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

• Published in: Drug design, development and therapy development and therapy, 2015-01, Vol.9 (default), p.3779-3787
• Main Authors: Revathi, Rajappan, Venkatesha Perumal, Ramachandran, Pai, Karkala Sreedhara Ranganath, Arunkumar, Govindakarnavar, Sriram, Dharmarajan, Kini, Suvarna Ganesh
• Format: Article
• Language: English
• Subjects: Acyl carrier protein; Animals; Antitubercular agents; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Care and treatment; Cercopithecus aethiops; Chemical compounds; Crystal structure; Data banks; Derivatives; Drug Design; Drug development; Drug resistance; Drugs; Fatty acids; Fourier transforms; Guanidine; Imines - chemical synthesis; Imines - chemistry; Imines - pharmacology; Microbial Sensitivity Tests; Minimum inhibitory concentration; Molecular docking; Molecular Docking Simulation; Molecular structure; Mycobacterium tuberculosis - drug effects; NMR; Nuclear magnetic resonance; Organic chemistry; Original Research; Pharmaceutical sciences; Pharmacology; Pharmacology, Experimental; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Properties; Protein structure; Proteins; R&D; Reductase; Research & development; Schiff bases; Selectivity; Structure-activity relationship (Pharmacology); Structure-activity relationships; Toxicity; Tuberculosis; Vero Cells
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S83047

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.