WO2001019792A1 - Molecules dimeres de liaison a l'adn liees de façon covalente - Google Patents

Molecules dimeres de liaison a l'adn liees de façon covalente Download PDF

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WO2001019792A1
WO2001019792A1 PCT/US2000/025325 US0025325W WO0119792A1 WO 2001019792 A1 WO2001019792 A1 WO 2001019792A1 US 0025325 W US0025325 W US 0025325W WO 0119792 A1 WO0119792 A1 WO 0119792A1
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compound
ring system
ring
groups
binding
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PCT/US2000/025325
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English (en)
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Lisa M. Turin
Andrew R. Pitt
Colin J. Suckling
Roger D. Waigh
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Genelabs Technologies, Inc.
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Priority to AU73816/00A priority Critical patent/AU7381600A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems

Definitions

  • the present invention relates to DNA binding compounds which are dimers of netropsin or netropsin analogs, linked by a polycychc linker group.
  • binding of the antiviral antibiotics netropsin and distamycin to AT-rich sequences in the minor groove of double stranded DNA is a well studied phenomenon. Because such binding can be used to regulate DNA expression, e.g. by blocking and/or displacement of regulatory proteins, or by inhibiting the activity of enzymes acting on DNA, such as reverse transcriptase or topoisomerase, optimization of this binding has been the subject of numerous recent studies.
  • Linkers employed in these studies included p-phenylene, trans-vinyl, cyclopropyl, 3,5- pyridyl, and six- and eight-carbon aliphatic chains. Several of these linkers restrict rotation around the linking group, thus reducing the extent of purely monodentate binding (i.e. by only one netropsin moiety) which can occur with flexible linkers.
  • Kissinger et al. ⁇ Chem. Res. Toxicol. 3(2): 162-8, 1990 reported that aryl-linked groups had reduced DNA binding affinity compared to alkyl and alkylene linkers, and Neamati et al.
  • the present invention includes, in one aspect, a DNA binding compound having the structure B-L-B', where B and B' are independently represented by the structure:
  • L is a fused polycychc ring system containing two or more fused 5- to 7-membered rings, and containing at least one aromatic ring; and B and B' are linked to different rings of said ring system, such that the shortest path connecting said groups B and B' comprises at least three contiguous bonds within the ring system when the two groups are on adjacent fused rings, and comprises at least five contiguous bonds within the ring system when the two groups are on non-adjacent (non-fused) rings. These contiguous bonds are preferably part of a conjugated pi system.
  • the linker L is 2,5-indolyl or 9,10-dihydro-2,7-phenanthrenyl.
  • Other preferred linkers include 2,7- phenanthrenyl, 3,7-dibenzofuranyl and 3,7-dibenzothiophenyl.
  • B and B' are typically identical groups.
  • the compound may be effective to block and/or displace a regulatory protein or to inhibit the activity of an enzyme acting on DNA, e.g. reverse transcriptase or topoisomerase.
  • Figures 1A-1H show UV absorption spectra of selected compounds of the invention
  • Figure 2 is a graphical analysis of a footprinting gel for invention compound 21, run on a DNA sequence (SEQ ID NO: 1) derived from human IL-l ⁇ , showing observed regions of partial or strong footprinting, as indicated, and the concentrations of binding compound and control compound.
  • concentrations of control compound (Distamycin, represented by D) and invention compound (in each case represented by C) are given along the left edge of the Figures in ⁇ M; e.g. , in Fig. 2, "C 0.1 " indicates 0.1 ⁇ M of invention compound 21.
  • Figures 3A-B are similar graphical analyses of a footprinting gel for invention compound
  • Figure 4 is a graphical analysis of a footprinting gel for invention compound 21, using a DNA sequence (SEQ ID NO: 3) derived from human IL-2;
  • Figure 5 is a graphical analysis of a footprinting gel for invention compound 25, using a DNA sequence (SEQ ID NO: 1) derived from human IL-l ⁇ ; and
  • Figures 6A-B are graphical analyses of a footprinting gel for invention compound 25, using a DNA sequence (SEQ ID NO: 2) derived from human IL-l ⁇ .
  • the DNA binding netropsin dimers, or analogs, of the invention have a structure represented by B-L-B', where B and B' each independently represent a netropsin-based structure as shown:
  • B and B' are the same in a given compound.
  • "A” may also be an aliphatic or alicyclic amine, represented by -CH 2 NRR', where R and R' are independently hydrogen or lower alkyl or together form a 5- to 7-member heterocyclic ring whose ring atoms are selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and include at least 3 carbon atoms.
  • a preferred embodiment of A is (dimethylamino)methyl (-CH 2 N(CH 3 ) 2 ).
  • heterocycle-containing embodiments of A include (1- morpholinyl)methyl, (l-piperazinyl)methyl, and (4-methyl-l-piperazinyl)methyl.
  • the linker L is a fused polycychc ring system containing at least one aromatic ring. In selected embodiments, L is a bicyclic or tricyclic ring system.
  • linkers examples include 2,5-indolyl, 2,6-indolyl, 2,7-phenanthrenyl, 9,10-dihydro-2,7-phenanthrenyl, 3,7- dibenzofuranyl, 3,7-dibenzothiophenyl, 3,7-fluorenyl, 3,7-fluorenonyl, 2,5-benzimidazolyl, and 2,6-benzimidazolyl.
  • the cyclic phosphate of 2,2'-biphenyldiol (6-hydroxy- dibenzo[d,f][l,3,2] dioxaphosphepin-6-oxide).
  • the ring system typically contains ring atoms selected from the group consisting of carbon, nitrogen, oxygen, and sulfur. In selected embodiments, all of the ring atoms are carbon (i.e. a polycychc hydrocarbon), or they are selected from carbon and nitrogen (i.e. a carbon-nitrogen heterocycle).
  • the linking group is substantially rigid, although some conformational flexing may occur (e.g. in 9,10-dihydrophenanthrene), and it is preferably planar or nearly planar.
  • each binding group B and B' (specifically, the leftmost carbonyl group in the structure shown above, in each group B and B') is linked to a different ring of the polycychc ring system.
  • the shortest path connecting the two groups comprises at least three contiguous bonds within the ring system.
  • they are on non-adjacent (non-fused) rings e.g. the 1 and 3 rings in a tricyclic ring system
  • the shortest path connecting the two groups comprises at least five contiguous bonds within the ring system. These contiguous bonds are preferably part of a conjugated pi system.
  • the connecting path lengths so defined provide that the bonds connecting the linker L to the two netropsin-based moieties B and B' are disposed in a linear or approximately linear arrangement; that is, the angle between these bonds (in a plane roughly defined by the linker moiety) is preferably greater than 90°, and more preferably between about 135° and 180°. Accordingly, linkers such as 1,8-naphthyl or 1,8-anthracyl (where the linking bonds would be essentially parallel) or 3,4-indolyl (where the linking bonds would be nearly parallel) would not be included.
  • the linkage is longer than those shown in the prior art based on e.g. phenyl, vinyl, pyridyl, or cycloalkyl groups. This longer spacing is expected to accommodate binding to target sequences for which these shorter linkers are less optimal.
  • the dimeric compounds bind to DNA with an affinity that is often much greater than that shown by the monomeric counterparts, and in some cases with differing sequence selectivity.
  • dimers of distamycin or lexitropsin analogs employing the polycychc linkers described herein; i.e.
  • the compounds can be prepared by condensation of two equivalents of a dipyrrole peptide, as described below, with a dicarboxylic acid of the form HOOC-L-COOH, where L is as defined above, or an activated derivative thereof such as a diacid chloride or diimidazolide.
  • the dipyrrole peptide has an amino group at the 3-position of the first pyrrolamide moiety.
  • Linked to the amide nitrogen of the terminal pyrrolamide moiety is a group of the form -(CH 2 ) n Y, where Y is a cyano group, an alkylamino methyl group, or -CH 2 X, with X representing an efficient leaving group such as halogen.
  • alkylamino can include nitrogen- containing heterocycles such as piperazine or morpholine.
  • n can range from 1 to 6, and is typically 2. Preparation of such dipeptides is described, for example, in Lown & Krowicki (J. Org. Chem. 50:3774-79, 1985) or in Nishiwaki et al. (Heterocycles 27(8): 1945-52, 1988).
  • dicarboxylic acids for preparing specific embodiments of the present compounds, the following dicarboxylic acids, or derivatives thereof, can be used: indole-2,5-dicarboxylic acid, indole-2,6-dicarboxylic acid, 2,7-phenanthrenedicarboxylic acid, 9, 10-dihydrophenanthrene-2,7-dicarboxylic acid, fluorene-2,7-dicarboxylic acid, fluorenone-2,7-dicarboxylic acid, 3,7-dibenzofurandicarboxylic acid, and 3,7-dibenzothiophenedicarboxylic acid.
  • Such compounds, as well as other diacids suitable for preparing compounds within the scope of the present claims, are frequently commercially available or can be prepared by one of ordinary skill in the art according to known synthetic methods.
  • 2-carboxyindoles can be prepared according to the method of D. Jones et al, U.S. Patent No. 3,838, 167 (1974); 2,5- and 2,6- substituted indoles can be synthesized by modified Fischer indole syntheses and further elaboration of the nucleus, as reported in A. I. Khalaf et al., J. Chem. Res. 751-54 (2000).
  • Dibenzofuran-3,7-dicarboxylic acid can be prepared by air oxidation of the corresponding dimethyl dibenzofuran (T. Kaneda et al., JP Kokai No. 53-12988 (1978); methyl-substituted dibenzofurans can in turn be efficiently prepared by dilithiation-oxidative coupling of methyl- substituted diphenyl ethers (F. Radner et al, J. Chem. Res. Synop. 8:362-62 (1996). M. Dotrong et al. (J. Polym. Sci., Part A: Polym. Chem.
  • 9,10-dihydrophenanthrene-2,7-dicarboxylic acid can be prepared by prepared by Friedel-Crafts acetylation of 9,10-dihydrophenanthrene, followed by iodine oxidation and aqueous base hydrolysis.
  • An alternate route employs bromination of 9, 10- dihydrophenanthrene, followed by Pd-catalyzed carbonylation (A.D. Abell et al, J. Chem. Soc. Perk. Trans. I 11: 1663-7, 1997).
  • fluorenone-2,7-dicarboxylic acid reported by Hodson et al. (U.S. Patent No. 3,987,088), fluorene is acetylated with Ac 2 0/AlCl 3 to give 2,7-diacetylfluorene, which is then oxidized to the final product.
  • the condensation reaction is carried out according to standard methods.
  • the aminopyrrole dipeptide component is dissolved in anhydrous DMF, the solution is cooled to a temperature of about -30°C to + 10°C, and the diacid chloride, in the presence of a base such as pyridine, triethylamine or diisopropylethylamine, or the diimidazolide is added dropwise in anhydrous THF.
  • a base such as pyridine, triethylamine or diisopropylethylamine, or the diimidazolide is added dropwise in anhydrous THF.
  • the reaction is stirred, with warming to room temperature if necessary, until completion; the solvent is removed and the residue purified by conventional techniques.
  • amidino-terminated dimers For preparation of amidino-terminated dimers, a cyano-terminated aminopyrrole dipeptide is employed. After condensation with an activated N-methyl-4-nitropyrrole-2-carboxylic acid monomer to give the nitrodimer, subsequent reaction with HCl/ethanol, followed by NH 3 /ethanol, as described in U.S. Patent No. 5,616,606, gives the amidinium chloride. Hydrogenation over palladium on charcoal then gives the required aminodimer (see Example 1).
  • an activated form of N-methyl-4-nitropyrrole-2-carboxylic acid is reacted with the appropriate substituted aliphatic amine (the substituent being, for example, mo ⁇ holino, N-methylpiperidinyl, pyrrolidinyl, bis(2- hydroxyethyl)amino, dimethyl- or diethylamino), to give the nitro monomer.
  • This compound is hydrogenated over palladium on charcoal and coupled to another activated N-methyl-4- nitropyrrole-2-carboxylic acid monomer to give the nitro dimer, which is the hydrogenated to furnish the amine for coupling to the linking group.
  • DNA Binding Assays Compounds of the invention exhibit sequence-specific or sequence-preferential binding and high binding affinity to DNA sequences, particularly A/T rich sequences. Binding of invention compounds to several DNA sequences was examined using nuclease footprinting, a technique well known in the art. Briefly, in footprinting, the region of DNA that is bound to a binding compound is protected from nuclease degradation. When samples are digested in the presence and absence of the binding compound, the sequence to which the compound binds appears as a gap, or footprint, in the array of bands obtained on electrophoresis. Preferably, several such experiments are run in parallel, using increasing amounts of the binding compound, in order to evaluate binding affinity.
  • Figs. 2-4 Graphical analyses of the footprinting gels, showing observed regions of partial or strong footprinting, as indicated in the Figures, are included in Figs. 2-4 for compound 21 (DNA sequences having SEQ ID NOs: 1-3, derived from human IL-l ⁇ , IL-l ⁇ , and IL-2, respectively) and in Figs. 5-6 for compound 25 (DNA sequences having SEQ ID NOs: 1-2, derived from IL- l ⁇ and IL-l ⁇ , respectively).
  • concentrations of control compound Distamycin, represented by D, and invention compound, in each case represented by C are given along the left edge of the Figures in ⁇ M; e.g., in Fig. 2, "C 0.1 " indicates 0.1 ⁇ M of invention compound 21.
  • Similar analyses were also conducted for the majority of the compounds in Table 1.
  • regions of binding generally overlapped those shown by the control compounds (distamycin or netropsin) but covered larger regions of DNA. Clear footprints of 8-11 bases were typical, though apparent footprints of 20-30 bases were observed, e.g. for compounds 21 and 25. Target sequences were generally A/T rich, as expected, though footprinting was often observed for regions with 50% or more G/C content. For some compounds, as noted below, footprinting was seen at regions where none was apparent for the control compounds. Less frequently (e.g. for compound 25), footprinting was not observed at regions where distamycin did give a footprint.
  • Binding affinities of the dimers were evaluated based on comparison of the concentrations at which the dimers produced clear footprinting, in comparison to the control compound. On this basis, binding affinity could be ordered roughly as follows, using the compound designations above: 21, 25 > 46, 45 > 26, 52, 50 > 49, 32, 51 > 48.
  • binding was generally seen at concentrations of 0.1 to 1 ⁇ M for sequences at which distamycin footprinting was seen at 25-50 ⁇ M, as shown in Table 3.
  • Compound 46 (phenanthrene linker) and prior art compound 45 (tr ⁇ «s-vinyl linker) were run side by side with netropsin and showed footprinting in similar regions but at lower concentrations than netropsin; e.g. typically 0.1 to 1 ⁇ M (45) vs 6.25 ⁇ M (netropsin) ; 1 ⁇ M (46) vs 25 ⁇ M (netropsin).
  • Compound 46 also showed footprinting, at fairly high concentrations (about 50 ⁇ M), at sequences where distamycin did not appear to bind (e.g. ATCACTCTCTTTAAT in IL-2) (SEQ ID NO: 19).
  • the netropsin dimers of the invention bind to DNA with an affinity that is at least comparable, and in some cases greatly exceeds, that of the monomeric compounds netropsin and distamycin.
  • Certain invention compounds exhibited significantly greater binding affinities than compounds of the prior art, and in some cases exhibited binding to regions not observed with the control compounds and prior art compounds.
  • Example 1 Preparation of Compound 21 (N.N'-di ⁇ -methyl-2-ri-methyl-2-(l-methyl-2- carboxamide(3-amidino)-4-pyrrole)-carboxyamido-4-pyrrolelcarboxamido-4-pyrrolvU-indolyl- 2.5-dicarboxamide)
  • a distamycin derivative having a 4-nitropyrrole at one terminus and a 2- (carboxamidopropionitrile)pyrrole on the other terminus (l-methyl-4-(l-methyl-4-aminopyrrole- 2-carboxamido)-pyrrole-2-carboxamidopropionitrile) was prepared according to the procedure of Lown et ⁇ t., 1985.
  • the nitrodimer compound in ethanol was hydrogenated over Pd/C- 10% (1 equivalent w/w) at 60°C for 5h.
  • the catalyst was removed by filtration and the solvent removed under reduced pressure to yield the amine, which was used immediately without further purification.
  • Nitrodistamycin prepared according to reported procedures (e.g. Nishiwaki et al , 1988), was reduced to the amino derivative by catalytic hydrogenation.
  • the nitro compound was dissolved in 1 : 1 DMF/MeOH and treated with 10% Pd/C (100 mg / 200 mg nitrodistamycin) for 2 hrs at room temperature, 40 psi.
  • the amino compound was recovered by filtration and evaporation of the solvent.
  • a mixture of phenanthrene-2,7-dicarboxylic acid, three equivalents of HBTU, and six equivalents of NMM in dry DMF were stirred under nitrogen at room temperature for 30 minutes. Three equivalents of the amine in DMF were added and the reaction stirred for

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Abstract

Cette invention a trait à des composés de liaison à l'ADN, qui sont des dimères de la nétropsine ou d'analogues de la nétropsine, et qui sont liés par un groupe lieur polycyclique. Ces composés de liaison sont de structure B-L-B', structure dans laquelle B et B' sont, de façon indépendante, de structure (I), structure dans laquelle A représente un amidinyl (-C(NH2)=NH) ou -CH2NRR', B et B' représentent, de façon indépendante, un hydrogène ou un alkyle de faible poids moléculaire ou, ensemble, forment un noyau hétérocyclique à 5 ou 7 chaînons dont les atomes de noyau sont choisis dans le groupe constitué par du carbone, de l'azote, de l'oxygène et du soufre et comprennent au moins 3 atomes de carbone, la valeur de n étant comprise entre 1 et 6. L représente un système fusionné à noyau polycyclique contenant au moins un noyau aromatique et B et B' sont liés aux différents noyaux du système à noyau, de sorte que le chemin le plus court entre B et B' comporte une séquence d'au moins trois liaisons à l'intérieur du système à noyau lorsque les groupes sont attachés aux noyaux adjacents (fusionné) ou au moins cinq liaisons à l'intérieur du système à noyau lorsque les groupes sont attachés à des noyaux non adjacents.
PCT/US2000/025325 1999-09-17 2000-09-15 Molecules dimeres de liaison a l'adn liees de façon covalente WO2001019792A1 (fr)

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Cited By (8)

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US6716866B2 (en) 2001-06-13 2004-04-06 Genesoft Pharmaceuticals, Inc. Aryl-benzimidazole compounds having antiinfective activity
US6777425B2 (en) 2001-06-13 2004-08-17 Genesoft Pharmaceuticals, Inc. Isoquinoline compounds having antiinfective activity
US6825228B2 (en) 2001-06-13 2004-11-30 Genesoft Pharmaceuticals, Inc. Benzothiophene compounds having antiinfective activity
US7129214B2 (en) 2002-12-10 2006-10-31 Oscient Pharmaceuticals Corporation Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif
US7265129B2 (en) 2002-10-25 2007-09-04 Genesoft Pharmaceuticals, Inc. Anti-infective biaryl compounds
US7498349B2 (en) 2002-08-02 2009-03-03 Genesoft Pharmaceuticals, Inc. Biaryl compounds having anti-infective activity
US7700765B2 (en) 2001-12-24 2010-04-20 University Of Strathclyde DNA minor groove binding compounds
US8012967B2 (en) 2006-09-30 2011-09-06 University Of Strathclyde Minor groove binders

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6716866B2 (en) 2001-06-13 2004-04-06 Genesoft Pharmaceuticals, Inc. Aryl-benzimidazole compounds having antiinfective activity
US6777425B2 (en) 2001-06-13 2004-08-17 Genesoft Pharmaceuticals, Inc. Isoquinoline compounds having antiinfective activity
US6825228B2 (en) 2001-06-13 2004-11-30 Genesoft Pharmaceuticals, Inc. Benzothiophene compounds having antiinfective activity
US7329765B2 (en) 2001-06-13 2008-02-12 Genesoft Pharmaceuticals, Inc. Benzothiophene compounds having antiinfective activity
US7700765B2 (en) 2001-12-24 2010-04-20 University Of Strathclyde DNA minor groove binding compounds
US7498349B2 (en) 2002-08-02 2009-03-03 Genesoft Pharmaceuticals, Inc. Biaryl compounds having anti-infective activity
US7265129B2 (en) 2002-10-25 2007-09-04 Genesoft Pharmaceuticals, Inc. Anti-infective biaryl compounds
US7129214B2 (en) 2002-12-10 2006-10-31 Oscient Pharmaceuticals Corporation Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif
US7642245B2 (en) 2002-12-10 2010-01-05 Oscient Pharmaceuticals Corporation Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif
US8012967B2 (en) 2006-09-30 2011-09-06 University Of Strathclyde Minor groove binders

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