Symmetrical aryl linked bis-iminothiazolidinones as new chemical entities for the inhibition of monoamine oxidases: Synthesis,in vitro biological evaluation and molecular modelling analysis |
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Affiliation: | 1. Department of Chemistry, Faculty of Life Science, The University of Haripur, KPK 22620, Pakistan;2. Department of Biochemistry, Faculty of Life Sciences, University of Central Punjab, Lahore 54590, Pakistan;3. Department of Physics, Hacettepe University, Beytepe-Ankara 06800, Turkey;4. Department of Chemistry, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand;5. Department of Food Science and Nutrition, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;6. Department of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;7. Department de Química, Universitat de les Illes Balears, Crta de Valldemossa km 7.5, Palma de Mallorca (Baleares) 07122, Spain;8. Department of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom |
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Abstract: | 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. |
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Keywords: | Heterocycles Inhibition Monoamine oxidases Neurodegenerative diseases |
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