E-2-[3-(3,4-dichlorophenyl)-1-oxo-2-propenyl]-3-methylquinoxaline-1,4-dioxide: a lead antitubercular agent which alters mitochondrial respiration in rat liver.
A series of 2-(3-aryl-1-oxo-2-propenyl)-3-methylquinoxaline-1,4-dioxides 1a-l and 2-acetyl-3-methylquinoxaline-1,4-dioxide 2 were evaluated against Mycobacterium tuberculosis H(37)Rv. With the exception of the 4-nitro analog 1k, significant antitubercular potencies were observed in series 1 and 2 which have IC(50) values in the range of 1-23 microM. Negative correlations were noted between the IC(50) values of 1a-j, l towards M. tuberculosis and both the sigma and pi constants of the substituents in the benzylidene aryl ring. In particular, 1h emerged as a lead compound having IC(50) and IC(90) figures of 1.03 microM and 1.53 microM, respectively. This molecule affected respiration in rat liver mitochondria which is likely one way that 1h and the bioactive analogs exert their antitubercular properties. The quinoxaline 2, which lacks an alpha,beta-unsaturated group, has no effect on mitochondrial respiration using concentrations which inhibit the growth of M. tuberculosis.
Das
Umashankar
U
Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada. umashankar.das@usask.ca
Das
Swagatika
S
Bandy
Brian
B
Gorecki
Dennis K J
DK
Dimmock
Jonathan R
JR
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008930:Mitochondria, Liver / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010087:Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy
D000995:Antitubercular Agents; D010087:Oxides; D011810:Quinoxalines