Synthesis, anti-tubercular evaluation and molecular docking studies of nitrogen-rich piperazine-pyrimidine-pyrazole hybrid motifs

Abstract

A convenient and efficient synthesis of a series of ethyl-1-(6-(4-substitutedacetylatedpiperazin-1-yl)pyrimidin-4-yl)-5-amino-1H-pyrazole-4-carboxylate (8a-8j) has been developed by five steps which include activation of a methylene group, hydrazinolysis, cyclisation and chloro-amine coupling reactions. Moreover, our proposed mechanism was confirmed in this study demonstrating that ethyl 5-amino-1-(6-chloropyrimidin-4-yl)-1H-pyrazole-4-carboxylate is the key intermediate to fulfill the desired outcomes. In silico and in vitro studies were carried out to identify the active agents among the developed adducts against mycobacterium tuberculosis (PDB ID:4TRO). Compound 8a (Docking Score:-26.81 and MIC: 1.6 ug/mL) was found to be the most potent among the synthesized molecules. All the synthesized compounds showed acceptable drug-like properties which make them suitable for further lead modification using in silico design approaches.