Growth Inhibition of Mycobacterium bovis, Mycobacterium tuberculosis and Mycobacterium avium In Vitro:  Effect of 1-β-d-2‘-Arabinofuranosyl and 1-(2‘-Deoxy-2‘-fluoro-β-d-2‘-ribofuranosyl) Pyrimidine Nucleoside Analogs

Abstract

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.

Design, synthesis and antimycobacterial activities of 1-methyl-2-alkenyl-4(1H)-quinolones

“…This implies that unsaturation of the aliphatic side chain is an essential structural feature for the in vitro antimycobacterial activity. This is further supported by recent findings which revealed that the aliphatic side chain, such as alkyl, alkenyl and alkynyl at position-5 of uracil significantly contributes to the antimycobacterial activity of pyrimidine nucleosides on M. tuberculosis 11 . To further explore the effect of degree of unsaturation on the antimycobacterial properties, methyl ketones having two carbon–carbon double bonds were synthesized and incorporated into the alkaloid.…”

Chemotherapeutic Interventions Against Tuberculosis

“…We designed, synthesized and examined a variety of known and unknown pyrimidine nucleosides substituted/unsubstituted at 2-, 4-, 5- and/or 6- positions of the base, and containing various deoxyribose, ribose, arabinose, dideoxyribose and acyclic sugar moieties. We found that 5-alkynyl substituted pyrimidine nucleosides demonstrated the most potent activity against mycobacteria [52,53]. The MIC 90 exhibited by compounds of this series ( 2 , 3 and 4 , Figure 2) was in the range of 1–5 μg/mL) against Mtb H37Ra.…”

Synthesis, reactivity and biological activity of 5-alkoxymethyluracil analogues

“…Johar and co-workers described the synthesis of 1-β-D-arabinofuranosyl-5-(1-methoxy-2-iodoethyl)uracil ( 79 ) (Scheme 11) in a recent article [19]. The compound was also reported by Kumar and co-workers in 1992 [20].…”