2. Academic Validation
  3. Introduction of benzyloxy pharmacophore into aryl/heteroaryl chalcone motifs as a new class of monoamine oxidase B inhibitors

Introduction of benzyloxy pharmacophore into aryl/heteroaryl chalcone motifs as a new class of monoamine oxidase B inhibitors

  • Sci Rep. 2022 Dec 27;12(1):22404. doi: 10.1038/s41598-022-26929-x.
Sachithra Thazhathuveedu Sudevan # 1,  Jong Min Oh # 2,  Mohamed A Abdelgawad 3 4,  Mohammed A S Abourehab 5,  T M Rangarajan 6,  Sunil Kumar 1,  Iqrar Ahmad 7,  Harun Patel 8,  Hoon Kim 9,  Bijo Mathew 10
Affiliations

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 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, 72341, Saudi Arabia.
  • 4 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
  • 5 Department of Pharmaceutics, College of Pharmacy, Umm Al-Qura University, Makkah, 21955, Saudi Arabia.
  • 6 Department of Chemistry, Sri Venketeswara College, University of Delhi, New Delhi, 110021, India.
  • 7 Department of Pharmaceutical Chemistry, Prof. Ravindra Nikam College of Pharmacy, Gondur, Dhule, 424002, Maharashtra, India.
  • 8 Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, 425405, Maharashtra, India.
  • 9 Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon, 57922, Republic of Korea. hoon@sunchon.ac.kr.
  • 10 Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682 041, India. bijomathew@aims.amrita.edu.
  • # Contributed equally.
PMID: 36575270 DOI: 10.1038/s41598-022-26929-x
Abstract

The inhibitory action of fifteen benzyloxy ortho/para-substituted Chalcones (B1-B15) was evaluated against human monoamine oxidases (hMAOs). All the molecules inhibited hMAO-B isoform more potently than hMAO-A. Furthermore, the majority of the molecules showed strong inhibitory actions against hMAO-B at 10 μM level with residual activities of less than 50%. Compound B10 has an IC50 value of 0.067 μM, making it the most potent inhibitor of hMAO-B, trailed by compound B15 (IC50 = 0.12 μM). The thiophene substituent (B10) in the A-ring exhibited the strongest hMAO-B inhibition structurally, however, increased residue synthesis did not result in a rise in hMAO-B inhibition. In contrast, the benzyl group at the para position of the B-ring displayed more hMAO-B inhibition than the other positions. Compounds B10 and B15 had relatively high selectivity index (SI) values for hMAO-B (504.791 and 287.600, respectively). Ki values of B10 and B15 were 0.030 ± 0.001 and 0.033 ± 0.001 μM, respectively. The reversibility study showed that B10 and B15 were reversible inhibitors of hMAO-B. PAMPA assay manifested that the benzyloxy Chalcones (B10 and B15) had a significant permeability and CNS bioavailability with Pe value higher than 4.0 × 10-6 cm/s. Both compounds were stabilized in protein-ligand complexes by the π-π stacking, which enabled them to bind to the hMAO-B enzyme's active site incredibly effectively. The hMAO-B was stabilized by B10- and B15-hMAO-B complexes, with binding energies of - 74.57 and - 87.72 kcal/mol, respectively. Using a genetic algorithm and multiple linear regression, the QSAR model was created. Based on the best 2D and 3D descriptor-based QSAR model, the following statistics were displayed: R2 = 0.9125, Q2loo = 0.8347. These findings imply that B10 and B15 are effective, selective, and reversible hMAO-B inhibitors.

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