Synthesis, characterization and studies on antitubercular activity of some 1,3,4-thiadiazole based molecules

Abstract

In the last few decades, the process of drug discovery program has undergone a fundamental transformation, thanks to the integrated approach of chemists and biologists resulting in the development of new chemical entities (NCEs). Although the increasing costs of production, research and development worries the pharmaceutical industry, synthetic organic approach towards designing innovative and low molecular weight chemical structures, which are also biologically active, will definitely aid in combating the ailments prevailing universally. Such endeavours have led us to domain of heterocyclic chemistry and thiadiazole is one such frequently encountered heterocycle which has proven itself with a diverse range of biological activities. Owing to this therapeutic degree of thiadiazole and its derivatives, in the current work, it has been planned to integrate various potent heterocyclic units with the thiadiazole skeleton to form a new molecular framework. Accordingly, five different libraries of thiadiazole based compounds comprising of benzimidazole (T1-T29), 1,2,3-triazole (T30-T49), thiazole (T50-T72), phenothiazine derivatives (T73-T93) and pyrazinamide (T94-T111) have been successfully synthesized through multistep organic synthetic protocols. Derivatives T1-T72 and T93-T111 were synthesized with a pharmacophore substitution at position-5 of imidazo[2,1-b] [1,3,4]thiadiazole ring. Derivatives of T73-T93 were synthesized by the reaction of 1,3,4-thiadiazole core with substituted phenothiazine as the pharmacophore unit. The chemical structures of the prepared molecules were established by various spectroscopic techniques viz. 1H NMR, 13C NMR, ESI-MS and elemental analyses. Additionally, 3-dimensional structures of a few molecules were confirmed by single crystal X-ray diffraction (SCXRD) studies. Further, the synthesized title compounds were subjected to preliminary in vitro antitubercular and antibacterial screening. The active molecules in each series were identified and tested for their toxicity on the benign noncancerous cells. The in silico molecular modeling studies of these active derivatives were also carried out.