2. Academic Validation
  3. New antileishmanial quinoline linked isatin derivatives targeting DHFR-TS and PTR1: Design, synthesis, and molecular modeling studies

New antileishmanial quinoline linked isatin derivatives targeting DHFR-TS and PTR1: Design, synthesis, and molecular modeling studies

  • Eur J Med Chem. 2023 Jan 15:246:114959. doi: 10.1016/j.ejmech.2022.114959.
Ahmed Sabt 1,  Wagdy M Eldehna 2,  Tamer M Ibrahim 3,  Adnan A Bekhit 4,  Rasha Z Batran 5
Affiliations

Affiliations

  • 1 Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, 12622, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt; School of Biotechnology, Badr University in Cairo, Badr City, 11829, Egypt.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt; Bioinformatics Group, Center for Informatics Sciences (CIS), School of Information Technology and Computer Science (ITCS), Nile University, Giza, Egypt.
  • 4 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.
  • 5 Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, 12622, Egypt. Electronic address: rasha_batran@yahoo.com.
PMID: 36493614 DOI: 10.1016/j.ejmech.2022.114959
Abstract

In a search for new drug candidates for one of the neglected tropical diseases, leishmaniasis, twenty quinoline-isatin hybrids were synthesized and tested for their in vitro antileishmanial activity against Leishmaniamajor strain. All the synthesized compounds showed promising in vitro activity against the promastigote form in a low micromolar range (IC50 = 0.5084-5.9486 μM) superior to the reference miltefosine (IC50 = 7.8976 μM). All the target compounds were then tested against the intracellular amastigote form and showed promising inhibition effects (IC50 = 0.60442-8.2948 μM versus 8.08 μM for miltefosine). Compounds 4e, 4b and 4f were shown to possess the highest antileishmanial activity against both promastigote and amastigote forms. The most active compounds were proven to exhibit their significant antileishmanial effects through Antifolate mechanism, targeting DHFR-TS and PTR1. To evaluate the safety profile of the most active derivatives 4e, 4b and 4f, the in vitro cytotoxicity test was carried out and displayed higher selectivity indices than the reference miltefosine. Molecular docking within putative target protein PTR1 confirmed the high potentiality of the most active compounds 4e, 4b and 4f to block the catalytic activity of Lm-PTR1.

Keywords

Antileishmanial; DHFR-TS; Molecular modeling; Neglected tropical diseases; PTR1; Quinoline-isatin hybrids.

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