Development of a New Class of Monoamine Oxidase-B Inhibitors by Fine-Tuning the Halogens on the Acylhydrazones

Jayalakshmi Jayan; Jiseong Lee; Sunil Kumar; Amritha Manoharan; Anishma Payyappilliparambil Narayanan; Reenoo Jauhari; Mohamed A Abdelgawad; Mohammed M Ghoneim; Hasnaa Ali Ebrahim; Subin Mary Zachariah; Hoon Kim; Bijo Mathew

doi:10.1021/acsomega.3c05719

Development of a New Class of Monoamine Oxidase-B Inhibitors by Fine-Tuning the Halogens on the Acylhydrazones

ACS Omega. 2023 Dec 6;8(50):47606-47615. doi: 10.1021/acsomega.3c05719. eCollection 2023 Dec 19.

Affiliations

¹ Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, India.
² Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea.
³ School of Pharmacy, Graphic Era Hill University, Dehradun 248002, Uttarakhand, India.
⁴ Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia.
⁵ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62514, Egypt.
⁶ Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah, Riyadh 13713, Saudi Arabia.
⁷ Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
⁸ Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.

Abstract

A total of 14 acyl hydrazine derivatives (ACH1-ACH14) were developed and examined for their ability to block monoamine oxidase (MAO). Thirteen analogues showed stronger inhibition potency against MAO-B than MAO-A. With a half-maximum inhibitory concentration of 0.14 μM, ACH10 demonstrated the strongest inhibitory activity against MAO-B, followed by ACH14, ACH13, ACH8, and ACH3 (IC₅₀ = 0.15, 0.18, 0.20, and 0.22 μM, respectively). Structure-activity relationships suggested that the inhibition effect on MAO-B resulted from the combination of halogen substituents of the A- and/or B-rings. This series concluded that when -F was substituted to the B-ring, MAO-B inhibitory activities were high, except for ACH6. In the inhibition kinetics study, the compounds ACH10 and ACH14 were identified as competitive inhibitors, with K_i values of 0.097 ± 0.0021 and 0.10 ± 0.038 μM, respectively. In a reversibility experiment using the dialysis methods, ACH10 and ACH14 showed effective recoveries of MAO-B inhibition as much as lazabemide, a reversible reference. These experiments proposed that ACH10 and ACH14 were efficient, reversible competitive MAO-B inhibitors. In addition, the lead molecules showed good blood-brain barrier permeation with the PAMPA method. The molecular docking and molecular dynamics simulation study confirmed that the hit compound ACH10 can form a stable protein-ligand complex by forming a hydrogen bond with the NH atom in the hydrazide group of the compound.