Design and Synthesis of Diaminotriazines as Anti-Tuberculosis DHFR Inhibitors

Arundhati C Lele,Mariam S Degani,M G.R Rajan,Archana Raju,M K Ray

doi:10.3844/crddsp.2014.45.50

Abstract

A series of novel 2,4 diamino-s-triazine was designed as potential Mycobacterium tuberculosis (Mtb) Dihydro folate reductase inhibitors. The synthesized compounds were evaluated in whole cells by employing Resazurin Microtitre Plate Assay (REMA) against Mtb H37Rv, using known DHFR inhibitors Methotrexate and Trimethoprim as standard drugs. The most active compound in the whole cell assay was selected for DHFR enzyme assay against the pathogen and human enzymes. The enzyme assay results revealed that this compound is a selective pathogenic DHFR inhibitor, with 13 fold more selectivity than Methotrexate. Thus, these derivatives have provided promising selective Hits/Leads as MTb DHFR inhibitors and can provide valuable information for further design of potent anti-TB drugs.

Highlights

Tuberculosis (TB) is an airborne, contagious disease caused by Mycobacterium tuberculosis (Mtb) in humans
Our research group has been involved in the search for DHFR inhibitors. Towards this goal we have reported molecular modeling studies for DHFR inhibitors and synthesized several classes of novel, diverse inhibitors of DHFR for opportunistic pathogens, including Mycobacterium avium (Bag et al, 2009; Tawari et al, 2011; Bag et al, 2010a; Degani et al, 2010; Bag et al, 2010b)
All the designed triazine derivatives were docked on the crystal structure of Mtb DHFR (1DF7), retrived from Brookhaven Protein Databank, to study the in-silico interaction of the designed compounds with the Mtb receptor active site

Summary

Introduction

Tuberculosis (TB) is an airborne, contagious disease caused by Mycobacterium tuberculosis (Mtb) in humans. WHO reported nearly 8.6 million new cases of TB in 2012 including 1.3 million deaths which represent the largest number of incidence of human deaths attributable to a single etiological agent (WHO, 2013). The current concern is the immense problem resulting from extensively drug-resistant tuberculosis, XDR-TB (Zignol et al, 2006). Dihydrofolate reductase is one of the well validated targets, where more than 100 3D-structures are available in Protein Data bank. DHFR has been successfully explored as a target for bacterial, protozoal infections (Gangjee et al, 2007) and anti-cancer activities. Some of the DHFR structures of organisms like Mycobacterium tuberculosis have been explored. There still exists scope for tailoring new molecules as antifolate against Mtb

Methods

Discussion

Conclusion