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We herein report a new category of 5-substituted pyrimidine nucleosides as potent inhibitors of mycobacteria. A series of 5-alkynyl derivatives of 2'-deoxyuridine (1-8), 2'-deoxycytidine (9-14), uridine (15-17), and 2'-O-methyluridine (18, 19) were synthesized and evaluated for their antimycobacterial activity in vitro. 5-Decynyl, 5-dodecynyl, and 5-tetradecynyl derivatives showed the highest antimycobacterial potency against M. bovis and M. avium, with the 2'-deoxyribose derivatives being more effective than the ribose analogues. Nucleosides bearing short alkynyl side chains 5-ethynyl, 5-propynyl, 5-pentynyl, and 5-heptynyl were mostly not inhibitory. Incorporation of a phenylethynyl function at the 5-position diminished the antimicrobial effect. Furthermore, related bicyclic analogues (20-24) were devoid of antimycobacterial activity, indicating that an acyclic side chain at the C-5 position of the pyrimidine ring is essential for potent activity. Compounds 1-17 were synthesized by the Pd-catalyzed coupling reactions of respective alkynes with 5-iodo derivatives of 2'-deoxyuridine, 2'-deoxycytidine, and uridine. Intramolecular cyclization of 1 and 3-6 in the presence of Cu afforded the corresponding bicyclic compounds 20-24. The investigated nucleosides are recognized here for the first time to be potent inhibitors of mycobacteria. This class of compounds could be of interest for lead optimization as antimycobacterial agents.

The resurgence of tuberculosis and the emergence of multiple-drug-resistant strains of Mycobacteria necessitate the search for new classes of antimycobacterial agents. We synthesized a series of 1-beta-D-2'-arabinofuranosyl and 1-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl) pyrimidine nucleosides possessing diverse sets of alkynyl, alkenyl, alkyl, and halo substituents at the C-5 position of the uracil and investigated their effect on activity against M. tuberculosis, M. bovis, and M. avium. Among these molecules, 5-alkynyl-substituted derivatives emerged as potent inhibitors of M. bovis, M. tuberculosis, and M. avium. Nucleosides 1-beta-D-2'-arabinofuranosyl-5-dodecynyluracil (5), 1-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl)-5-dodecynyluracil (24), and 1-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl)-5-tetradecynyluracil (25) showed the highest antimycobacterial potency against M. bovis and M. tuberculosis. The MIC90 exhibited by compounds 5, 24, and 25 was similar or close to that of the reference drug rifampicin. The most active compounds 5, 24, and 25 were also found to retain sensitivity against a rifampicin-resistant strain of M. tuberculosis H37Rv at similar concentrations. Some of these analogs also revealed in vitro antimicrobial effect against several other gram-positive pathogens.

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.

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