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 H37Rv. With the exception of the 4-nitro analog 1k, significant antitubercular potencies were observed in series 1 and 2 which have IC50 values in the range of 1–23 μM. Negative correlations were noted between the IC50 values of 1a–j, l towards M. tuberculosis and both the σ and π constants of the substituents in the benzylidene aryl ring. In particular, 1h emerged as a lead compound having IC50 and IC90 figures of 1.03 μM and 1.53 μM, 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 α,β-unsaturated group, has no effect on mitochondrial respiration using concentrations which inhibit the growth of M. tuberculosis.

Graphical abstractA number of substituted quinoxaline-1,4-dioxides 1 display excellent potency towards Mycobacterium tuberculosis from which a lead compound 1h (R1 = R2=Cl; R3 = H) having IC50 and IC90 values of 1.03 μM and 1.53 μM, respectively, was identified.Figure optionsDownload full-size imageDownload as PowerPoint slide