2. Academic Validation
  3. Design, synthesis, and repurposing of O6-aminoalkyl-sulfuretin analogs towards discovery of potential lead compounds as antileishmanial agents

Design, synthesis, and repurposing of O6-aminoalkyl-sulfuretin analogs towards discovery of potential lead compounds as antileishmanial agents

  • Eur J Med Chem. 2023 May 5;251:115256. doi: 10.1016/j.ejmech.2023.115256.
Ahmed H E Hassan 1,  Trong-Nhat Phan 2,  Suyeon Moon 3,  Chae Hyeon Lee 3,  Yeon Ju Kim 3,  Soo Bin Cho 3,  Selwan M El-Sayed 4,  Yeonwoo Choi 3,  Joo Hwan No 2,  Yong Sup Lee 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea. Electronic address: ahmed_hassan@mans.edu.eg.
  • 2 Host-Parasite Research Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea.
  • 3 Department of Fundamental Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
  • 5 Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea; Department of Fundamental Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea. Electronic address: kyslee@khu.ac.kr.
PMID: 36944273 DOI: 10.1016/j.ejmech.2023.115256
Abstract

Up to date, there are still significantly unmet clinical needs for treatment of the fatal visceral leishmaniasis; a neglected tropical disease. Herein, a recently reported antileishmanial hit sulfuretin analog suffering from a low potency and a problematic aqueous solubility that hindered further development was used as a starting point. A mitigation rational via incorporation of O6-aminoalkyl moiety suggest structures analogous to literature-known compounds as cholinesterase inhibitors. Consequently, preparation and repurposing of a library of these compounds unveiled their potential activity against the parasite Leishmania donovani promastigotes. Further evaluation against intracellular form of the Parasite and host cells suggested compounds 2a, 2c, and 2o derived from sulfuretin analogs bearing 2'-methoxy or 2',5'-dimethoxy substituents at ring-B as promising lead compounds with potential activity and acceptable safety window relative to the standard edelfosine. In silico simulation predicted plausible binding modes of these compounds to L. donovani fumarate reductase. Together this work presents compound 2o as a potential lead compound for further development.

Keywords

Amastigotes; Leishmania donovani; Natural products analogs; Promastigotes; Sulfuretin.

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