Discovery of novel 5-(ethyl or hydroxymethyl) analogs of 2'-'up' fluoro (or hydroxyl) pyrimidine nucleosides as a new class of Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium inhibitors.
Discovery of novel antimycobacterial compounds that work on distinctive targets and by diverse mechanisms of action is urgently required for the treatment of mycobacterial infections due to the emerging global health threat of tuberculosis. We have identified a new class of 5-ethyl or hydroxy (or methoxy) methyl-substituted pyrimidine nucleosides as potent inhibitors of Mycobacterium bovis, Mycobacterium tuberculosis (H37Ra, H37Rv) and Mycobacterium avium. A series of 2'-'up' fluoro (or hydroxy) nucleosides (1, 2, 4-6, 9, 10, 13, 16, 18, 21, 24) was synthesized and evaluated for antimycobacterial activity. Among 2'-fluorinated compounds, 1-(3-bromo-2,3-dideoxy-2-fluoro-β-d-arabinofuranosyl)-5-ethyluracil (13) exhibited promising activity against M. bovis and Mtb alone, and showed synergism when combined with isoniazid. The most active compound emerging from these studies, 1-(β-d-arabinofuranosyl)-4-thio-5-hydroxymethyluracil (21) inhibited Mtb (H37Ra) (MIC(50)=0.5 μg/mL) and M. bovis (MIC(50)=0.5 μg/mL) at low concentrations, and was ten times more potent against Mtb (H37Ra) than cycloserine (MIC(50)=5.0 μg/mL), a second line drug. It also showed an additive effect when combined with isoniazid. Compound 21 retained sensitivity against a rifampicin-resistant (H37Rv) strain of Mtb (MIC(50)=1 μg/mL) at concentrations similar to that for a rifampicin-sensitive (H37Rv) strain, suggesting that it has no cross-resistance to a first-line anti-TB drug. In addition, the replication of M. avium was also inhibited by 21 (MIC(50)=10 μg/mL). No cellular toxicity of 13 or 21 was observed up to the highest concentration tested (CC(50)>100 μg/mL). These observations offer promise for a new drug treatment regimen to augment and complement the current chemotherapy of TB.
Department of Laboratory Medicine and Pathology, 7-28 Heritage Medical Research Centre, University of Alberta, Edmonton, AB, Canada T6G 2H7.
Neeraj
N
Shakya
Naveen C
NC
Srivastav
Sudha
S
Bhavanam
Chris
C
Tse
Nancy
N
Desroches
Babita
B
Agrawal
Dennis Y
DY
Kunimoto
Rakesh
R
Kumar
D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D006801:Humans; D009162:Mycobacterium avium / Q000187:drug effects*; D009163:Mycobacterium bovis / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010432:Pentoxyl / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D011741:Pyrimidine Nucleosides / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D014498:Uracil / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
D000995:Antitubercular Agents; D011741:Pyrimidine Nucleosides; C048011:5-ethyluracil; C008055:5-hydroxymethyluracil; D014498:Uracil; D010432:Pentoxyl