Exploiting NDH-2 Vulnerability: Quinolines as Antitubercular Agents

Authors

Sau, S., Kumar, R., Roy, A., Agnivesh, P. K., Saha, P., Bhalerao, H. A., Sonti, R., Sharma, D. K., Kalia, N. P.

Abstract

Mycobacterium tuberculosis possesses a flexible metabolic system helping it to survive inside the host. The type II NADH dehydrogenase, composed of Ndh and NdhA, essential for bacilli, is a promising drug target. Based on ATP depletion values, two quinoline scaffolds were shortlisted after screening of a library of drug like molecules. Structurally, both 64-9C and 64-9D carry ester moieties at the 5- and 8-positions of the quinoline core, respectively. Ease to re-synthesise 64-9D resulted in synthesis of a focused library of compounds, with MIC values of 0.25-4 ?g/mL, consistent with ATP depletion. These compounds exhibited bactericidal activity against non-replicating mycobacteria, and showed potent efficacy against multidrug-resistant isolates. Altered, intracellular NADH/NAD+ ratio and reduced respiration was indicative of oxidative phosphorylation inhibition. Inhibition of the purified recombinant NDH protein uncompetitively, SNPs in gene encoding NDH-2 for selected one step mutants and, molecular modelling of 4FQN and 2FQN validated NDH-2 as a target for these compounds. The derivative 2FQN exhibited dose dependent bactericidal efficacy in mice, underscoring the potential of the series as a promising anti tuberculosis candidates.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 10 Jun 2026.

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