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

Nayera W Hassan; Ahmed Sabt; Maryam A Z El-Attar; Mikko Ora; Alaa El-Din A Bekhit; Kikuko Amagase; Adnan A Bekhit; Ahmed S F Belal; Perihan A Elzahhar

doi:10.1016/j.ejmech.2023.115333

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

Eur J Med Chem. 2023 May 5:253:115333. doi: 10.1016/j.ejmech.2023.115333. Epub 2023 Apr 5.

Authors

Nayera W Hassan¹, Ahmed Sabt², Maryam A Z El-Attar¹, Mikko Ora³, Alaa El-Din A Bekhit⁴, Kikuko Amagase⁵, Adnan A Bekhit⁶, Ahmed S F Belal⁷, Perihan A Elzahhar⁸

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
² Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, 12622, Egypt.
³ Department of Chemistry, University of Turku, 20500, Turku, Finland.
⁴ Department of Food Science, University of Otago, Dunedin, 9054, New Zealand.
⁵ Laboratory of Pharmacology & Pharmacotherapeutics, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt; Pharmacy Program, Allied Health Department, College of Health Sciences, University of Bahrain, P.O. Box 32038, Bahrain.
⁷ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address: ahmed.belal@alexu.edu.eg.
⁸ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address: perihan.elzahhar@alexu.edu.eg.

PMID: 37031526
DOI: 10.1016/j.ejmech.2023.115333

Abstract

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 antileishmanial 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 characteristics of these compounds demonstrated their suitability as antileishmanial lead compounds.

Keywords: 1,2,3-Triazoles; Anti-folate; Click reaction; Coumarin; Docking; Drug likeness; Leishmania.

MeSH terms

Animals
Antiprotozoal Agents*
Chlorocebus aethiops
Coumarins / chemistry
Humans
Leishmania*
Pteridines / pharmacology
Triazoles / chemistry
Triazoles / pharmacology
Vero Cells

Substances

Antiprotozoal Agents
Coumarins
Pteridines
Triazoles
coumarin-1,2,3-triazole