Exploration of chlorinated thienyl chalcones: A new class of monoamine oxidase-B inhibitors.
Chalcone has been reported to be a valid scaffold for the design of monoamine oxidase (MAO) inhibitors. This scenario has amplified the momentum for the discovery of heteroaryl based chalcone MAO inhibitors. In the present study, we have synthesized a series of eleven chlorinated thienyl chalcone derivatives substituted with a different functional groups at the para- position on the ring B and investigated for their ability to inhibit human MAO-A and -B. With the exception of compound (2E)-1-(4-chlorocyclopenta-1,3-dien-1-yl)-3-(4-nitrophenyl)prop-2-en-1-one (TC7), which was a selective MAO-A inhibitor, all the other derivatives inhibited hMAO-B potently and selectively with competitive mode of inhibition. The most potent compound (2E)-1-(4-chlorocyclopenta-1,3-dien-1-yl)-3-(4-ethylphenyl)prop-2-en-1-one (TC6) was found to be the best activity and higher selectivity towards hMAO-B with Ki and SI values of 0.31±0.02μM and 16.84, respectively. All the compounds presented in the current study are completely non-toxic with 74-88% viable cells to hepatic cells at 100μM concentration. Molecular docking and molecular dynamics simulation studies were carried out using Autodock-4.2 and Amber 14 to understand the molecular level interaction and energy relation of MAO isoforms with selective MAO-B inhibitor TC6.
Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad 678557, Kerala, India. Electronic address: bijovilaventgu@gmail.com.
Bijo
B
Mathew
Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad 678004, Kerala, India.
Abitha
A
Haridas
Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey. Electronic address: gulberk@hacettepe.edu.tr.
Gülberk
G
Uçar
Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey.
Ipek
I
Baysal
School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4001, South Africa.
Adebayo A
AA
Adeniyi
School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4001, South Africa.
Mahmoud E S
ME
Soliman
The School of Pure & Applied Physics, M.G. University, Kottayam, India.
Monu
M
Joy
Department of Pharmacology, Grace College of Pharmacy, Palakkad 678004, Kerala, India.
Githa Elizabeth
GE
Mathew
Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad 678004, Kerala, India.
Baskar
B
Lakshmanan
Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835 215, India.
Venkatesan
V
Jayaprakash
D020134:Catalytic Domain; D016923:Cell Death / Q000187:drug effects; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D054879:Halogenation; D056945:Hep G2 Cells; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry; D007700:Kinetics; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D025341:Principal Component Analysis; D013816:Thermodynamics
D047188:Chalcones; D007527:Isoenzymes; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase
Human monoamine oxidase; Molecular docking; Molecular dynamics; Thienyl chalcones