Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor
نویسندگان
چکیده
Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.
منابع مشابه
Antitubercular Activity of Pyrrole Schiff bases and Computational Study of M. Tuberculosis InhA
Pursuing our search program for new antitubercular drugs we decided to explore the potentiality of pyrrole moiety by molecular modeling and synthesizing novel pyrrole Schiff bases analogues of phthivazid. Enoyl-acyl carrier protein reductase catalyzes the last rate-limiting step in the elongation cycle of the fatty-acid biosynthesis pathway and has been validated as a potential antitubercular d...
متن کاملA slow, tight binding inhibitor of InhA, the enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis.
InhA, the enoyl-ACP reductase in Mycobacterium tuberculosis is an attractive target for the development of novel drugs against tuberculosis, a disease that kills more than two million people each year. InhA is the target of the current first line drug isoniazid for the treatment of tuberculosis infections. Compounds that directly target InhA and do not require activation by the mycobacterial ca...
متن کاملA slow, tight-binding inhibitor of InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis
InhA, the enoyl-ACP reductase in Mycobacterium tuberculosis is an attractive target for the development of novel drugs against tuberculosis, a disease that kills more than two million people each year. InhA is the target of the current first line drug isoniazid (INH) for the treatment of tuberculosis infections. Compounds that directly target InhA and do not require activation by the mycobacter...
متن کاملDevelopment of 1,2,4-triazole-5-thione derivatives as potential inhibitors of enoyl acyl carrier protein reductase (InhA) in tuberculosis.
Tuberculosis (TB) ranks second, next to AIDS making it most formidable disease if the present age. One of the crucial enzymes involved in cell wall synthesis of Mycobacterium tuberculosis, InhA (enoyl acyl carrier protein reductase) has been authenticated as an effective target for anti-mycobacterial drug development. In the current work, we have developed novel derivatives of 1,2,4-triazole-5-...
متن کاملDevelopment of 1,2,4-triazole-5-thione derivatives as potential inhibitors of enoyl acyl carrier protein reductase (InhA) in tuberculosis.
Tuberculosis (TB) ranks second, next to AIDS making it most formidable disease if the present age. One of the crucial enzymes involved in cell wall synthesis of Mycobacterium tuberculosis, InhA (enoyl acyl carrier protein reductase) has been authenticated as an effective target for anti-mycobacterial drug development. In the current work, we have developed novel derivatives of 1,2,4-triazole-5-...
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