Hydrazone compositions for treatment of infections with drug resistant mycobacteria have been developed[1] for the treatment of infections with mycobacteria resistant to at least one of the following drugs: rifampicin, isoniazid, pyrazinamide, or ethambutol. The hydrazone compds. have high activity against drug resistant mycobacteria, in particular, Mycobacterium tuberculosis (Mtb) complex strains resistant to isoniazid and rifampicin (multidrug-resistant Mtb, MDR-Mtb), or MDR-Mtb strains further being resistant to one of the injectable aminoglycosides amikacin, kanamycin or capreomycin, and to fluoroquinolones (extremely drug-resistant XDR-Mtb). The growth inhibitory activity of compd. PH22-33 on Mtb-infected macrophages was demonstrated in vitro.
Rib-X Pharmaceuticals, Inc., USA has applied for a patent application[2] for preparation of pyrimidinyl ureas useful in treatment and prevention of microbial infections caused by, e.g., linezolid-resistant organisms. Same company has also filed a patent application[3] for Preparation of substituted pyrrolopyrimidinones, triazolopyrimidinones and triazafluorenones as antimicrobial compounds which can be used for infections caused by linezolid resistant organisms.
Vinnik et al. have claimed in a Russian patent application[4] β-carboline derivatives which were found to be the most active in various in vitro (including resistant Mycobacteria) and vivo (mice) assays compared to that of the std. drug isoniazid, while displaying low toxicity at therapeutical doses.
Snyder et al.[5] of Boston University have filed a patent application for preparation of tetrahydropyranonaphthyridine derivatives for use as tuberculostatics. Compound of formula III (see patent application) demonstrated aa MIC M. tuberculosis activity of 3.8 mM and an IC50 value (vero cell) of >50 mg/mL.
Imidazo[2,1-b][1,3]oxazine derivatives as antimycobacterials have been claimed by Barry, Clifton et al.[6] compound of Formula-III(see patent document) exhibited a MIC value of <0.039 mM and a MAC value of 1.5 mM.
Antimycobacterial activity of novel N-(substituted)-2-isonicotinoylhydrazinocarbothioamide endowed with high activity towards isoniazid resistant tuberculosis has been claimed by Sriram, Dharmarajan et al.[7] Among the synthesized compds., 2-isonicotinoyl-N-[2-(trifluoromethyl)phenyl]hydrazinecarbothioamide (4i) was found to be the most potent compd. with min. inhibitory concn. of 0.58 mM against M. tuberculosis H37Rv and INH resistant M. tuberculosis. When compared to INH, 4i was found to be 1.24 and 157 times more active against M. tuberculosis H37Rv and INH resistant M. tuberculosis resp., with a selectivity index of >218.
Pleuromutilin selectively inhibits bacterial protein synthesis in prokaryotic ribosomes, and has been found to exhibit promising levels of antibacterial activity ([mu]M range) against a number of bacterial cell lines. However, pleuromutilin suffers from insufficient in vivo potency due to rapid metabolic degradation by cytochrome P-450. Several semi-synthetic analogs of pleuromutilin have been identified and developed for use as anti-bacterial and anti-tubercular agents. Through systematic chemical modifications of pleuromutilin, scientists at GlaxoSmithKline created the pleuromutilin relative retapamulin. Retapamulin is a semi-synthetic derivative of pleuromutilin. It is significant because it targets the 50S subunit of the bacterial ribosome, yet is unaffected by resistance to other 50S-targeting classes of antibiotics such as the erythromycins. Another pleuromutilin relative developed is tiamulin. A method of synthesizing a pleuromutilin analog has been claimed in a patent application[8] filed by UNIV. PRINCETON [US].
Council of Scientific and Industrial Research (India) has filed a patent application[9] in respect of quinolylpiperazino substituted thiolactone compounds useful as potential anti-tubercular agents against Mycobacterium tuberculosis H37Rv, and drug-resistant Mycobacterium tuberculosis, and a process for the preparation thereof. In vivo efficacy of compounds in murine model of M. tuberculosis H37Rv infection, their cytotoxicity etc. are discussed in the patent application.
Otsuka Pharma Co Ltd., Japan, has filed a patent application[10] claiming 2,3-dihydro-6-nitroimidazo[2,1-b]oxazole compound which, according to the inventors, has an excellent bactericidal action against mycobacterium tuberculosis, multidrug resistant tuberculosis and atypical acid-fast bacteria.
California Department of Public Health Tuberculosis Control Branch's Multidrug-Resistant Tuberculosis (MDR-TB) Service reviewed cases in which a new antibiotic linezolid was used for the MDR-TB treatment[11]. Although several small case series suggest that linezolid is poorly tolerated because of the side effects of anemia/thrombocytopenia and peripheral neuropathy, it was observed and concluded by these researchers that linezolid was well tolerated, had low rates of discontinuation, and may have efficacy in the treatment of MDR-TB. Side effects occurred in 9 (out of 30) patients, including peripheral and optic neuropathy, anemia/thrombocytopenia, rash, and diarrhea. However, only 3 patients stopped linezolid treatment because of side effects. 22 (73%) of 30 patients had successfully completed treatment. Five continued to receive treatment. There were no deaths. Three patients had a poor outcome, including 2 defaults and 1 treatment failure. Anger et al.[12] have concluded that majority of MDR TB patients on linezolid had favorable treatment outcomes, although treatment was complicated by adverse events that required extensive clin. management.
Substituted quinoline derivatives are disclosed in WO 2004/011436. The use of these substituted quinoline derivatives for the preparation of a medicament for the treatment of a warm-blooded mammal infected with a drug resistant Mycobacterium strain has been disclosed in another patent application filed by JANSSEN PHARMACEUTICA NV [BE][13]. These compounds are reported to be highly active against drug resistant Mycobacterium strains. There is no evidence of cross-resistance with antituberculosis drugs : isoniazid, rifampin, streptomycin, ethambutol, fluoroquinolones and pyrazinamide. Combination of these substituted quinoline derivatives with one or more other antimycobacterial agents is also discussed in the patent.
(6,7-Dihydro-2-nitro-5H-imidazol[2,1-b] [1,3]oxazin-6-yl) amide compounds and their pharmaceutically acceptable salts are disclosed in a patent application[14] filed by SHANGHAI SUN SAIL PHARMACEUTICAL SCIENCE & TECHNOLOGY CO LTD [CN]. The application also discloses use of claimed compounds in medicament for treatment of infectious diseases caused by multi-drug resistant Mycobacterium tuberculosis.
Polymedix Inc. has filed a patent application[15] for novel compounds and compositions thereof, useful for the treatment of MDR/XDR strains of M. Tuberculosis, which work in shorter duration of time and do not interfere with existing HIV therapies. Claimed compounds can also be incorporated into compositions such as polishes, paints, sprays, or detergents formulated for application to a surface to inhibit the growth of a Mycobacterium species thereon. These surfaces include countertops, desks, chairs, laboratory benches, tables, floors, bed stands, tools, equipment, doorknobs, windows etc. The compounds can also be incorporated in soaps and hand lotions.
Novel
isocyanurate derivatives (1,3,5-triazine-2,4,6-triones) have been disclosed in
RU2424235 (2011-07-20) having high antituberculosis activity, even towards
multi-drug resistant mycobacteria strains, high species specificity and low
toxicity.
Panacea
Biotech Ltd. has filed a patent application [US2011245258] claiming novel phenyl
oxazolidinone compounds useful as antimicrobial agents, effective against a
number of aerobic and anaerobic, Gram positive, Gram negative pathogens such as
Multi-drug Resistant species of Staphylococcus, Streptococcus, Enterococcus,
Bacterioides, Clostridia, H. influenza, Moraxella, Mycobacterium tuberculosis
as well as Linezolid resistant species of Staphylococcus and Enterococcus.
A
patent application [US2011160193, 2011-06-30] has been filed by Leibniz Institute
for Natural Product Research and Infection Biology E V [DE] claiming New
Benzothiazinone Derivatives and their use as antibacterial agents with activity
against mycobacteria as potential new tuberculosis drugs to overcome problems
concerning resistance and drug intolerance.
The compounds of the invention are non-mutagenic at 5 mg/ml in the SOS
chromotest and demonstrate a high level of selectivity for mycobacteria only,
which reduces the potential for adverse side effects dramatically. The compounds are in vivo therapeutically
active in the murine model of tuberculosis infection superior compared to the
main antituberculosis drug isoniazid used as a positive control. The invented
compounds, particularly compound no 2 [2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-8-nitro-6-(trifluoro-methyl)-1,3-benzothiazin-4-one]
is non toxic after per os administration of doses ranging up to 2000 mg/kg was
the compound was well endured by animals in the first and 24 next coming hours
after introducing. During 7 days of investigations the compound 2 did not cause
changes in general state and behavior of the mice, it did not affect motor and
reflex activity, active and calm cycles, grooming, food consumption, there were
no cases of animal death. LD50 for compound 2 is >2000 mg/kg.
Key Words: multidrug resistant tuberculosis, extensively drug
resistant tuberculosis, multidrug resistant TB, extensively drug resistant TB, MDR TB, XDR TB,
mycobacterium tuberculosis, mycobacterial infection, literature, research,
publications, patents, caprazamycin derivatives, CPZEN 45
Inventors from Microbial Chemistry
Research Foundation, Japan and Infectious Disease Research Institute USA have
found that among caprazamycin derivatives disclosed by them in WO2004/067544,
the compound “CPZEN 45” (chemical structure disclosed in patent CA2739505) had an excellent
pharmacological efficacy against multi-drug-resistant and extensively drug
resistant tuberculosis bacteria. A
combination anti-TB agent comprising CPZEN 45 and rifampicin (RFP) &
isonicotinic acid hydrazide (INH) against tuberculosis bacteria having
susceptibility to existing anti-tuberculous agents is reported to be effective.
[1] Hydrazone compositions for treatment of infections with drug resistant mycobacteria. Seydel, Joachim et al., Christian-Albrechts-Universitaet zu Kiel, Germany. PCT Int. Appl. WO 2011047814 A1 28 Apr 2011, 32pp.
[2] Preparation of pyrimidinyl ureas as antimicrobial compounds. Duffy, Erin M.; Bhattacharjee, Ashoke (Rib-X Pharmaceuticals, Inc., USA). PCT Int. Appl. WO 2011047323 A2 21 Apr 2011, 200pp.
[3] PCT Int. Appl. WO 2011047319 A2 21 Apr 2011, 353 pp.
[4] Vinnik, A. A.; Fedichev, P. O. (Nesteruk, Vladimir Viktorovich; Kholin, Maksim Nikolaevich, Russia). Russ. RU 2419431 C1 27 May 2011, 19pp. (Russian).
[5] U.S. Pat. Appl. Publ. US 20110003776 A1 6 Jan 2011, 49pp.
[6] WO 2011087995 A2 21 Jul 2011, 90pp.
[7] Sriram, Dharmarajan et al., (Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India). Biomedicine & Pharmacotherapy, 63(1), 36-39 (English) 2009.
[8] ANTIMICROBIAL AND ANTITUBERCULAR COMPOUNDS. US2012010281 (A1) ― 2012-01-12.
[9] QUINOLYLPIPERAZINO SUBSTITUTED THIOLACTONE COMPOUNDS AND PROCESS FOR THE PREPARATION THEREOF WO2011138666 (A1) ― 2011-11-10.
[10]2,3-Dihydro-6-nitroimidazo[2,1-b]oxazoles US2006094767 2006-05-04.
[11] Linezolid in the treatment of multidrug-resistant tuberculosis. Schecter et al., Tuberculosis Control Branch, Division of Communicable Disease Control, California Department of Public Health, Center for Infectious Disease, Richmond, USA). Clinical Infectious Diseases, Volume Date 2010, 50(1), 49-55 (English) 2009 University of Chicago Press.
[12] Linezolid use for treatment of multidrug-resistant and extensively drug-resistant tuberculosis, New York City, 2000-06. Anger et al., Bureau of Tuberculosis Control, New York City Department of Health and Mental Hygiene, New York, NY 10007, USA). Journal of Antimicrobial Chemotherapy, 65(4), 775-783 (English) 2010 Oxford University Press.
[13] WO2005117875 (A1)
[14] WO2011134296 (A1)
[15]Antimicrobial molecules for treating multi-drug resistant and extensively drug resistant strains of mycobacterium WO2010068700 (A1)
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