2. Academic Validation
  3. Synthesis and biological evaluation of O4'-benzyl-hispidol derivatives and analogs as dual monoamine oxidase-B inhibitors and anti-neuroinflammatory agents

Synthesis and biological evaluation of O4'-benzyl-hispidol derivatives and analogs as dual monoamine oxidase-B inhibitors and anti-neuroinflammatory agents

  • Bioorg Med Chem. 2024 Aug 1:110:117826. doi: 10.1016/j.bmc.2024.117826.
Ahmed H E Hassan 1,  Yeonwoo Choi 2,  Rium Kim 3,  Hyeon Jeong Kim 3,  Aya M Almatary 4,  Selwan M El-Sayed 5,  Yeongae Lee 2,  Jong Kil Lee 2,  Ki Duk Park 6,  Yong Sup Lee 7
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, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea.
  • 2 Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
  • 3 Center for Brain Disorders, Brain Science Institute, Korea Institute of Science & Technology (KIST), Seoul 02792, Republic of Korea.
  • 4 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.
  • 5 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura National University, Gamasa 7731168, Egypt.
  • 6 Center for Brain Disorders, Brain Science Institute, Korea Institute of Science & Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea. Electronic address: kdpark@kist.re.kr.
  • 7 Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul 02447, Republic of Korea; Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea. Electronic address: kyslee@khu.ac.kr.
PMID: 39004050 DOI: 10.1016/j.bmc.2024.117826
Abstract

Design, synthesis, and biological evaluation of two series of O4'-benzyl-hispidol derivatives and the analogous corresponding O3'-benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O4'-benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O3'-benzyl derivatives series. The most potential compound 2e of O4'-benzyl derivatives elicited sub-micromolar MAO-B IC50 of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O3'-benzyl derivatives showed only 0.95 MAO-B IC50 and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO Enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds.

Keywords

Anti-neuroinflammatory; Hispidol; Hybrid molecules; MAO-B; Natural products derivatives.

Figures
Products