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  3. Synthesis and mechanistic insights of Coumarinyl-Indolinone hybrids as potent inhibitors of Leishmania major

Synthesis and mechanistic insights of Coumarinyl-Indolinone hybrids as potent inhibitors of Leishmania major

  • Eur J Med Chem. 2025 Apr 15:288:117392. doi: 10.1016/j.ejmech.2025.117392.
Rasha Z Batran 1,  Manal S Ebaid 2,  Sherry N Nasralla 3,  Ninh The Son 4,  Nguyen Xuan Ha 5,  Hoda Atef Abdelsattar Ibrahim 6,  Mahmoud Abdelrahman Alkabbani 7,  Yusuke Kasai 8,  Hiroshi Imagawa 8,  Mohammad M Al-Sanea 9,  Tamer M Ibrahim 10,  Abdelsamed I Elshamy 11,  Adnan A Bekhit 12,  Wagdy M Eldehna 13,  Ahmed Sabt 14
Affiliations

Affiliations

  • 1 Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Center, Dokki, Cairo, 12622, Egypt.
  • 2 Department of Chemistry, College of Science, Northern Border University, Arar, Saudi Arabia. Electronic address: Manalshaabanebied@gmail.com.
  • 3 Pharmacy Program, Allied Health Department, College of Health Sciences, University of Bahrain, P.O. Box 32038, Bahrain.
  • 4 Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Caugiay, Hanoim, 10000, Viet Nam.
  • 5 Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Caugiay, 10000, Hanoim, Viet Nam.
  • 6 Pediatric Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
  • 7 Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian-Russian University, 11829, Badr City, Cairo, Egypt.
  • 8 Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, Japan.
  • 9 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, 72388, Sakaka, Aljouf, Saudi Arabia.
  • 10 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, 33516, Kafrelsheikh, Egypt.
  • 11 Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Center, Dokki, Cairo, 12622, Egypt; Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, Japan.
  • 12 Pharmacy Program, Allied Health Department, College of Health Sciences, University of Bahrain, P.O. Box 32038, Bahrain; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, 21521, Alexandria, Egypt.
  • 13 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, 33516, Kafrelsheikh, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St., 21648, Alexandria, Egypt. Electronic address: wagdy2000@gmail.com.
  • 14 Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Center, Dokki, Cairo, 12622, Egypt. Electronic address: sabt.nrc@gmail.com.
PMID: 39999741 DOI: 10.1016/j.ejmech.2025.117392
Abstract

Leishmaniasis, recognized as a neglected tropical disease, is a major global health issue that impacts millions of individuals across the globe. The limitations of existing treatments underscore the urgent need for novel antileishmanial drugs. In response, this study synthesized and evaluated fifteen hybrid compounds (7a-c, 10a-j, and 13a-b) combining 4-hydroxycoumarin and pyrazolyl indolin-2-one motifs for their in vitro antileishmanial efficacy towards Leishmania major. These molecules demonstrated remarkable activity against the promastigote form, with IC50 values ranging from 1.21 to 7.21 μM, surpassing the reference drug miltefosine (IC50 = 7.83 μM). Assessment against the intracellular amastigote form revealed efficient inhibitory action (IC50: 2.41-9.44 μM vs. 8.07 μM for miltefosine). Compounds 7a and 7b exhibited exceptional antileishmanial activity against both forms while maintaining favorable safety profiles. Mechanistic studies indicated that the most effective compounds act through an Antifolate mechanism, targeting pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS). Molecular docking and dynamics simulations of compounds 7a and 7b revealed strong in-silico binding and stable dynamics against PTR1, suggesting a high potential for Enzyme inhibition. These findings present a promising new class of antileishmanial agents targeting the folate pathway.

Keywords

Antifolate mechanism; Biological evaluation; In vivo safety; Leishmania; Molecular dynamics.

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