Modulating leishmanial pteridine metabolism machinery via some new coumarin-1,2,3-triazoles: Design, synthesis and computational studies

: Hassan Nayeara W, Sabt Ahmedd, El-Attar Maryam AZ, Ora Mikko, Bekhit Alaa EA, Amagase Kikuko, Bekhit Adnan A, Belal Ahmed SF, Elzahhar Perihan A

Publisher: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

: 2023

: European Journal of Medicinal Chemistry

: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

: EUR J MED CHEM

: 115333

: 253

: 15

: 0223-5234

DOI: https://doi.org/10.1016/j.ejmech.2023.115333

: https://doi.org/10.1016/j.ejmech.2023.115333

In accordance with WHO statistics, leishmaniasis is one of the top neglected tropical diseases, affecting around 700 000 to one million people per year. To that end, a new series of coumarin-1,2,3-triazole hybrid compounds was designed and synthesized. All new compounds exerted higher activity than miltefosine against L. major promastigotes and amastigotes. Seven compounds showed single digit micromolar IC50 values whereas three compounds (13c, 14b and 14c) displayed submicromolar potencies. A mechanistic study to elucidate the antifolate-dependent activity of these compounds revealed that folic and folinic acids abrogated their anti-leishmanial effects. These compounds exhibited high safety margins in normal VERO cells, expressed as high selectivity indices. Docking simulation studies on the folate pathway enzymes pteridine reductase and DHFR-TS imparted strong theoretical support to the observed biological activities. Besides, docking experiments on human DHFR revealed minimal binding interactions thereby highlighting the selectivity of these compounds. Predicted in silico physicochemical and pharmacokinetic parameters were adequate. In view of this, the structural char-acteristics of these compounds demonstrated their suitability as antileishmanial lead compounds.