Synthesis and Structure–Activity Relationship of 2,6-Disubstituted Thiosemicarbazone Derivatives of Pyridine as Potential Antituberculosis Agents
Dagmara Ziembicka, Katarzyna Gobis, Małgorzata Szczesio, Andrzej Ołczak, Ewa Augustynowicz‐Kopeć, Agnieszka Głogowska, Izabela Korona‐Głowniak, Krzysztof Bojanowski
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.