title: Design, development, drug-likeness, and molecular docking studies of novel piperidin-4-imine derivatives as antitubercular agents.
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-hydroxy-hydrazinecarbo-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.
authors.affiliation: Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, India.
authors.forename: Rajappan
authors.initials: R
authors.lastname: Revathi
authors.affiliation: Bharathi College of Pharmacy, Bharathi Nagara, Karnataka, India.
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Venkatesha Perumal
authors.affiliation: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, India.
authors.forename: Karkala Sreedhara Ranganath
authors.initials: KS
authors.lastname: Pai
authors.affiliation: Manipal Centre of Virus Research, Manipal University, Manipal, Karnataka, India.
authors.forename: Govindakarnavar
authors.initials: G
authors.lastname: Arunkumar
authors.affiliation: Pharmacy Group, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad, India.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.affiliation: Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, India.
authors.forename: Suvarna Ganesh
authors.initials: SG
authors.lastname: Kini
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D015195:Drug Design; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D007097:Imines; D010880:Piperidines
keywords: Mycobacterium tuberculosis; Schiff’s reaction; benzimidazole; enoyl-acyl carrier protein reductase