg EC) (primary cause of disease in HTV patients).

[ 0218 ] In E. coli, high-level fluoroquinolone resistance is typically associated with the presence of multiple mutations in the quinolone resistance-determining regions (QRDRs) of the genes that code for the intracellular targets of these antibiotics, gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE). However, efflux mechanisms are considered to contribute to drug resistance (Heisig P. 1996. Antimicrob Agents Chemother 40:879-885, which is incorporated herein by reference in its entirety). Preliminary results illustrate that the MFQ drug candidates as disclosed herein are effective in inhibiting growth of E.coli at concentrations of less than 1 micromolar.

SALMONELLA SPECIES

[ 0219 ] Salmonella organisms live in the intestines of most food animals. Transmission of Salmonella spp. to humans can occur by many routes, including consumption of contaminated food of animal origin (e.g. meat, poultry, eggs and milk), although many other foods, including green vegetables contaminated from manure, have been implicated. In recent years, problems related to Salmonella have increased significantly, both in terms of incidence and severity of cases of human salmonellosis. Salmonellosis is a common zoonotic disease in humans.

[0220] In Salmonella spp., resistance to fluoroquinolones can arise from a combination of different resistance mechanisms, including, for example, mutational modifications of the target enzymes for fluoroquinolones, the DNA gyrase, and enhanced active efflux and gradually increased levels of production of the AcrAB pump, which has been found in mutants increasingly resistant to ciprofloxacin and other antibiotics (Giraud, Etienne, et al. 2000. Antimicrob Agents Chemother 44(5): 1223—1228, which is incorporated herein by reference in its entirety).

[0221] Routes of administration useful in the disclosed methods include but are not limited to oral and parenteral routes, such as intravenous (iv), intraperitoneal (ip), rectal, topical, ophthalmic, nasal, and transdermal. Formulations for these dosage forms are described above.

[0222] An effective amount of a MFQ compound will depend, at least, on the particular method of use, the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition. A "therapeutically effective amount" of a composition is a quantity of a specified compound sufficient to achieve a desired effect in a subject (host) being treated. For example, this can be the amount of a MFQ compound necessary to prevent, inhibit, reduce or relieve a condition caused by infection by a target pathogen.

[0223 ] Therapeutically effective doses (or growth inhibitory amounts) of a disclosed MFQ compound or pharmaceutical composition can be determined by one of skill in the art, with a goal of achieving local (e.g., tissue) concentrations that are at least as high as the IC₅₀ of the applicable compound disclosed in the examples herein. The effective amount administered to the subject depends on a variety of factors including, but not limited to the age, body weight, general health, sex and diet of the subject being treated, the condition being treated, the severity of the condition, the activity of the specific MFQ compound being administered, the metabolic stability and length of action of that compound, mode and time of administration, rate of excretion and the drug combination. The amount of the pharmaceutical composition that is effective in the treatment or prevention of a condition, such as a bacterial infection, can be determined by standard clinical techniques well known to those of skill in the art In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. One of ordinary skill in the art will readily be able determine the precise dose to be employed. Suitable effective dosage amounts, however, typically range from about 0.1 mg kg of body weight to about 50 mg/kg of body weight, from about 0.5 mg kg of body weight to about 25 mg kg of body weight, from about 0.75 mg/kg of body weight to about 20 mg kg of body weight, or from about 1 mg kg of body weight to about 15 mg kg of body weight. The effective dosage amounts described herein refer to total amount of MFQ compound administered. For example, if more than one MFQ compound is administered, the effective dosage amounts correspond to the total amount of MFQ compound administered.

[0224] In some embodiments, the pharmaceutical composition can be administered parenterally. In some embodiments, the pharmaceutical composition can be administered subcutaneously. In some embodiments, the pharmaceutical composition can be administered intravenously. In some embodiments, the pharmaceutical composition can be administered orally.

[0225] In some embodiments, the pharmaceutical composition can be administered by injection, which includes, but is not limited to, the following means of delivery: intradermal; intramuscular; intraperitoneal; intravenous; and subcutaneous.

[0226] In some embodiments, the effective amount of the pharmaceutical composition is administered once per day until 2-3 days after cessation of the condition.

[0227] In some embodiments, the effective amount of the pharmaceutical composition is administered as two doses per day until 2-3 days after cessation of the condition.

[0228] In some embodiments, the effective amount of the pharmaceutical composition is administered once per day for from about 1 to about 10 days. For example, the effective amount of the pharmaceutical composition can be administered once per day for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.

[0229] In some embodiments, the effective amount of the pharmaceutical composition is administered as two doses per day for from about 1 to about 10 days. For example, the effective amount of the pharmaceutical composition can be administered as two doses per day for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.

[0230] In some embodiments, the effective amount of the pharmaceutical composition is administered once per day for about 14 days.

[0231] In some embodiments, the effective amount of the pharmaceutical composition is administered as two doses per day for about 14 days.

[0232] In some embodiments, the effective amount of the pharmaceutical composition is administered once per day for about 21 days.

[0233] In some embodiments, the effective amount of the pharmaceutical composition is administered as two doses per day for about 21 days.

[ 0234] In some embodiments, to treat some conditions, the pharmaceutical compositions of the invention can be administered for even longer periods of time, for example several months. [0235] An example of a dosage range is from about 0.1 to about 200 mg/kg body weight orally in single or divided doses. In some embodiments, a dosage range is from about 1.0 to about 100 mg kg body weight orally in single or divided doses, including from about 1.0 to about 50 mg/kg body weight, from about 1.0 to about 25 mg kg body weight, from about 1.0 to about 10 mg/kg body weight (assuming an average body weight of approximately 70 kg; values adjusted accordingly for persons weighing more or less than average). For oral administration, the compositions can be, for example, provided in the form of a tablet containing from about 50 to about 1000 mg of the active ingredient, particularly about 75 mg, about 100 mg, about 200 mg, about 400 mg, about 500 mg, about 600 mg, about 750 mg, or about 1000 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject being treated. In an exemplary oral dosage regimen, a tablet containing from about 500 mg to about 1000 mg active ingredient is administered once (e.g., a loading dose) followed by administration of 1/2 dosage tablets (e.g., from about 250 to about 500 mg) each 6 to 24 hours for at least 3 days.

[0236] Having described the invention in detail, it will be apparent that modifications, variations, and equivalent embodiments are possible without departing the scope of the invention defined in the appended claims. Furthermore, it should be appreciated that all examples in the present disclosure are provided as non-limiting examples.

EXAMPLES

[0237] The following non-limiting examples are provided to further illustrate embodiments of the invention disclosed herein. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent approaches that have been found to function well in the practice of the invention, and thus can be considered to constitute examples of modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

EXAMPLE 1

S YNTHESIS OF A MODIFIED FLUOROQUINOLONE COMPOUND

[0238] Step 1: 3-Trifluoromethylaniline (3 g, 0.0186 mol) was dissolved in dichloromethane (50 mL) and triethylamine (2.07 g, 0.0205 mol) was added. The reaction mixture was cooled to <10°C and chloroacetyl chloride (2.31 g, 0.0205 mol) was added, keeping the temperature below 10°C. After stirring for 2 hours at room temperature, saturated sodium bicarbonate solution was added and the mixture was shaken and separated. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 2-chloro-N-(3- txifluoromethylphenyl)acetarnide which was used without further purification. Yield = approximately 97%.

O

1

[0239] Step 2: 2-Chloro-N-(3-trifluoromethylphenyl)acetarnide (0.80 g, 0.0033 mol) was dissolved in DMF (25 mL), and ciprofloxacin (1.00 g, 0.003 mol), sodium bicarbonate carbonate (0.28 g, 0.0033 mol) and potassium iodide (0.60 g, 0.0033 mol). After stirring at 60 C for 6 days TLC (silica) indicated the reaction was complete. The reaction was cooled to room temperature and the DMF was removed under vacuum. The residue was dissolved in chloroform and washed with water. The organic layer was separated, dried over magnesium sulfate, and evaporated. The product was purified by column chromatography on silica, eluting with chloroform: methanol 4:1 to give l-cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(3- (trifluoromethy lphenyl)amino)ethy l)piperazin- 1 -yl)- 1 ,4-dihy droquinoline-3-carboxylic acid. Yield = approximately 68%.

EXAMPLE 2

MODIFIED FLUOROQUINOLONES (MFQs) EXHIBIT ANTI-BACTERIAL ACTIVITY IN

VITRO (MICso DATA)

[0240] Modified fluoroquinolone (MFQ) compounds were designed and synthesized as disclosed herein. Exemplary MFQ compounds as illustrated in Figure 1 were assayed in an initial bacterial screen in which various bacterial strains were treated with a dose range of the MFQ compounds to measure the minimal inhibitory concentration that inhibits the growth of 50% of organisms (MICso). Reference antibiotics used for comparison were vancomycin hydrochloride (e.g. Sigma Cat. #V-2002) and ciprofloxacin (eg. Fluka 17850).

[0241] All MFQ compounds were prepared as 6.4 mg/ml stock solutions in DMSO and further diluted with sterile water or appropriate diluent. A working stock of 256pg/ml was used to perform 1:2 serial dilutions in 96-well plates. Final MIC concentrations tested in the study ranged from 64 Mg/ml to 0.12 Mg/ml. [0242] Bacterial inoculums were prepared by making a direct sterile water suspension of isolated colonies from 18 to 24-hour agar plates for all organisms in Table 1 (using Mueller Hinton or Blood Agar media plates). Each bacterial suspension was adjusted for reading between 0.09 and 0.11 absorbance at 620nm (0.5 McFarland Standard). The suspensions were further diluted 1:100 in Mueller Hinton broth (MHB) for inoculating the 96- well plates. The final concentrations for Listeria monocytogenes had 3% lysed horse blood.

Table 1. Test organisms for MIC 50 studies of MFQ compounds

[0243] Once mixed in the 96-well plates, all bacterial plates containing test MFQ compounds and reference antibiotics were incubated for 18 hours at 35°C. Plates were read using a Beckman Automated Plate Reader at 650nm. Readings were confirmed by visual examination of plates. Minimal inhibitory concentrations are reported as complete visual inhibition.

[ 0244] Table 2 illustrates the results of the MICso assay. The results indicate that all compounds demonstrate effective activity against the Staphylococcal species tested as well as good to moderate activity against the E. coli, Salmonella and Shigella strains included in the panel. DP- 100 (DM1021) demonstrates good to moderate activity against all organisms tested in the panel. The results indicate that MFQ compounds have effective anti-bacterial activity in vitro.

EXAMPLE 3

MODIFIED FLUOROQUINOLONES (MFQs) EXHIBIT ANTI-BACTERIAL ACTIVITY IN

VITRO (IC50 DATA)

[0245] Modified fluoroquinolone (MFQ) compounds were designed and synthesized as disclosed herein. Exemplary MFQ compounds as illustrated in Figure 1 and 7-11 were assayed in a bacterial screen in which various bacterial strains were treated with a dose range of the MFQ compounds to measure the inhibitory concentration that inhibits the growth of 50% of organisms (IC50). Reference antibiotics used for comparison were vancomycin hydrochloride {e.g. Sigma Cat. #V-2002), ciprofloxacin {e.g. Fluka 17850) and rifampin.

[0246] The assays were set up in 96-well plates. Overnight cultures of bacteria were diluted to OD₆oo = 0.5 in 3mL media and incubated at 37°C and 250 rpm for about 1.5 hours to achieve log phase growth. The bacteria were then pipetted into the 96-well plates with the test compounds and reference antibiotics for the assay. The test compounds were assayed for dose- responsive anti-bacterial activity at concentrations ranging from 1 nM to 100 μΜ (1:3 dilution). Negative control wells were left untreated with chemicals, while positive control wells were treated with the reference antibiotics. At 18-22 hours post-chemical treatment, a microplate reader was used to quantitate bacterial growth, using absorbance at 600nm (OD600). Wells treated with test compounds or reference antibiotics at effective concentrations exhibited anti-bacterial activity as shown by markedly lower OD600 values. Wells treated with test compounds or reference antibiotics that are not effective anti-bacterial agents illustrated little to no difference in OD600 values from the negative (untreated) control wells.

[ 0247 ] Table 3 provides a list of organisms used for the inhibition assay.

[0248] Tables 4-5 and Figures 12-16 illustrate the results of the IC₅0 assay. Figures 12-16 illustrate the dose-dependent growth inhibition curves for the test compounds listed in Tables 4-5. The results indicate that the modified compounds exhibit a reasonably broad spectrum of activity against different bacterial species and that generally, the MFQ compounds developed as disclosed herein have effective anti-bacterial activity in vitro.

EXAMPLE 4

MODIFIED FLUOROQUINOLONES (MFQs) EXHIBIT ANTI-BACTERIAL ACTIVITY IN

VITRO (MIC DATA FROM MICROMYX CULTURE COLLECTION)

[0249] Modified fluoroquinolone (MFQ) compounds were designed and synthesized as disclosed herein. Exemplary MFQ compounds as illustrated in Figure 1 and 7-11 were assayed in a bacterial screen in which various bacterial strains were treated with a dose range of the MFQ compounds to measure the rriinimal inhibitory concentration that inhibits the growth of organisms (MIC). Reference compounds used for comparison included linezolid (ChemPacific 35710 Lot CHPC091007-01), vancomycin (Sigma V2002 Lot 087K0694), gentamicin (Sigma 3632 Lot 047K075), cefotaxime (Sigma 7912 Lot 084K0674), ciprofloxacin (USP Rockville 1134335 Lot IOC265), imipenem (USP Rockville 1337809 Lot 3IOH217) and levofloxacin (Biochemka 446423/1).

[0250] The MFQ compounds were solubilized in 100% DMSO at a final concentration of 1.28 mg/ml, with the exception of DM1021 and DM1023, which fell out of solution and were applied to bacteria as a suspension. Reference compounds were solublized in sterile deionized water. Stocks were made to achieve a starting concentration in the assay of 64 g/mL. The assay was split in two parts with the Gram positive organisms tested on one day and the Gram negative organisms tested two days later. The DMSO stocks of the investigational compounds were frozen after the first assay, and then thawed at room temperature for use in the second assay. Staphylococcus aureus ATCC 29213 and Escherichia coli ATCC 25922 were tested on both days with all MFQ compounds in order to evaluate the effect of freeze-thaw on the potency of each compound.

[0251] The test organisms consisted of 25 clinical isolates from the Micromyx Culture Collection (Kalamazoo, Michigan). Also included were 5 ATCC strains which provided quality control data for the assay. Table 6 lists the isolates that were tested.

[0252 ] The test medium employed for the broth microdilution MIC assay was Mueller Hinton Π broth (MHBII; BBL 212322, Lot 9044411). The medium was supplemented with 4% laked horse blood (Cleveland Scientific Lot 27211-1) to support the growth of streptococci.

[0253 ] MIC values were determined using the CLSI- recommended broth microdilution procedure (Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard— Eighth Edition. CLSI document M07-A8 [ISBN 1-56238-689-1]. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2009.). Automated liquid handlers (Multidrop 384, Biomek 2000 and Multimek 96; BeckmanCoulter, Brea, CA) were used to conduct serial dilutions and liquid transfers.

[ 0254] The wells in Columns 2 to 12 of four standard 96- well microdilution plates (Falcon 3918; Becton Dickinson, Franklin Lakes, NJ) were filled with 150 uL of the appropriate diluent: 100% DMSO for investigational compounds and sterile deionized water for comparators. Three hundred microliters of each test drug was added to Column 1 of the microplate. These plates were used to prepare the drug "mother plates" which provided the serial drug dilutions for the replicate "daughter plates" (Falcon 3918). The Biomek 2000 was used to complete the serial dilutions through Column 11 in the mother plates. The wells in Column 12 contained no drug and were the organism growth control wells.

[0255] The Multidrop was used to transfer media to the daughter plates, and the Multimek 96 transferred transferred 5 μL· of drug solution from each well of a mother plate to each corresponding well of each daughter plate in a single step. For streptococci, each well of the daughter plates contained 185μΙ_^ of MHB Π 4% laked horse blood, 5 μL· of drug solution and 10 μΐ_^ of bacterial inoculum. For all other organisms, each well of the daughter plates contained 85 uL of MHB II, 5 μ]_ of drug solution, and 10uL of bacterial inoculum.

[0 56] Standardized inoculum of each organism was prepared per CLSI guidelines (Clinical and Laboratory Standards Institute. 2009. supra). The inoculum for each organism was dispensed into sterile reservoirs and the Biomek 2000 was used to add 10 μL· of bacterial inoculum to each well.

[0257] Plates were stacked 3 high, covered with a lid on the top plate, placed in plastic bags, and incubated at 35oC for 18-20 hours. Following incubation, the microplates were viewed from the bottom using a plate viewer. An un-inoculated solubility control plate was observed for evidence of drug precipitation. The MIC was read and recorded as the lowest concentration of drug that inhibited visible growth of the organism.

[0258] For all organisms except the streptococci, the MFQcompounds were tested at 12 different concentrations, from 0-64 Mg ml using serial two-fold dilutions that began at 0.06 μ^ηιΐ. Streptococci were tested from 0-32 μ^πιΐ since the final DMSO concentration for these organisms cannot be greater than 2.5%, thereby requiring more dilution of the original DMSO stock. The final DMSO concentration for all other organisms was 5%. A solubility control plate was included in which bacterial inoculum was not added. Some of the compounds fell out of solution, producing a precipitate in the wells. Therefore, the MIC value could not be read at or above the concentration that produced a precipitate. This resultede in MIC values of greater than 16 ug/ml for some of the isolates, indicating that the drug was not soluble above mis concentration.

[0259] The susceptibility data obtained for Gram-positive pathogens is shown in Table 7 for each of the MFQ compounds and the seven reference compounds. Good activity was observed for most of the MFQ compounds for each of the 2 MSSA isolates tested; MIC values ranged from 0.12 μ§/πύ for compound 1066 to >64 μ^ιηΐ for compound 1101. When comparing the activity of the MFQ compounds against the 2 MSSA isolates, the MIC values were within one serial two-fold dilution of each other, and therefore a given MFQ compound had similar activity against each isolate. For S. epidermidis, each of the MFQ compounds exhibited good activity against the single MSSE isolate. In addition, Isolate 3185 (VSE. faecalis) was sensitive to the MFQ compounds.

[0260] Table 8 contains susceptibility data for the test agents and comparators against Gram-negative isolates. Compounds 1021 and 1086 appeared to be very active against the ciprofloxacin-sensitive isolates, producing MIC values of =8 μg/πll for all such isolates. In general, compounds that produced on scale MIC values were more active against ciprofloxacin- sensitive A. baumannii, followed by E. coli, K. pneumoniae, and finally P. aeruginosa.

[0261] Table 9 represents susceptibility data obtained for the ATCC reference strains on each of two testing days. The MFQ compounds were dissolved in DMSO on the first testing day and aliquoted for the MIC assay that day; the compounds were then frozen for future use on a second assay two days later. Thus, the effect of freeze/thawing on MFQ compound activity could be observed. Table 9 indicates that the majority of MFQ compounds produced similar MIC values on each of the test days, demonstrating that freeze thaw had little or no effect on compound activity.

EXAMPLE 5

METHOD OF TREATING AN INFECTION CAUSED BY METHYCILLIN RESISTANT

STAPHYLOCOCCUS BACTERIA

[0262] A subject presents with a bacterial infection, which is identified as being caused by a methycillin-resistant strain of Stapholococcus aureus (MRSA). The subject is treated with an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein. The composition is administered orally at a dose of 1.0 mg/kg of body weight twice per day for a period of 5-7 days. Upon administration of the pharmaceutical composition, the bacterial infection begins to subside, and the subject presents with improved symptoms {e.g. abatement of fever and fatigue, improved appetite and energy )by the end of the administration period.

EXAMPLE 6

METHOD OF TREATING AN INFECTION CAUSED BY SHIGELLA BACTERIA

[0263] A subject presents with a bacterial infection, which is identified as being caused by Shigella sonnet. The subject is treated with an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein. The composition is administered orally at a dose of 0.5 mg kg of body weight once daily for a period of 7-10 days. Upon administration of the pharmaceutical composition, the bacterial infection begins to subside, and the subject presents with improved symptoms (e.g. abatement of fever and fatigue, improved appetite and energy )by the end of the administration period.

EXAMPLE 7

METHOD OF TREATING AN INFECTION CAUSED BY ENTEROCOCCUS BACTERIA

[0264] A subject presents with a bacterial infection, which is identified as being caused by Enterococcus faecium. The subject is treated with an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein. The composition is administered orally at a dose of 1.5 mg kg of body weight twice daily for a period of 7-10 days. Upon administration of the pharmaceutical composition, the bacterial infection begins to subside, and the subject presents with improved symptoms (e.g. abatement of fever and fatigue, improved appetite and energy )by the end of the administration period.

EXAMPLE 8

METHOD OF TREATING AN INFECTION CAUSED BY PSEUDOMONAS BACTERIA

[0265] A subject presents with a bacterial infection, which is identified as being caused by Pseudomonas aeruginosa. The subject is treated with an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein. The composition is administered orally at a dose of 1.0 mg kg of body weight twice daily for a period of 3-5 days. Upon administration of the pharmaceutical composition, the bacterial infection begins to subside, and the subject presents with improved symptoms {e.g. abatement of fever and fatigue, improved appetite and energy )by die end of the administration period.

EXAMPLE 9

METHOD OF PREVENTING AN INFECTION CAUSED BY METHYCILLIN RESISTANT

STAPHOLOCOCCUS BACTERIA

[0266] A subject is exposed to a methycillin-resistant strain of Stapholococcus aureus (MRSA) and is presented with a risk for bacterial infection. The subject is prophylactically administered an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein. The composition is administered orally at a dose of 1.0 mg/kg of body weight twice per day for a period of 5-7 days. During and after administration of the pharmaceutical composition, the subject presents with milder symptoms of bacterial infection.

EXAMPLE 10

METHOD OF PREVENTING AN INFECTION CAUSED BY SHIGELLA BACTERIA

[0267 ] A subject is exposed to Shigella sormei and is presented with a risk for bacterial infection. The subject is prophylactically administered an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein. The composition is administered orally at a dose of 0.5 mg kg of body weight once daily for a period of 7-10 days. During and after administration of the pharmaceutical composition, the subject exhibits few to no symptoms of bacterial infection and overall presents with a healthy outlook.

EXAMPLE 11

METHOD OF PREVENTING AN INFECTION CAUSED BY ENTEROCOCCUS

BACTERIA

[0268] A subject is exposed to Enterococcus faecium and is presented with a risk for bacterial infection. The subject is prophylactically administered an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein. The composition is administered orally at a dose of 1.5 mg kg of body weight twice daily for a period of 7-10 days. During early administration of the pharmaceutical composition, the subject presents with full symptoms of bacterial infection. Upon completion of the dosage regimen, the bacterial infection begins to subside, and the subject presents with improved symptoms {e.g. abatement of fever and fatigue, improved appetite and energy ) within days of regimen completion.

EXAMPLE 12

METHOD OF PREVENTING AN INFECTION CAUSED BY PSEUDOMONAS BACTERIA

[0269] A subject is exposed to Pseudomonas aeruginosa and is presented with a risk of bacterial infection. The subject is prophylactically administered an effective amount of a pharmaceutical composition comprising an MFQ compound as disclosed herein. The composition is administered orally at a dose of 1.0 mg/kg of body weight twice daily for a period of 3-5 days. During and after administration of the pharmaceutical composition, the subject presents with bacterial infection begins to subside, and the subject exhibits no symptoms of bacterial infection and overall presents with a healthy outlook.

[0270] The various methods and techniques described above provide a number of ways to carry out the invention. Of course, it is to be understood that not necessarily all objectives or advantages described may be achieved in accordance with any particular embodiment described herein. Thus, for example, those skilled in the art will recognize that the methods can be performed in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objectives or advantages as may be taught or suggested herein. A variety of advantageous and disadvantageous alternatives are mentioned herein. It is to be understood that some preferred embodiments specifically include one, another, or several advantageous features, while others specifically exclude one, another, or several disadvantageous features, while still others specifically mitigate a present disadvantageous feature by inclusion of one, another, or several advantageous features.

[0271] Furthermore, the skilled artisan will recognize the applicability of various features from different embodiments. Similarly, the various elements, features and steps discussed above, as well as other known equivalents for each such element, feature or step, can be mixed and matched by one of ordinary skill in this art to perform methods in accordance with principles described herein. Among the various elements, features, and steps some will be specifically included and others specifically excluded in diverse embodiments.

[0272] Although the invention has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the embodiments of the invention extend beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and modifications and equivalents thereof.

[0273 ] Many variations and alternative elements have been disclosed in embodiments of the present invention. Still further variations and alternate elements will be apparent to one of skill in the art. Among these variations, without limitation, are the fluoroquinolone base structure used for making an MFQ compound, the type of modification made to the fluoroquinolone base structure, and the bacterial source of infection to be treated by methods as disclosed herein. Various embodiments of the invention can specifically include or exclude any of these variations or elements.

[0274] In some embodiments, the numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term "about." Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0275] In some embodiments, the terms "a" and "an" and "the" and similar references used in the context of describing a particular embodiment of the invention (especially in the context of certain of the following claims) can be construed to cover both the singular and the plural. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0276] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0277] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. It is contemplated that skilled artisans can employ such variations as appropriate, and the invention can be practiced otherwise than specifically described herein. Accordingly, many embodiments of this invention include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0278] Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above cited references and printed publications are herein individually incorporated by reference in their entirety.

[0279] In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that can be employed can be within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention can be utilized in accordance with the teachings herein. Accordingly, embodiments of the present invention are not limited to that precisely as shown and described.

Claims

wherein

Xi is nitrogen or carbon;

X2 is selected from a hydrogen, a halogen, and an alkoxy group having 1-6 carbons in the alkyl part;

X₃ is selected from a straight-chain or branched alkyl group with 1 to 6 carbons optionally having a substituted halogen on the terminal carbon, a phenyl, a substituted phenyl, and a cycloalkane having 1 to 6 carbons; or

X₂ and X3 together form a 6-membered ring that comprises at least one heteroatom at any position that valence requirements permit;

(X4>n is selected from a hydrogen, an alkyl group having 1-6 carbon atoms, a halo, a haloalkyl, an amino, a hydroxyl, an alkoxy, an alkylamino, and an arylamino; n is an integer from zero to 4; and

X₅ is carbon or nitrogen,

or salts or solvates or stereoisomers or prodrugs thereof.

2. The compound of Claim 2, wherein Ring 1 has the formula of (II):

wherein G is

and wherein

Xe is a straight chain or branched alkyl or heteroalkyl group having from 1 to 12 atoms, and

R₁ and R2 are independently selected from a hydrogen, a straight-chain or branched alkyl having from 1 to 12 carbon atoms, a straight-chain or branched heteroalkyl group having from 1 to 12 atoms and comprising at least one heteroatom, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl, or

R₁ and R2 together with N form a monocyclic ring or a polycyclic ring system.

3. The compound of Claim 2, wherein ¾ is selected from the group of: an alkyl, an alkoxy, an alkylamino, -N-, or -0-.

4. The compound of Claim 2, wherein R₁ and R2 independently have the structural formula of GV):

wherein

s is an integer from zero to 5; and

Y2 is selected from C, S, or N.

5. The compound of Claim 4, wherein (X₇)_s is selected from fluoro, chloro, trifluoromethyl, methoxy, amine, carboxyl, sulfonamide, and hydroxylalkyl.

6. The compound of Claim 4, wherein Y₂ is nitrogen.

7. The compound of Claim 4, wherein R₁ and R₂ are the same.

8. The compound of Claim 4, wherein R₁ and R₂ are different.

9. The compound of Claim 2, wherein R and R₂ together with N form a monocyclic ring.

10. The compound of Claim 2, wherein R₁ and R₂ together with N form the central ring of a polycyclic ring system.

11. The compound of Claim 10, wherein the central ring formed by R₁, R₂, and N is a 5-, 6-, or 7-membered ring.

12. The compound of Claim 11, wherein the polycyclic ring system comprised of R₁, R₂ and N has the structure (V):

wherein

(X )_q and (¾). are independently selected from H, alkyl, halo, haloalkyl, alkoxy, amino, hydroxyl, alkylamino, cyano, and mercapto;

q is an integer from zero to 4;

t is an integer from zero to 4; and

13. The compound of Claim 10, wherein the polycyclic ring system comprised of R₁, R₂ and N has the structure (VI):

wherein

Y2 is selected from NR₄, O, and S, and wherein R is selected from H, lower alkyl and acyl;

(X₉)_q and (Xs)_t are independently selected from H, alkyl, halo, haloalkyl, alkoxy, amino, hydroxyl, alkylamino, cyano, and mercapto;

q is an integer from zero to 4;

t is an integer from zero to 4; and

14. The compound of Claim 10, wherein the polycyclic ring system comprised of R₁, R₂ and N has the structure (VII):

R₃ is selected from H, alkyl, heteroalkyl, =0, amino, amine, amide, sulfonamide, halo, cyano, hydroxy, mercapto, haloalkyl, alkoxy, alkylthio, thioalkoxy, arylalkyl, heteroaryl, alkylamino, dialkylamino, and alkylsulfano;

q is an integer from zero to 4;

t is an integer from zero to 4; and

15. The compound of Claim 1 selected from the group of:

1 -cycIopropyl-7-(4-(2-(diemylamino)- 2-oxoethyl)piperazin- 1 -yl)-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid;

l-cyclopropyl-7-(4-(2-(cyclopropylarnmo)-2-oxoemyl)piperazin-1-yl)-6-fluoro-4- oxo- 1 ,4-dihydroquinoline-3-carboxylic acid;

l-cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(4- (trifluoromemyl)phenylamino)ethyl)piperazin- 1-yl)- 1 ,4-dihydroquinoline-3-carboxylic acid;

9-fluoro-3-methyl-7-oxo- 10-(4-(2-oxo-2-(phenylamino)ethy l)piperazin- 1 -yl)-3 ,7- dmycho-2H-[1,4]oxazmo[2,3,4-ij]qumoline-6-carboxylic acid,

1 -cyclopropyl-7-(4-(2-(adamantalammo)-2-oxoethyl)piperazin-1-yl)-6-fluoro-4- oxo- 1 ,4-dmydroquinoline-3-carboxylic acid;

7-(4-(2-(cyclohexylamino)-2-oxoethy piperazin- 1 -yl)- 1 -cyclopropyl-6-fluoro-4- oxo- 1 ,4-dmydroquinoline-3-carboxylic acid;

l-cyclopropyl-6-fluoro-7-(4-(2-(mesitylammo)-2-oxoethyl)piperazin-1-yl)-4- oxo- 1 ,4-dihydroquinoline-3-carboxylic acid;

l-cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(3- (trifluoromemyl)phenylamino)ethy Opiperazin- 1-yl)- 1 ,4-dihydroquinoline-3-carboxylic acid;

l-cyclopropyl-6-fluoro-7-(4-(2-(memyl(phenemyl)ammo)-2-oxc«thyl)piperazin- 1 -yl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid;

l-cyclopropyl-6-fluoro-7-(4-(2-(memyl(phenyl)ammo)-2-oxc«myl)piperazin-1- yl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid; l-cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(phenylamino)ethyl)piperazin-1-yl)- 1,4-dihydroquinoline-3-carboxylic aeid;

l-cyclopropyl-7-(4-(2-(diphenylamino)-2-oxoethyl)pipera2in-1-yl)-6-fluoro-4- oxo- 1 ,4-dihydroquinoline-3-carboxylic acid;

1 -cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(9-oxoacridin- 10(9H)- yl)ethyl)piperazin- 1 -yl)- 1 ,4-dihydroquinoline-3-carboxylic acid;

l-cyclopropyl-6-fiuoro-4-oxo-7-(4-(2-oxo-2- (perfluorophenylamino)ethyl)piperazin- 1 -yl)- 1 ,4-dihydroquinoline-3-carboxylic acid; l-cyclopropyl-7-(4-(2-(10,l l-dihydro-5H-dibenzo[b,flazepin-5-yl)-2- oxoethy l)piperazin- 1 -y l)-6-fluoro-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylic acid;

l-cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(pyridin-4-ylamino)elhyl)piperazin- 1 -yl)-l ,4-dihydroquinoline-3-carboxylic acid;

l-cyclopropyl-6-fluorc^-oxo-7-(4-(2-oxo-2-(2,4,4-lrimetb.ylpentan-2- ylamino)ethyl)piperazin-l -yl)-l ,4-dihydroquinoline-3-carboxylic acid;

l-cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(phenyl(pyridin-4- yl)amino)etbyl)piperazin-l -yl)-l ,4-dihydroquinoline-3-carboxylic acid;

l-cyclopropyl-6-fluoro-4-oxo-7-(4-(2-oxo-2-(tritylamino)ethyl)piperazin-1-yl)^ 1 ,4-dihydroquinoline-3-carboxylic acid;

l-cyclopropyl-7-(4~(2-(dicyclohexylamino)-2-oxoethyl)piperazin-1-yl)-6-fluoro- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

l-cyclopropyl-7-(4-(2-(dipyridin-2-ylaniiiio)-2-oxoethyl)piperazin-1-yl)-6- fluoro-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid;

1 -cyclopropyl-6-fluorc-7-(4-(2-(octylan-ino)-2-oxoethyl)piperazin- 1 -yl)-4-oxo- 1,4-dihydroquinoline-3 -carboxylic acid; and

l-cyclopropyl-7-(4-(2-(dodecylamino)-2-oxoethyl)piperazin-1-yl)-6-fluoro-4- oxo-1,4-dihydroquinoline-3-carboxylic acid ("DM1086/DP116")'.

or salts or solvates or stereoisomers or prodrugs thereof.

16. The compound of any one of Claims 1-15, wherein the salt is a pharmaceutically acceptable salt.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of Claims 1-15, or a prodrug or salt thereof; and a pharmaceutically acceptable carrier.

18. A kit comprising a compound of any one of Claims 1-15.

19. A medicament in dosage unit form comprising a therapeutically effective amount of a compound of any of Claims 1-15, or a prodrug or salt thereof.

20. A method of treating an infection in a subject, comprising:

administering a therapeutically effective amount of a compound of any one of Claims 1-15, or a prodrug or salt thereof, to said subject,

wherein the administration of a therapeutically effective amount of compound results in a diminishment of infection.

21. A method of reducing the likelihood of developing an infection in a subject, comprising:

wherein the administration of a therapeutically effective amount of compound results in a reduced likelihood of infection relative to that of a subject who has not received an administration of compound.

22. The use of a therapeutically effective amount of a compound of any one of Claims 1-15 modified fluoroquinolone (MFQ) compound as disclosed herein, or a prodrug or salt thereof, in the manufacture of a medicament for treatment of an infection.