Symmetrical aryl linked bis-iminothiazolidinones as new chemical entities for the inhibition of monoamine oxidases: Synthesis,in vitro biological evaluation and molecular modelling analysis

The multifactorial nature of Parkinson’s disease necessitates the development of new chemical entities with inherent ability to address key pathogenic processes. To this end, two series of new symmetrical 1,2- and 1,4-bis(2-aroyl/alkoylimino-5-(2-methoxy-2-oxoethylidene)-4-oxo-thiazolidin-3-yl)benzene derivatives (3a–g and 5a–e) were synthesized in good yields by the cyclization of 1,2- and 1,4-bis(N′-substituted thioureido)benzene intermediates with dimethyl acetylenedicarboxylate (DMAD) in methanol at ambient temperature. The bis-iminothiazolidinone compounds were investigated in vitro for their inhibition of monoamine oxidase (MAO-A & MAO-B) enzymes with the aim to identify new and distinct pharmacophores for the treatment of neurodegenerative disorders like Parkinson’s disease. Most of the designed compounds exhibited good inhibitory efficacy against monoamine oxidases. Compound 5a was identified as the most potent inhibitor of MAO-A depicting an IC₅₀ value of 0.001 μM, a 4-fold stronger inhibitory strength compared to standard inhibitor (clorgyline: IC₅₀ = 0.0045 μM). Molecular docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed inhibition towards monoamine oxidases.