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

Journal of Enzyme Inhibition and Medicinal Chemistry

Acássia Benjamim Leal Pires¹  Camila Carane Bitencourt Brito²  Thamires Quadros Froes²  André Lacerda Braga Teles³  Bárbara Velame Ferreira Teixeira⁴  Suellen Gonçalves da Silva⁴  Marcelo Santos Castilho⁵  Humberto Fonseca de Freitas⁵ 

[1] Departamento de Ciências da Vida, Universidade do Estado da Bahia, Salvador, BA, Brazi;Programa de Pós-Graduação em Biotecnologia, Universidade Estadual de Feira de Santana, Feira de Santana, BA, Brazil;Programa de Pós-Graduação em Biotecnologia, Universidade Estadual de Feira de Santana, Feira de Santana, BA, Brazil;Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Estadual da Bahia, Salvador, BA, Brazil;Departamento de Ciências da Vida, Universidade do Estado da Bahia, Salvador, BA, Brazi;Programa de Pós-Graduação em Farmácia, Universidade Federal da Bahia, Salvador, BA, Brazil;Programa de Pós-Graduação em Farmácia, Universidade Federal da Bahia, Salvador, BA, Brazil;Programa de Pós-Graduação em Biotecnologia, Universidade Estadual de Feira de Santana, Feira de Santana, BA, Brazil;

关键词: Dual inhibitors;    pteridine reductase 1;    dihydrofolate reductase-thymidylate synthase;    Leishmania chagasi;    selective inhibitors;   

DOI  :  10.1080/14756366.2019.1651311

来源: publisher

【 摘 要 】

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).

【 授权许可】

CC BY