Synthesis, molecular docking, antioxidant and cholinesterase inhibitory activity of coumarin based tri-hybridized molecules: An MTDL approach for the development of anti-Alzheimer drugs

Alzheimer’s disease (AD) also known as “senile dementia” is a progressive neurodegenerative disease that is multifactorial in nature. Due to this, one drug one target approach of drug development is not practical. Hence there is a need to design safer, effective and more potent drugs capable of acting at multiple targets. The molecular hybridization of various structures that have scientifically proven pharmacological activity may yield highly potent drug candidates. We, therefore, synthesized linked 1, 3, 4-oxadiazole derivatives as multi targeted drug ligands (MTDLs) to treat AD. Coumarin motif is selected as one of the core structures in the design owing to its anticholinesterase activity beside several other biological activities. With the help of a linker, the coumarin moiety is connected to various substituted carboxylic acids to form intermediates, which was then subjected to dehydrative cyclization to obtain trihybridized compounds in which coumarin is tethered to 1, 3, 4-oxadiazole derivatives. Some of the synthesized compounds showed excellent free radical scavenging activity and In vitro anticholinesterase activity in addition to COX inhibition. Further, computational and molecular docking studies proved that hybridized compounds showed very low binding energy and good interactions with the target proteins. The most potent compound exhibited activity which was better than the positive control, galanthamine. Based on the obtained results, it can be concluded that the synthesized hybrids are powerful and promising drug candidates that can act at multiple targets involved in the pathogenesis of AD and may prove beneficial in alleviating the symptoms in AD.