Dual and selective inhibitors of pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS) from Leishmania chagasi

• Published in: Journal of enzyme inhibition and medicinal chemistry 2019-01, Vol.34 (1), p.1439-1450
• Main Authors: Teixeira, Bárbara Velame Ferreira, Teles, André Lacerda Braga, Silva, Suellen Gonçalves da, Brito, Camila Carane Bitencourt, Freitas, Humberto Fonseca de, Pires, Acássia Benjamim Leal, Froes, Thamires Quadros, Castilho, Marcelo Santos
• Format: Article
• Language: English
• Subjects: Catalysis; Chromatography, Affinity; Cloning, Molecular; dihydrofolate reductase-thymidylate synthase; Drug Evaluation, Preclinical; Dual inhibitors; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors - pharmacology; Escherichia coli - genetics; Inhibitory Concentration 50; Leishmania chagasi; Leishmania infantum - enzymology; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - genetics; Multienzyme Complexes - isolation & purification; Multienzyme Complexes - metabolism; Oxidoreductases - antagonists & inhibitors; Oxidoreductases - genetics; Oxidoreductases - isolation & purification; Oxidoreductases - metabolism; pteridine reductase 1; Research Paper; selective inhibitors; Tetrahydrofolate Dehydrogenase - genetics; Tetrahydrofolate Dehydrogenase - isolation & purification; Tetrahydrofolate Dehydrogenase - metabolism; Thymidylate Synthase - antagonists & inhibitors; Thymidylate Synthase - genetics; Thymidylate Synthase - isolation & purification; Thymidylate Synthase - metabolism
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2019.1651311

Leishmaniasis is a tropical disease found in more than 90 countries. The drugs available to treat this disease have nonspecific action and high toxicity. In order to develop novel therapeutic alternatives to fight this ailment, pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHF-TS) have been targeted, once Leishmania is auxotrophic for folates. Although PTR1 and DHFR-TS from other protozoan parasites have been studied, their homologs in Leishmania chagasi have been poorly characterized. Hence, this work describes the optimal conditions to express the recombinant LcPTR1 and LcDHFR-TS enzymes, as well as balanced assay conditions for screening. Last but not the least, we show that 2,4 diaminopyrimidine derivatives are low-micromolar competitive inhibitors of both enzymes (LcPTR1 Ki = 1.50-2.30 µM and LcDHFR Ki = 0.28-3.00 µM) with poor selectivity index. On the other hand, compound 5 (2,4-diaminoquinazoline derivative) is a selective LcPTR1 inhibitor (Ki = 0.47 µM, selectivity index = 20).