Inhibition of Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium avium by novel dideoxy nucleosides.

Dinesh Rai, Monika Johar, Naveen C Srivastav, Tracey Manning, B Agrawal, Dennis Y Kunimoto, Rakesh Kumar

Index: J. Med. Chem. 50 , 4766-74, (2007)

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Abstract

The prevalence of tuberculosis (TB) and mutidrug-resistant tuberculosis (MDR-TB) has been increasing, leading to serious infections, high mortality, and a global health threat. Here, we report the identification of a novel class of dideoxy nucleosides as potent and selective inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis, and drug-resistant Mycobacterium tuberculosis. A series of 5-acetylenic derivatives of 2',3'-dideoxyuridine (3-8) and 3'-fluoro-2',3'-dideoxyuridine (22-27) were synthesized and tested for their antimycobacterial activity against M. bovis, M. tuberculosis, and M. avium. 2',3'-Dideoxyuridine possessing 5-decynyl, 5-dodecynyl, 5-tridecynyl, and 5-tetradecynyl substituents (4-7) exhibited the highest antimycobacterial activity against all three mycobacteria. In contrast, in the 3'-fluoro-2',3'-dideoxyuridine series, a 5-tetradecynyl analogue (26) displayed the most potent activity against these mycobacteria. Among other derivatives, 5-bromo-2',3'-dideoxycytidine (11), 5-methyl-2',3'-dideoxycytidine (12), and 5-chloro-4-thio-2',3'-dideoxyuridine (19) exhibited modest inhibition of M. bovis and M. tuberculosis. In the series of dideoxy derivatives of adenosine, guanosine, and purines, 2-amino-6-mercaptoethyl-9-(2,3-dideoxy-beta-d-glyceropentofuranosyl)purine (32) and 2-amino-4-fluoro-7-(2,3-dideoxy-beta-d-glyceropentofuranosyl)pyrrolo[2,3-d]pyrimidine (35) were the most efficacious against M. bovis and M. tuberculosis, and M. avium, respectively.