title: Inhibition of mycobacterial replication by pyrimidines possessing various C-5 functionalities and related 2'-deoxynucleoside analogues using in vitro and in vivo models.
abstract: Tuberculosis (TB) has become an increasing problem since the emergence of human immunodeficiency virus and increasing appearance of drug-resistant strains. There is an urgent need to advance our knowledge and discover a new class of agents that are distinct than current therapies. Antimycobacterial activities of several 5-alkyl, 5-alkynyl, furanopyrimidines and related 2'-deoxynucleosides were investigated against Mycobacterium tuberculosis. Compounds with 5-arylalkynyl substituents (23-26, 33, 35) displayed potent in vitro antitubercular activity against Mycobacterium bovis and Mycobacterium tuberculosis. The in vivo activity of 5-(2-pyridylethynyl)-uracil (26) and its 2'-deoxycytidine analogue, 5-(2-pyridylethynyl)-2'-deoxycytidine (35), was assessed in BALB/c mice infected with M. tuberculosis (H37Ra). Both compounds 26 and 35 given at a dose of 50 mg/kg for 5 weeks showed promising in vivo efficacy in a mouse model, with the 2'-deoxycytidine derivative being more effective than the uracil analogue and a reference drug d-cycloserine. These data indicated that there is a significant potential in this class of compounds.
authors: Department of Laboratory Medicine and Pathology, 1-71 Medical Sciences Building, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors: Naveen C
authors: NC
authors: Srivastav
authors: Dinesh
authors: D
authors: Rai
authors: Christopher
authors: C
authors: Tse
authors: B
authors: B
authors: Agrawal
authors: Dennis Y
authors: DY
authors: Kunimoto
authors: Rakesh
authors: R
authors: Kumar
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003853:Deoxyribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009163:Mycobacterium bovis / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy; D014498:Uracil / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C552108:5-(2-pyridylethynyl)-2'-deoxycytidine; C552107:5-(2-pyridylethynyl)uracil; D000480:Alkynes; D000995:Antitubercular Agents; D003853:Deoxyribonucleosides; D011725:Pyridines; D011743:Pyrimidines; D003841:Deoxycytidine; D014498:Uracil