Rational design, synthesis, biological evaluation, and molecular modeling of novel naphthamide derivatives possessing potent, reversible, and competitive inhibitory mode of action over human monoamine oxidase

Ahmed Elkamhawy; Jong Min Oh; Minkyoung Kim; Lamiaa O El-Halaby; Magda H Abdellattif; Ahmed A Al-Karmalawy; Hoon Kim; Kyeong Lee

doi:10.1007/s11030-024-10841-9

Rational design, synthesis, biological evaluation, and molecular modeling of novel naphthamide derivatives possessing potent, reversible, and competitive inhibitory mode of action over human monoamine oxidase

Mol Divers. 2024 May 10. doi: 10.1007/s11030-024-10841-9. Online ahead of print.

Authors

Ahmed Elkamhawy^#^{1

2}, Jong Min Oh^#³, Minkyoung Kim¹, Lamiaa O El-Halaby², Magda H Abdellattif⁴, Ahmed A Al-Karmalawy^{5

6}, Hoon Kim⁷, Kyeong Lee⁸

Affiliations

¹ BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea.
² Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
³ Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon, 57922, Republic of Korea.
⁴ Chemistry Department, College of Sciences, University College of Taraba, Taif University, P.O. Box 11099, 21944, Taif, Saudi Arabia.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt.
⁶ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, 12566, Giza, Egypt.
⁷ Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon, 57922, Republic of Korea. hoon@sunchon.ac.kr.
⁸ BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea. kaylee@dongguk.edu.

^# Contributed equally.

PMID: 38727994
DOI: 10.1007/s11030-024-10841-9

Abstract

Herein, a novel series of naphthamide derivatives has been rationally developed, synthesized, and evaluated for their inhibitory activity against monoamine oxidase (MAO) and cholinesterase (ChE) enzymes. Compared to the reported naphthalene-based hit IV, the new naphthamide hybrids 2a, 2c, 2g and 2h exhibited promising MAO inhibitory activities; with an IC₅₀ value of 0.294 μM, compound 2c most potently inhibited MAO-A, while compound 2g exhibited most potent MAO-B inhibitory activity with an IC₅₀ value of 0.519 μM. Compounds 2c and 2g showed selectivity index (SI) values of 6.02 for MAO-A and 2.94 for MAO-B, respectively. On the other hand, most compounds showed weak inhibitory activity against ChEs except 2a and 2h over butyrylcholinesterase (BChE). The most potent compounds 2c and 2g were found to be competitive and reversible MAO inhibitors based on kinetic and reversibility studies. Plausible interpretations of the observed biological effects were provided through molecular docking simulations. The drug-likeness predicted by SwissADME and Osiris property explorer showed that the most potent compounds (2a, 2c, 2g, and 2h) obey Lipinski's rule of five. Accordingly, in the context of neurological disorders, hybrids 2c and 2g may contribute to the identification of safe and potent therapeutic approaches in the near future.

Keywords: MAO-A; MAO-B; Monoamine oxidase; Naphthamide; Reversible inhibitors.

Abstract

Grants and funding