Synthesis and Structure-Activity Relationship of 2,6-Disubstituted Thiosemicarbazone Derivatives of Pyridine as Potential Antituberculosis Agents.

Abstract

In this study, six new 2,6-disubstituted thiosemicarbazone derivatives of pyridine were synthesized (4-9), and their tuberculostatic activity was evaluated. All of them showed two- to eightfold higher activity (minimum inhibitory concentration (MIC) 0.5-4 µg/mL) against the resistant strain compared with the reference drug. Compounds 5 and 7, which contained the most basic substituents-pyrrolidine and piperidine-in their structure, strongly inhibited the growth of the standard strain (MIC 2 µg/mL). Furthermore, the same derivatives exhibited activity comparable to that of the reference drugs against some types of Gram-positive bacteria (MIC 0.49 µg/mL) and showed no cytotoxicity (IC50 > 50 µg/mL) in HaCaT cells. The zwitterionic structure of each compound was determined using X-ray crystallography. Absorption, distribution, metabolism, and excretion analyses showed that all compounds are good drug candidates. Thus, compounds 5 and 7 were identified as leading structures for further research on antituberculosis drugs with extended effects.