Multitarget synthetic piperates against key drug targets of Alzheimer's and diabetes mellitus

Abstract

A library of piperate derivatives 3–25 was synthesized in a two-step reaction scheme starting from piperine 1, which was converted to piperic acid 2 first, and then reacted with various alkyl and aryl halides to afford the final products. Compounds were fully characterized and evaluated for their multitarget potential against well-established drug targets involved in diabetes and Alzheimer's diseases. In vitro assay revealed strong inhibitory activity against acetylcholinesterase (AChE), butylcholinesterase (BChE), α-glucosidase, and α-amylase. Compounds 6–15, 19, and 21–23 were potent inhibitors of AChE, and compounds 6–8, 12–15, 19, and 21–23 were also more effective inhibitors of BChE than the standard donepezil. Compounds bearing halogens (F, Cl, and Br) exhibited noteworthy inhibitory potency against both targets. In addition, compounds 2, 3, 17, 18, and 25 were recognized as potent α-glucosidase and α-amylase inhibitors, outperforming standard acarbose. In particular, piperic acid (2) and compounds containing the cyanomethyl (compound 3), 3-methoxyphenyl (compounds 17, 18), and 2-nitrophenyl (compound 25) moieties showed remarkable inhibitory potential. Further, kinetic studies were conducted to unravel the inhibition mechanism against all four enzymes, while in silico studies identified key interactions between inhibitors and the active-site residues of each target. All compounds also displayed reasonable antioxidant potential, as evidenced by FRAP, CUPRAC, and DPPH assays, compared with the standard butylated hydroxytoluene (BHT). Detailed pharmacokinetic and ADME profiles were also predicted to assess the druggability of the compounds. The identified ligands have multitarget potential to inhibit the key enzymes associated with diabetes and Alzheimer's. They may serve as lead candidates for later stages of drug development.