Landi Giacomo, Linciano Pasquale, Borsari Chiara, Bertolacini Claudia P, Moraes Carolina B, Cordeiro-da-Silva Anabela, Gul Sheraz, Witt Gesa, Kuzikov Maria, Costi Maria Paola, Pozzi Cecilia, Mangani Stefano
Department of Biotechnology, Chemistry and Pharmacy-Department of Excellence 2018-2020 , University of Siena , via Aldo Moro 2 , 53100 Siena , Italy.
Department of Life Science , University of Modena and Reggio Emilia , via Campi 103 , 41125 Modena , Italy.
ACS Infect Dis. 2019 Jul 12;5(7):1105-1114. doi: 10.1021/acsinfecdis.8b00358. Epub 2019 May 1.
Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of PTR1 (PTR1). A small library of cycloguanil derivatives was developed, resulting in and having IC values of 692 and 186 nM, respectively, toward PTR1. Structural analysis revealed that the increased potency of and is due to the combined contributions of hydrophobic interactions, H-bonds, and halogen bonds. Moreover, cell-growth-inhibition tests indicated that is also effective on . The simultaneous inhibition of DHFR and PTR1 activity in is a promising new strategy for the treatment of human African trypanosomiasis. For this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.
环氯胍是一种已知的二氢叶酸还原酶（DHFR）抑制剂，但没有证据表明其对蝶啶还原酶（PTR）有活性，而PTR是锥虫寄生虫中DHFR抑制的主要代谢旁路。在此，我们提供了环氯胍作为PTR1抑制剂的实验证据。开发了一个环氯胍衍生物的小型文库，其中 和 对PTR1的IC值分别为692和186 nM。结构分析表明， 和 效力的提高是由于疏水相互作用、氢键和卤键的共同作用。此外，细胞生长抑制试验表明， 对 也有效。在 中同时抑制DHFR和PTR1活性是治疗人类非洲锥虫病的一种有前景的新策略。为此，1,6 - 二氢三嗪代表了开发强效双PTR和DHFR抑制剂的新分子工具。
