2. Academic Validation
  3. Bestatin analogs-4-quinolinone hybrids as antileishmanial hits: Design, repurposing rational, synthesis, in vitro and in silico studies

Bestatin analogs-4-quinolinone hybrids as antileishmanial hits: Design, repurposing rational, synthesis, in vitro and in silico studies

  • Eur J Med Chem. 2023 Mar 15;250:115211. doi: 10.1016/j.ejmech.2023.115211.
Ahmed H E Hassan 1,  Kazem Mahmoud 2,  Trong-Nhat Phan 3,  Moataz A Shaldam 4,  Chae Hyeon Lee 5,  Yeon Ju Kim 5,  Soo Bin Cho 5,  Waleed A Bayoumi 6,  Selwan M El-Sayed 7,  Yeonwoo Choi 5,  Suyeon Moon 5,  Joo Hwan No 3,  Yong Sup Lee 8
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 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt.
  • 3 Host-Parasite Research Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt.
  • 5 Department of Fundamental Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea.
  • 6 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
  • 7 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
  • 8 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: 36827952 DOI: 10.1016/j.ejmech.2023.115211
Abstract

Amongst different forms of leishmaniasis, visceral leishmaniasis caused by L. donovani is highly mortal. Identification of new hit compounds might afford new starting points to develop novel therapeutics. In this lieu, a rationally designed small library of bestatin analogs-4-quinolone hybrids were prepared and evaluated. Analysis of SAR unveiled distinct profiles for hybrids type 1 and type 2, which might arise from their different molecular targets. Amongst type 1 bestatin analog-4-quinolone hybrids, hybrid 1e was identified as potential hit inhibiting growth of L. donovani promastigotes by 91 and 53% at 50 and 25 μM concentrations, respectively. Meanwhile, hybrid 2j was identified amongst type 2 bestatin analog-4-quinolone hybrids as potential hit compound inhibiting growth of L. donovani promastigotes by 50 and 38% at 50 and 25 μM concentrations, respectively. Preliminary safety evaluation of the promising hit compounds showed that they are 50-100 folds safer against human derived monocytic THP-1 cells relative to the drug erufosine. In silico study was conducted to predict the possible binding of hybrid 1e with methionine aminopeptidases 1 and 2 of L. donovani. Molecular dynamic simulations verified the predicted binding modes and provide more in depth understanding of the impact of hybrid 1e on LdMetAP-1 and LdMetAP-2.

Keywords

Antileishmanial agents; Calpain-like cysteine peptidase; Leishmania donovani promastigote; Methionine aminopeptidase; Visceral Leishmaniasis.

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