2016
DOI: 10.2174/1568026616666160216152540
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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 … Show more

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Cited by 12 publications
(6 citation statements)
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“…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.…”
Section: Discussionmentioning
confidence: 99%
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“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Section: Discussionmentioning
confidence: 99%
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“…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.…”
Section: ■ Introductionmentioning
confidence: 99%
“…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. 3,915,27 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.…”
Section: Introductionmentioning
confidence: 99%