3,5-disubstituted pyridines with potent activity against drug-resistant clinical isolates.

We designed and synthesized a series of compounds with a 3,5-disubstituted pyridine moiety and evaluated them against (Mtb) and drug-resistant Mtb clinical isolates. A library of 3,5-disubstituted pyridine was synthesized. The compounds were screened for activity against H37Rv. The optimal substitutions needed for the activity were identified through structure-activity relationship (SAR) studies. From the screening studies, compounds and were identified as potent members of this series with Minimum Inhibitory Concentration (MIC) of 1.56 μg/ml against H37Rv. These compounds did not show any inhibition against a panel of ESKAPE pathogens at >50 μg/ml indicating their selective killing of H37Rv. Importantly, compound showed a selectivity index of 54.64 against CHO-K1 and 78.26 against VERO cell lines, while compound showed a selectivity index of 108.5 against CHO-K1 and 63.2 against VERO cell lines, respectively. Compound formed a stable complex with the target protein DprE1 with predicted binding energy -8.73 kcal/mol and inhibited multidrug-resistant clinical isolate of at 6.25 μg/ml. This study identified the 3,5-disubstituted pyridine derivative with potent antituberculosis activity and can be taken forward to generate new preclinical candidate.