Design, Synthesis and Cholinesterase Inhibitory Potential of 6H-benzo[c] Chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c] Chromen-6-one Derivatives

Alzheimer’s disease (AD) is one of the neurodegenerative diseases of the central nervous system. Although its first diagnosis by Alois Alzheimer goes back to century, its pathophysiology has not been clearly described. Therefore, there is no drug present that totally cures the disease. The main symptom of the disease, disability in cognitive symptoms, has triggered scientists to discover agents aiding in the relief of the decline in the cognition. Today, we have several agents employed in clinic to slow down the progress of the cognitive decline. These drugs are cholinesterase inhibitor molecules and they do not completely cure the disease state, but they are beneficial in the treatment of AD symptoms. The limited number of drugs and the debate on their efficiency as well as the incidence and economic burden of AD create big opportunities to medicinal chemists to design novel drug candidates that might possess better potency and efficacy for the treatment of the AD. From this point of view; we have designed novel urolithin analogs as drug candidates for the treatment of cognitive symptoms of AD within this study. Urolithins are benzo [c] chromen analogues, available as ellagitannin metabolites. Ellagitannins are abundant in berry-fruits and various types of nuts obtained through nutrition. Although these type nutrition have been suggested to relief the symptoms of AD, their main absorbed metabolites within the biological systems, urolithins, are not potent inhibitor of cholinesterase enzymes, the validated targets of AD. Employing the drug-like properties of urolithins we have designed ten novel urolithin analogues promising to be the potent inhibitors of AD. The ten novel urolithin derivative compounds were synthesized with appropriate methodology and their structure identification studies were achieved utilizing modern chromatography and instrumental-spectral techniques. The title compounds synthesized were evaluated in biological experiments. At one hand, their potential to inhibit cholinesterase enzymes was screened. On the other hand, the title compounds were also assayed in the cholinesterase induced amyloid beta aggregation assays. The results indicated that, the title compounds are promising and their potency is comparable to the activity of current drugs, also employed as references in biological assays. In addition to these, the possible interaction of the title compounds with the active site of the cholinesterase enzyme was also investigated employing the molecular docking programs. The results revealed out potential functional groups present within the design crucial for the determination of the pharmacophore system. Keywords: Cholinesterase inhibitor, Amyloid beta aggregation, Urolithin derivatives