Design and synthesis of novel benzothiazole-piperazine propanamide derivatives for multi-targeted approach in Alzheimer's disease treatment

In this study, seventy novel benzothiazole-piperazine propanamide derivatives were synthesized with the aim of obtaining multi-target directed ligands for the treatment of Alzheimer's disease. The structures of synthesized compounds were elucidated by spectroscopic analyses and their purities were confirmed. Firstly, in vitro cholinesterase inhibitory activity assays were performed. Compounds possessed potent cholinesterase inhibitory activities were further subjected to in vitro radioligand binding assays for sigma 1/2 receptors and GluN2B subunit of NMDA receptor. In general, alkyl derivatives possessed higher binding affinities. Overall, eight compounds (4, 5, 8, 11, 12, 13, 16 and 48) were found to possess potent cholinesterase inhibitory activity, sigma 1 and/or 2 receptor and GluN2B binding affinity. Among them, compounds 12, 13 and 16 were determined as lead compounds demonstrating nanomolar scale activity against all tested targets. Furthermore, elelven compounds (4, 5, 7, 8, 11, 12, 13, 16 and 47 - 49) were tested for their P2X7 receptor inhibitory activities. Derivatives with nitrogen bearing aromatic ring (47, 48 and 49) displayed good P2X7 inhibitory activity whereas lead compounds did not show any activity. Compounds demonstrated cytotoxicity of similar to or lower than that of donepezil against human neuroblastoma cell line (SH-SY5Y). All of the predicted drug-likeliness properties regarding these compounds were in the range of recommended values. Lastly, docking studies were performed for compounds which displayed the highest activity to elucidate the responsible interactions with corresponding active site of each target. General scaffold demonstrated similar interactions with donepezil on acetylcholinesterase active site by π-π stacking with Trp286 and hydrogen bond with Phe295. Additional interactions were observed in accordance with piperazine substitution pattern.