We report design of a series of 2,4-diamino triazines as Mycobacterium tuberculosis (Mtb) dihydrofolate reductase inhibitors. The synthesized compounds were evaluated against Mtb (H 37 Rv and Dormant stage H 37 Ra), their cytotoxicity was assessed (HepG2 and A549 cell lines), and selectivity toward Mtb was evaluated by testing against other bacterial strains. Some derivatives showed promising activity along with low cytotoxicity. The most potent compound in the whole cell assay (MIC 0.325 μM against H 37 Rv) showed selectivity in the enzyme assay and exhibited synergy with second line anti-TB agent p-amino salicylic acid. This study therefore provides promising molecules for further development as antituberculosis DHFR inhibitors.

This study provides promising antituberculosis dihydrofolate reductase inhibitors that can act as potential leads for further development.

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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 H 37 Rv, 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.

Development of new drugs is a time-consuming, hugely expensive and an uncertain endeavor. The pharmaceutical industry is looking for cost-effective alternatives with reduced risks of drug failure. Validated target machinery along with established inhibitors indicates usefulness in drug design, discovery and further development. Folate metabolism, found in both prokaryotes and eukaryotes, represents an essential druggable target for chemotherapy. Numerous enzymes in the cell replication cycle use folate either as a cofactor or as a substrate. DHFR, an enzyme of the folate biosynthesis pathway is an established chemotherapeutic target, initially explored for anti-cancer drug discovery. Diaminopteridines e.g. methotrexate and aminopterin, primarily used as anti-cancer agents, are folic acid analogues, first reported in late 1940's, used to produce temporary remission of acute leukaemia in children. However, due to the toxicity of these drugs, they could not be used for other therapeutic implications such as in the treatment of infectious diseases. Development of newer diaminopteridine derivatives has helped in repositioning their therapeutic usefulness. These analogues have now been proven as anti-parasitic, immuno-suppressants, anti-bacterial agents, to enlist a few therapeutic applications. Likewise, diaminopyrimidine, diaminoquinazoline and diaminodihydrotriazines are being explored for structural modifications by which they can be repurposed from their originally developed medicinal applicability and exploited for various other infectious disease conditions. In this review, we encompass the study of DHFR inhibitors potentially to be repurposed for different infectious disease case scenario and also highlight the novel anti-infective drug discovery benefits therein.