Curcumin-based pyrazoline analogues as selective inhibitors of human monoamine oxidase A

Chandrani Nath, Vishnu Nayak Badavath, Abhishek Thakur, Gulberk Ucar, Orlando Acevedo, Mohd Usman Mohd Siddique, Venkatesan Jayaprakash

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

A series of 2-methoxy-4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenol (pyrazoline) derivatives (2-6) have been synthesized and tested for human monoamine oxidase (hMAO) inhibitory activity. The most active derivative (2) behaved as a competitive hMAO-A inhibitor, with an inhibition constant value of 0.08 μM and a strong hMAO-A selectivity (Ki(hMAO-B)/Ki(hMAO-A) > 1751). In addition, 2 exhibited little to no cytotoxic effects up to a 25 μM concentration and provided the best blood-brain barrier permeability among the derivatives synthesized. Molecular dynamics simulations revealed that a chlorine substituent at the para-position of the phenyl ring in 2 enabled a π-π stacking interaction with Tyr407 and Tyr444 that resulted in the formation of an “aromatic sandwich” structure. Consequently, this tight-binding aromatic cage culminated in a dramatically reduced active site volume that is believed to be the origin of the observed selectivity between the hMAO-A and hMAO-B isozymes. Removal of the chlorine from 2 disrupted the favorable intermolecular interactions and resulted in a selectivity change towards hMAO-B.

Original languageEnglish (US)
Pages (from-to)1164-1171
Number of pages8
JournalMedChemComm
Volume9
Issue number7
DOIs
StatePublished - 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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