Inhibition of Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium avium by Novel Dideoxy Nucleosides

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.

Drug Design and Identification of Potent Leads Against Mycobacterium tuberculosis Thymidine Monophosphate Kinase

“…However, recent reports on potent and selective antimycobacterial activities for pyrimidine dideoxynucleosides featuring 5-alkynyl substituents [51] and nucleoside bisubstrate analogs [52] are encouraging and seem to suggest that further finetuning of the physicochemical properties may one day afford TMPK inhibitors with the expected antimycobacterial activity. …”

4-Hydroxy-2-quinolones. 154*. Pyrimidin- 2-ylamides of 1-r-4-hydroxy-2-oxo-1,2-dihydro- quinoline-3-carboxylic acids. synthesis, structure, and properties

“…In particular, many publications relate to the search for novel and efficient antimycobacterial agents [11][12][13][14][15][16] and this is explained by an exceptionally high surge in tubercular morbidity, approaching an epidemic scale in many countries of the world. In many examples of this kind it is necessary to include also the tendency of stimulation of the tubercular mycobacterium to active mutation contributing to rapid formation of resistance (often multiple) to known antitubercular medicines.…”

Chemotherapeutic Strategies and Targets Against Resistant TB

“…During our continued search of novel anti-TB agents, we found that 5-alkynyl substituted pyrimidine nucleosides were very potent inhibitors of mycobacteria (Rai et al, 2005). We , reported that pyrimidine nucleoside analogs 1--D-2'-arabinofuranosyl-5-dodecynyluracil (10), 1-(2'-deoxy-2'-fluoro--D-ribofuranosyl)-5-dodecynyluracil (11), and 1-(2'-deoxy-2'-fluoro--D-ribofuranosyl)-5-tetradecynyluracil (12) In the same year, we (Rai et al, 2007) further reported syntheses and evaluation of a series of 5-acetylenic derivatives of 2',3-dideoxyuridine, and 3'-fluoro-2',3'-dideoxyuridine for their antimycobacterial activity against M. bovis, Mtb, and M. avium. Compound 13 (among 2',3'-dideoxyuridine series) and compound 14 (among 3'-fluoro-2',3'-dideoxyuridine series) demonstrated excellent antimycobacterial activity (MIC 1-2 g/mL) against Mtb H 37 Ra.…”