WO2001072304A1 - Nouvelle composition antimicrobienne et procede de production de celle-ci - Google Patents

Nouvelle composition antimicrobienne et procede de production de celle-ci Download PDF

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Publication number
WO2001072304A1
WO2001072304A1 PCT/IN2000/000031 IN0000031W WO0172304A1 WO 2001072304 A1 WO2001072304 A1 WO 2001072304A1 IN 0000031 W IN0000031 W IN 0000031W WO 0172304 A1 WO0172304 A1 WO 0172304A1
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WO
WIPO (PCT)
Prior art keywords
composition
aπeether
quinolone
resistance
concentration
Prior art date
Application number
PCT/IN2000/000031
Other languages
English (en)
Inventor
Suman Preet Singh Khanuja
Suchi Srivastava
Ranganathan Tiruppadiripuliyur Santha Kumar
Ajit Kumar Shasany
Dhram Chand Jain
Mahendra Pandurang Darokar
Dharmendra Saikia
Sushil Kumar
Original Assignee
Council Of Scientific And Industrial Research
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Council Of Scientific And Industrial Research filed Critical Council Of Scientific And Industrial Research
Priority to PCT/IN2000/000031 priority Critical patent/WO2001072304A1/fr
Priority to RU2002128749/15A priority patent/RU2241457C2/ru
Priority to AU2000255627A priority patent/AU2000255627A1/en
Priority to CNB008194637A priority patent/CN1210030C/zh
Priority to BR0017199-9A priority patent/BR0017199A/pt
Publication of WO2001072304A1 publication Critical patent/WO2001072304A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention is related to the development of strategic and novel anti-microbial composition comprising ⁇ arteether.
  • quinolones and similar drugs which can be used as an advanced generation drug composition against infections and simultaneously to counter the resistance development in bacteria by an in built mechanism of action to eliminate resistant cells
  • the applicants used a unique composition of known compounds with different and specific counter modes of actions to control the resistance menace in bacteria
  • This invention is novel in terms of the l ⁇ ea of combining two known molecules for not oniv controlling / killing bacteria out also preventing the appearance of resistant strains ⁇ ue to counter-actions wherein, one molecule kills bacte ⁇ a resistant to other and vice versa and finally leading to prevention of resistance ⁇ evelopment itself
  • This phenomenon of sensitivity of cells to the one upon resistance ⁇ evelopment against other and vice versa is genetically governe ⁇ , and hence is a self sustaining process once the nght kind of anti-microbial molecules have been identified through study of specific mutations, which was achieved in the invention
  • the compounds ⁇ ana ⁇ a ⁇ eethers were synthesized from dihydroa ⁇ emisinin bv ethenfication with ethanol These earlier were developed as anti-malarial drugs in India by Central Institute of Medicinal and Aromatic Plants (CIMAP), Lucknow and Central Drug Research Institute (CDRI), Lucknow, India after phase III clinical trial Absolute stereochemistry of a ⁇ eethers at C-12 were also determined and found that it is 2-3 times more potent than a ⁇ emisi n
  • CIMAP Central Institute of Medicinal and Aromatic Plants
  • CDRI Central Drug Research Institute
  • Lucknow India after phase III clinical trial Absolute stereochemistry of a ⁇ eethers at C-12 were also determined and found that it is 2-3 times more potent than a ⁇ emisi n
  • US Patent Application No 09/176,204 the Applicants had demonstrated that the compound ⁇ a ⁇ eether can specifically kill ce ⁇ ain ⁇ rug resistant bacte ⁇ a. hence capable of being used as an antibiotic
  • DNA gyrase enzyme is essential for being involved in the replication of DNA ana hence cell division This enzyme transiently breaks the DNA strands and introduces negative superhelical turns in an ATP-dependent process
  • the E.coli DNA gyrase enzvme is a tetramer with two subumts A and B
  • the subunit A is nahdixic acid sensitive but ce ⁇ ain mutat ⁇ on(s) in this subunit makes the bacteria resistant to nahdixic acid
  • the Applicant had shown that normal wild type bacte ⁇ a are not killed by ⁇ arteether but the mutants resistant to nalidixic acid and other fluoroquinolones (with modified gyrase) are highly sensitive to ⁇ a ⁇ eether. whereas the Dactena with normal A subunit are killed by nahdixic acid
  • the mam ooiect of the invention is to deveioD a nov ei anu-microDial comDOSition comprising a arteether quinolones ana similar ⁇ rugs
  • Another ooiect is to Drovi ⁇ e a nov el anti-microoial comDOSition useful in countering the ⁇ eveioDment of resistance itself
  • anotner ooject is to deveioD an anti-microoial composition capable of killing bacte ⁇ a resistant to conventional ⁇ rugs ana Drevent proliferation of resistant or mutant strains oi bacte ⁇ a
  • This inv ention is related to the development of strategic and novel composition
  • ⁇ a ⁇ eether, quinolones and similar drugs which can be use ⁇ as advance ⁇ generation drug(s) to counter the resistance development itself while, having a potential to be use ⁇ treating infectious diseases pa ⁇ iculariy m those cases where drug resistant strains are known to appear very frequently
  • the uniqueness and most useful feature is that because tne composition is a comDination of ⁇ a ⁇ eether ana quinolone arugs, the spontaneous mutants ansmg resistant to Quinoiones or its ⁇ e ⁇ vatives will be killed by a ⁇ eetner ana at the same time any ⁇ a ⁇ eetner resistant strains become highlv sensitiv e to nahdixic aci ⁇ and hence eliminated bv it through the combination approacn
  • the new composition innibits the resistance ⁇ evelopment due to mutation in the gyr 4 gene of bacteria in which one comDonent is
  • Drovi ⁇ es fou ⁇ h generation anti-microDial composition for inhibitin ⁇ ⁇ rus resistance sai ⁇ composition compnsina two components vnerein one component is ⁇ -a ⁇ eether and the other component is a drug selected from quinolones, their derivatives or anv other similar compound against which the resistance develops
  • tne quinolone compound used is but not limited to nahdixic acid
  • the ratio of ⁇ -a ⁇ eether and quinolones in the composition is about 8 1 to 20 1
  • the quinolone derivatives are selected from the group of fluoroquinolones comprising Ciprofloxacin, Norfioxacm, Levofloxacm, Sparfloxacm Oxfloxacin and Lomefloxacm
  • the concentration of nahdixic acid is at least 50 ⁇ g/ml
  • concentration of ⁇ -arteether in the composition is about 2mg to 500 mg/ml
  • the concentration of ⁇ -arteether in the composition is about 400 ⁇ g/ml
  • concentration of quinolone drugs in the composition is about 0 5 mg to 500 mg
  • the neutralized sterile vegetable oil or a similar solvent is used as a base in an amount of at least 1 ml
  • the said components are selected from DNA gyrase inhibitors with counter-action properties against resistant mutants of each other which include ⁇ -a ⁇ eether and quinolone derivatives
  • the said components are selected from DNA gyrase inhibitors with counter-action prope ⁇ ies against resistant mutants of the first and a second components I e to ⁇ -a ⁇ eether and quinolones. its denvatives or similar compounds
  • the composition has inhibitor activity on DN A replication in prokarvotes and thus can be used as a potential fou ⁇ h generation drug composition
  • the second component used mav be a first generation quinolone drug selected from but not limited to nahdixic acid and oxa nic acid
  • the second component used may be a second generation quinolone drug selected from but not limited to Ciprofloxacin Norfioxacm, Levofloxacm, Sparfloxacm and Oxfloxacin
  • the second component used may be a third generation quinolone drug selected from but not limited to Lomefloxacm tosufloxacin, temafloxacin
  • the said composition can be used in place of first, second and third generation drugs against resistant as well as sensitive infections
  • the said composition can be used to prevent the development of resistance against first, second and third generation ⁇ rugs
  • the invention provides a method for the development of fou ⁇ h generation antimicrobial composition for inhibiting drug resistance, said method comprising the steps of mixing ⁇ -a ⁇ eether and a drug selected from quinolones, their denvatives or any other similar compound against which bacte ⁇ a develop resistance
  • the ratio of ⁇ -a ⁇ eether and qumolones in the composition is about 8 1 to 20 1
  • the quinolone compound used is but not limited to nahdixic acid
  • the quinolone derivatives are selected from the group of fluoroquinolones comprising Ciprofloxacin. Norfloxacin. Levofloxacm. Sparfloxacin. Oxfloxacm and Lomefloxacm.
  • the concentration of nalidixic acid is at least 50 ⁇ g/ml.
  • the concentration of ⁇ -a ⁇ eether in the composition is about 2 ⁇ g to 500 ⁇ g/ml.
  • the concentration of ⁇ -a ⁇ eether in the composition is about 400 ⁇ g/ml.
  • concentration of quinolone drugs in the composition is about 0.5 mg to 500 mg.
  • neutralized sterile vegetable oil or a similar solvent is used as a base in an amount of at least 1 ml.
  • the applicants have developed a novel composition or drug system to successful check the resistance development as a result of the mutants arising from nahdixic acid application (or any future resistance that will develop from ⁇ a ⁇ eether if the compounds are applied individually) by treating the bactenal infection with the composition.
  • those compounds are already tested for their safe level of application in human, it is possible to develop and directly use the combination drug to fight infections and simultaneously check resistance menace.
  • the composition of this invention can be used to treat bactenai infections, pa ⁇ icularlv the cases where the emergence of drug resistance is known to have high incidence level
  • the said composition/composition can be emploved for prevention of resistance development through random mutations occurnng in bacte ⁇ a against antibiotics V a ⁇ ous classes of quinolone drugs thus can be administered along with ⁇ -a ⁇ eether in form of injection DV suspending the compound in the neutralised vegetable oil
  • Quinolone drugs in the composition can be administered in variable doses ranging from 0 5 mg to 500 mg
  • composition 1 ⁇ -a ⁇ eether (2mg to 500 mg)
  • Quinolone drugs comprise of Nahdixic acid, Ciprofloxacin Norfioxacm. Levofloxacm Sparfloxacm, Oxfloxacm and Lomefloxacm etc
  • the invention provides a new composition of antimicrobial compounds inhibiting the resistance development due to mutation in the gyr A gene of bacte ⁇ a, in which one component is ⁇ -a ⁇ eether and the other may be nahdixic acid or fluoroquinolones (comprising of Ciprofloxacin, Norfioxacm, Levofloxacm Sparfloxacm, Oxfloxacm and Lomefloxacm etc ) or compounds of similar nature against which the resistance develops
  • the components of the novel composition are but not limited to ⁇ -a ⁇ eether and nalidixic acid
  • the components of the compositions could be DNA gyrase inhibitors with counter-action prope ⁇ ies against mutants developing resistance to any one of the two drugs of the combination, which include ⁇ -arteether and quinolone derivatives
  • the invention provides a new composition wherein the components of the compositions could be ⁇ -a ⁇ eether (2mg to 500 mg), quinolone drugs (0 5 mg to 500 mg) and neutralized sterile vegetable oil at least 1ml
  • figure 1 represents the poison disk assay of the composition of the invention against the mutants in E.coli
  • figure 1 represents the poison disk assay of the composition of the invention against the mutants in E.coli
  • Example 1 Monito ⁇ ng emergence of NaT mutants
  • the applicants first determined the frequencv of spontaneous mutations in the bacteria Escherchia coli (Kumar, S 1976 Journal of Bacteriology, 125 545-555 ) and Mycobactenum smegmatis (Snapper, S B , Melton, R E . Mustafa, S , Kieser, T and Jacobs.
  • Table 1 Frequency of spontaneous resistance developed against Nalidixic acid.
  • Escherchia coli ( " Wild tvpe ) 7 1 X 10 '
  • Table 2 Frequency of spontaneous resistance developed against ⁇ -arteether.
  • Example 3 Counter-action studv of na dixic acid and ⁇ -a ⁇ eether in combination against resistant mutants of each other
  • Table 3 Sensitivity of E. coli strains to nalidixic acid and ⁇ arteether.
  • Escherchia coli cultures which were resistant to nalidixic acid at varying degrees (concentrations). Based on the minimal inhibitory concentration of nalidixic acid, Escherchia coli mutants were grouped as highly sensitive (MIC less than or equal to 10 ⁇ g ml), resistant (MIC 10 to 200 ⁇ g/ml), highly resistant sensitive
  • strains were then tested for their sensitivity against ⁇ -a ⁇ eether by estimating their growth (Absorbance at 620 nano meter wavelength of light) in presence of increasing concentrations of ⁇ -a ⁇ eether.
  • the absorbance data was conve ⁇ ed to percent growth by considering the absorbance in control as 100%.
  • the growth was then quantified as follows : 1.) greater than 80% growth : the mutant is highly resistant to ⁇ -arteether; 2.) 20 to 80% growth : the mutant is moderately resistant to ⁇ -a ⁇ eether; 3.) less than 20% growth : the mutant is sensitive to ⁇ -arteether.
  • the experimental data demonstrates that the Escherchia coli mutants that are highly resistant to nalidixic acid are on the other hand highly sensitive to ⁇ -a ⁇ eether. In other words Escherchia coli mutants most resistant to nalidixic acid are most efficiently killed by ⁇ -a ⁇ eether (Table 4) and vice versa.
  • Example 5 Evaluating the development of resistant strains against the combination by co-culturing of counter resistant strains.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne la mise au point d'une nouvelle composition stratégique renfermant de l'arté-éther α et de l'acide nalidixique ou des médicaments à base de quinolone. Cette composition peut servir de médicament de génération avancée contre le développement d'une résistance et possède un potentiel utile dans le traitement de maladies infectieuses et pour inhiber une résistance due à une mutation du gène gyr A de bactéries, particulièrement dans les cas où des souches résistantes aux médicaments apparaissent très fréquemment.
PCT/IN2000/000031 2000-03-28 2000-03-28 Nouvelle composition antimicrobienne et procede de production de celle-ci WO2001072304A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/IN2000/000031 WO2001072304A1 (fr) 2000-03-28 2000-03-28 Nouvelle composition antimicrobienne et procede de production de celle-ci
RU2002128749/15A RU2241457C2 (ru) 2000-03-28 2000-03-28 Противомикробная композиция и способ ее получения
AU2000255627A AU2000255627A1 (en) 2000-03-28 2000-03-28 A novel anti-microbial composition and method for producing the same
CNB008194637A CN1210030C (zh) 2000-03-28 2000-03-28 一种新的抗微生物组合物和其制备方法
BR0017199-9A BR0017199A (pt) 2000-03-28 2000-03-28 Composição antimicrobiana e um processo para produção da mesma

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2000/000031 WO2001072304A1 (fr) 2000-03-28 2000-03-28 Nouvelle composition antimicrobienne et procede de production de celle-ci

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WO2001072304A1 true WO2001072304A1 (fr) 2001-10-04

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CN (1) CN1210030C (fr)
AU (1) AU2000255627A1 (fr)
BR (1) BR0017199A (fr)
WO (1) WO2001072304A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110339189B (zh) * 2019-08-23 2023-05-12 西南大学 双氢青蒿素与喹诺酮偶联物在制备抗疟药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0290959A2 (fr) * 1987-05-08 1988-11-17 Hoechst Aktiengesellschaft Mélange de médicaments pour la prophylaxie et thérapie de la malaria
EP0362810A1 (fr) * 1988-10-07 1990-04-11 Hoechst Aktiengesellschaft Compositions contre la malaria et méthodes de traitement utilisant la quinidine, artémisinine ou leurs dérivés
EP0464233A1 (fr) * 1990-07-02 1992-01-08 Hoechst Aktiengesellschaft Mélanges pharmaceutiques contre la malaria

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0290959A2 (fr) * 1987-05-08 1988-11-17 Hoechst Aktiengesellschaft Mélange de médicaments pour la prophylaxie et thérapie de la malaria
EP0362810A1 (fr) * 1988-10-07 1990-04-11 Hoechst Aktiengesellschaft Compositions contre la malaria et méthodes de traitement utilisant la quinidine, artémisinine ou leurs dérivés
EP0464233A1 (fr) * 1990-07-02 1992-01-08 Hoechst Aktiengesellschaft Mélanges pharmaceutiques contre la malaria

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CN1452487A (zh) 2003-10-29
AU2000255627A1 (en) 2001-10-08
BR0017199A (pt) 2003-04-08
CN1210030C (zh) 2005-07-13

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