Design and studies of novel 5-substituted alkynylpyrimidine nucleosides as potent inhibitors of mycobacteria.
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.
Rai
Dinesh
D
Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Johar
Monika
M
Manning
Tracey
T
Agrawal
B
B
Kunimoto
Dennis Y
DY
Kumar
Rakesh
R
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D015195:Drug Design; D006801:Humans; D009162:Mycobacterium avium / Q000187:drug effects*; D009163:Mycobacterium bovis / Q000187:drug effects*; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D011741:Pyrimidine Nucleosides