Structure-based optimization and discovery of novel 1,3,5-triazine derivatives as bacterial translation inhibitor with favourable metabolic fate

Introduction

We have recently moved into an era not just of multiple resistant bacteria but of totally resistant pathogens, which now include vancomycin-resistant enterococci, carbapenem-resistant Acinetobacter baumannii, vancomycin-resistant MRSA and, very recently, NDM-1. Thus, increased incidence of bacterial resistance to currently available antibiotics necessitates the discovery and introduction of new and effective drugs. In our earlier studies, we have discovered a potent antibacterial lead molecule from 1,3,5-triazine (first generation) and its subsequent optimization till its tenth generation results much more advanced analogue with enhanced activity and less toxicity [1].

Objectives

Present study deals with the advancement of novel derivatives of 1,3,5-triazines to increase its efficacy and potency to make them viable drug candidate (eleventh generation).

Methods

The synthesis of analogues was achieved by means of S_NAr reaction utilizing distinguished amines. These molecules were then subjected to antibacterial screening against pathogenic Gram-positive and Gram-negative micro-organisms. MetaPrint2D-React from University of Cambridge, UK was utilized for the prediction of metabolites of the compounds.

Results

Entire set of derivatives demonstrated excellent antibacterial activity (1.56 - 25 µg ml^-1), and in some instance found equipotent to cefixime as standard. The molecular docking study on eubacterial ribosomal decoding A site (Escherichia coli 16S rRNA A site) confirmed the stability of target compounds into the inner groove of active site by making close H-bonds with highly conserved residues, e.g. Ade38, Gua37, Ade39, and Gua40. Moreover, the most active compound 7e, in MetaPrint2D-React study was not found to be deactivated by human metabolic process, which conform the utility of designed molecules.

Conclusion

We have discovered an another novel 1,3,5-triazine analogs as potent antibacterial agent through structure-based optimization of our defined lead.

Disclosure of interest

None declared.