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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.

SUBMITTER: Revathi R

PROVIDER: S-EPMC4516184 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Revathi Rajappan R Venkatesha Perumal Ramachandran R Pai Karkala Sreedhara Ranganath KS Arunkumar Govindakarnavar G Sriram Dharmarajan D Kini Suvarna Ganesh SG

Drug design, development and therapy 20150721

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 ...[more]

PMID: 26229439

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Project description:Despite significant progress made in drug discovery and development over the past few decades, malaria remains a life-threatening infectious disease across the globe. Because of the widespread emergence of drug-resistant strains of Plasmodium falciparum, the clinical utility of existing drug therapies including Artemisinin-based Combination Therapies (ACTs) in the treatment of malaria has been increasingly limited. It has become a serious health concern which, therefore, necessitates the development of novel drug molecules and/or alternative therapies to combat, particularly resistant P. falciparum. The objective of the present study was to develop 1,2,4-trioxane derivatives as novel antimalarial agents that would be effective against resistant P. falciparum. In our study, 15 new trioxane derivatives were designed by molecular modification of the 1,2,4-trioxane scaffold as possible antimalarial agents. Molecular modeling studies of trioxane derivatives were performed based on the CADD approach using Biovia Discovery Studio (DS) 2018 software. The protein-ligand docking study was performed against P. falciparum falcipain 2 (FP-2) using the simulation-based docking protocol LibDock by the flexible docking method. The assessment of drug-likeness, ADMET properties, and toxicity was also performed. Furthermore, the compounds CC3 and CC7, which showed the best binding affinity against the target P. falciparum FP-2, were investigated by molecular dynamics (MD) simulation studies followed by the calculation of MM-PBSA binding free energy of protein-ligand complexes using DS 2020. Results of the docking study showed that among the 15 compounds, three trioxane derivatives were found to possess promising binding affinity with LibDock scores ranging from 117.16 to 116.90. Drug-likeness, ADMET, and toxicity properties were found to be satisfactory for all the compounds. Among the 15 compounds, two compounds, namely CC3 and CC7, showed the highest binding affinity against FP-2 with LibDock score of 117.166 and 117.200, respectively. The Libdock score of the co-crystal inhibitor was 114.474. MD studies along with MM-PBSA calculations of binding energies further confirmed the antimalarial potential of the compounds CC3 and CC7, with the formation of well-defined and stable receptor-ligand interactions against the P. falciparum FP-2 enzyme. Additionally, the selectivity of trioxane hits identified as potential inhibitors of P. falciparum cysteine protease FP-2 was determined on human cysteine proteases such as cathepsins (Cat K and Cat L), which are host homologous. Finally, it was concluded that the newly designed 1,2,4-trioxane derivatives can be further studied for in vitro and in vivo antimalarial activities for their possible development as potent antimalarial agents effective against resistant P. falciparum.

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

Publications

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

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