Exploration of chlorinated thienyl chalcones: A new class of monoamine oxidase-B inhibitors

• Synthesized eleven chlorinated thienyl chalcones.
• Compounds showed reversible, selective and competitive MAO-B inhibition except TC7.
• X-ray data of structure refinement of lead compound TC6.
• Structure–activity relationship has been established.
• Molecular docking and Molecular dynamics study of the lead compound.

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 ± 0.02 μM 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 100 μM 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.