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  3. Synthesis, Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO-B Inhibitors

Synthesis, Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO-B Inhibitors

  • ChemMedChem. 2016 Jun 6;11(11):1161-71. doi: 10.1002/cmdc.201600122.
Bijo Mathew 1,  Abitha Haridas 2,  Gülberk Uçar 3,  Ipek Baysal 4,  Monu Joy 5,  Githa E Mathew 6,  Baskar Lakshmanan 2,  Venkatesan Jayaprakash 7
Affiliations

Affiliations

  • 1 Division of Drug Design and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, 678557, Kerala, India. bijovilaventgu@gmail.com.
  • 2 Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad, 678004, Kerala, India.
  • 3 Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey. gulberk@hacettepe.edu.tr.
  • 4 Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey.
  • 5 School of Pure & Applied Physics, Mahatma Gandhi University, Kottayam, 686560, India.
  • 6 Department of Pharmacology, Grace College of Pharmacy, Palakkad, 678004, Kerala, India.
  • 7 Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, 835215, Jharkhand, India.
PMID: 27159243 DOI: 10.1002/cmdc.201600122
Abstract

A series of (2E)-1-(5-bromothiophen-2-yl)-3-(para-substituted phenyl)prop-2-en-1-ones (TB1-TB11) was synthesized and tested for inhibitory activity toward human Monoamine Oxidase (hMAO). All compounds were found to be competitive, selective, and reversible toward hMAO-B except (2E)-1-(5-bromothiophen-2-yl)-3-(4-nitrophenyl)prop-2-en-1-one (TB7) and (2E)-1-(5-bromothiophen-2-yl)-3-(4-chlorophenyl)prop-2-en-1-one (TB8), which were selective inhibitors of hMAO-A. The most potent compound, (2E)-1-(5-bromothiophen-2-yl)-3-[4-(dimethylamino)phenyl]prop-2-en-1-one (TB5), showed the best inhibitory activity and higher selectivity toward hMAO-B, with Ki and SI values of 0.11±0.01 μm and 13.18, respectively. PAMPA assays for all compounds were carried out in order to evaluate the capacity of the compounds to cross the blood-brain barrier. Moreover, the most potent MAO-B Inhibitor, TB5, was found to be nontoxic at 5 and 25 μm, with 95.75 and 84.59 % viability among cells, respectively. Molecular docking simulations were carried out to understand the crucial interactions responsible for selectivity and potency.

Keywords

chalcones; cytotoxicity; molecular docking; monoamine oxidases.

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