Design, synthesis and biological evaluation of (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase

Abstract

New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc₁-aa₃ supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc₁ complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc₁ complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc₁ complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log₁₀ reduction in viable counts which increased to ∼4-log₁₀ when combined with Q203.

Keywords: (4-oxoquinazoline-3(4H)-yl)acetamide; (Quinazoline 4-yloxy)acetamide; Mycobacterium tuberculosis bd-oxidase.