Design, development, drug-likeness, and molecular docking studies of novel piperidin-4-imine derivatives as antitubercular agents

Abstract

Rajappan Revathi,1 Ramachandran Venkatesha Perumal,2 Karkala Sreedhara Ranganath Pai,3 Govindakarnavar Arunkumar,4 Dharmarajan Sriram,5 Suvarna Ganesh Kini1 1Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, 2Bharathi College of Pharmacy, Bharathi Nagara, 3Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, 4Manipal Centre of Virus Research, Manipal University, Manipal, Karnataka, India; 5Pharmacy Group, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad, India Abstract: Tuberculosis remains one of the major grievous diseases worldwide. The emergence of resistance to antituberculosis drugs emphasize the necessity to discover new therapeutic agents for preferential tuberculosis therapy. In this study, various novel 1-(1H-benzimidazol-2-ylmethyl)piperidin-4-imine derivatives were developed and checked for favorable pharmacokinetic parameters based on drug-likeness explained by Lipinski’s rule of five. All 20 of the novel chemical entities were found to possess a favorable pharmacokinetic profile since they were not violating Lipinski’s rule of five. The title compounds were also synthesized, characterized, and tested for ex vivo antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294). The results revealed that four compounds (2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]hydrazinecarbothioamide, 2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]-N-hydroxyhydrazinecarbo-thioamide, 1-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]guanidine, and 2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]hydrazinecarboxamide) were the most potent (minimum inhibitory concentration 6.25 µg/mL) antitubercular agents, with less toxicity (selectivity index more than 10). The molecules were also subjected to three-dimensional molecular docking on the crystal structure of enoyl-acyl carrier protein (EACP) reductase enzyme (code 1ZID, Protein Data Bank), which represents a good prediction of the interactions between the molecules and EACP reductase with minimum binding energy. Keywords: enoyl-acyl carrier protein reductase, Schiff’s reaction, benzimidazole, Mycobacterium tuberculosis