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

Revathi, Rajappan and Pai, Sreedhara Ranganath K and Arunkumar, G and Kini, Suvarna G (2015) Design, development, drug-likeness, and molecular docking studies of novel piperidin-4-imine derivatives as antitubercular agents. Drug Design, Development and Therapy, 9. pp. 3779-3787.

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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.

Item Type: Article
Uncontrolled Keywords: Enoyl-acyl carrier protein reductase; Schiff’s reaction; benzimidazole; Mycobacterium tuberculosis.
Subjects: Departments at MU > Manipal Centre for Virus Research
Pharmacy > MCOPS Manipal > Pharmaceutical Chemistry
Pharmacy > MCOPS Manipal > Pharmacology
Depositing User: KMC Library
Date Deposited: 22 Sep 2015 15:04
Last Modified: 22 Sep 2015 15:04
URI: http://eprints.manipal.edu/id/eprint/144021

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