MOLECULAR DOCKING STUDIES AND SYNTHESIS OF 3, 4 - DISUBSTITUTED TRIAZOLES AS MYCOBACTERIUM TUBERCULOSIS ENOYL-ACP REDUCTASE AND CYP-51 INHIBITORS

Neethu Dasan,G Babu,Shiny George

doi:10.22159/ijpps.2019v11i1.29428

Abstract

Objective: To design, synthesize and in vitro antitubercular, antifungal and antioxidant evaluation of some novel mercapto 1, 2, 4–triazole derivatives.Methods: New derivatives were designed by using various software like ACD Lab chemsketch, molinspiration and autodock. Designed molecules are obeying Lipinski’s rule of five and having highest binding score was selected for the synthesis. The synthesized compounds were subjected to TLC, melting point determination, FTIR, 1H NMR, 13C NMR and mass spectral analysis. The newly synthesized compounds were investigated for in vitro antitubercular evaluation by MABA method, antifungal evaluation by cup plate method and antioxidant evaluation by DPPH scavenging assay.Results: A virtual screening was carried out through docking designed compounds into the InhA and CYP-51 binding site to predict if these compounds have an analogous binding mode of the enoyl ACP reductase (InhA) and CYP-51 inhibitors. Three derivatives (4a1, 4a2 and 4a3) were selected for the synthesis with the help of in silico modeling. The selected derivatives were synthesized by a conventional method. All the synthesized compounds showed a characteristic peak in FT IR, 1H and 13C NMR and mass spectroscopic studies. All the selected derivatives showed antitubercular, antifungal and antioxidant activity.Conclusion: The derivatives were synthesized adopting simple and laboratory friendly reaction conditions to give the target compounds in quantitative yields. Newer derivatives possess good antitubercular, antifungal and antioxidant activity.

Highlights

In the past, most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery
We present an evaluation of the antioxidant effect of substituted triazole derivatives
In silico molecular analysis of different triazole derivatives was done. All these compounds obeyed “Lipinski rule of five”. These analogues were taken for computing molecular descriptors and which have the best docking score was taken for synthesis

Summary

Introduction

Most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery. Molecular docking has become an increasingly important tool for drug discovery. Due to the reduced effectiveness of current drugs resulting from the emergence of multidrug-resistant tuberculosis (MDR TB) and co-infection with human immunodeficiency virus (HIV), there is an urgent need to develop new natural or synthetic antitubercular drugs. The major drawbacks with the therapeutic agents for mycobacterial and fungal infections are prolonged treatment regimen with a combination of drugs associated with significant toxicity and the emergence of multi-drug resistant bacteria and fungi causing morbidity and mortality in immunocompromised hosts. The necessity for effective therapy has stimulated research into the design and synthesis of novel compounds which can treat both mycobacterial and fungal infections. Design of compounds having good anti-tubercular activity is gaining much importance in the field of tuberculosis research due to the resurgence of antibiotic-resistant strains

Methods

Results

Conclusion