Repositioning of DHFR Inhibitors

Abstract

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.

Diaminoquinazoline MMV675968 from Pathogen Box inhibits Acinetobacter baumannii growth through targeting of dihydrofolate reductase

“…There are at least four major classes of DHFR inhibitors, namely, diaminopteridine, diaminodimethyltriazine, diaminopyrimidine, and diaminoquinazoline (Fig. 4A) 19 . MTX, an anti-cancer diaminopteridine, showed strong in vitro Ab DHFR inhibition (Fig.…”

“…Diaminodimethyltriazines such as cycloguanil, MMV667486, and MMV667487, which are Plasmodium DHFR inhibitors 19,21,22 , did not inhibit Ab DHFR in vitro or show any growth inhibitory activity against A. baumannii (Fig. 4B,D), highlighting structural differences between Ab DHFR and Plasmodium DHFR.…”

“…Diaminopyrimidines such as PYR and TMP are inhibitors of Plasmodium and bacterial DHFR, respectively 19 . While being moderately effective in inhibiting Ab DHFR in vitro (Fig.…”

Exploration and Biological Evaluation of 1,3-Diamino-7H-pyrrol[3,2-f]quinazoline Derivatives as Dihydrofolate Reductase Inhibitors

“…21 Currently, the anti-infective and antitumor DHFR inhibitors used in clinical practice possess common structures, which simulate the DHFR folic acid substrate and occupy the conserved binding pocket in the catalytic domain of DHFR. 22 Most of the clinically used anti-infective DHFR inhibitors have the 2,4-diaminopyrimidine structure as the backbone structure (e.g., TMP, PYR, and Tetroxoprim in Figure 1), whereas the antitumor DHFR inhibitors use the pteridine ring as the backbone structure (e.g., MTX and Aminopterin in Figure 1). Despite the robust DHFR inhibitory activity displayed by classical antifolates, their extensive clinical application has been impeded by varying levels of drug resistance issues, particularly concerning antimicrobial-resistant pathogens.…”

Structure-Based Design of Dimeric Bisbenzimidazole Inhibitors to an Emergent Trimethoprim-Resistant Type II Dihydrofolate Reductase Guides the Design of Monomeric Analogues

“…This unusual binding promiscuity has resulted in DfrBs being considered as poorly evolved enzymes and led to the identification of nonselective inhibitors of DfrB1, some among which bind in two copies. 4,8,27 2,4-Diaminopyrimidines, including methotrexate (MTX) and aminopterin (AMT), known for decades to be antimicrobial or antineoplastic inhibitors that target chromosomal Dfrs, 3,31,32 bind weakly to apo-DfrB1, although no binding was observed with holo-DfrB1. 3,9−15,27 Pemetrexed (PMTX), 2-desamino-5,8-dideazafolic acid, 5,8-dideazapterin analogues, and 5-deazafolic acid analogues nonspecifically not only inhibit DfrB1 in the low micromolar range but also inhibit the human Dfr (hDfr) and other mammalian enzymes from the folate pathway with higher affinity, precluding their use as antibiotic agents.…”