Inhibition of Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium avium by novel dideoxy nucleosides.
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.
Rai
Dinesh
D
Department of Laboratory Medicine and Pathology, 1-71 Medical Sciences Building, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
Johar
Monika
M
Srivastav
Naveen C
NC
Manning
Tracey
T
Agrawal
B
B
Kunimoto
Dennis Y
DY
Kumar
Rakesh
R
D000241:Adenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D000480:Alkynes / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D006151:Guanosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009162:Mycobacterium avium / Q000187:drug effects*; D009163:Mycobacterium bovis / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014529:Uridine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
D000480:Alkynes; D000900:Anti-Bacterial Agents; D015224:Dideoxynucleosides; D011684:Purine Nucleosides; D006151:Guanosine; D000241:Adenosine; D014529:Uridine