Novel Sunifiram-carbamate hybrids as potential dual acetylcholinesterase inhibitor and NMDAR co-agonist: simulation-guided analogue design and pharmacological screening.

An efficient method for synthesising NMDAR co-agonist Sunifiram (DM235), in addition to Sunifram-carbamate and anthranilamide hybrids, has been developed in high yields protecting group-free stepwise unsymmetric diacylation of piperazine using -acylbenzotiazole. Compounds , and exhibited promising nootropic activity by enhancing acetylecholine (ACh) release in A549 cell line. Moreover, the carbamate hybrid was found to exhibit higher potency than donepezil with IC = 18 ± 0.2 nM, 29.9 ± 0.15 nM for and donepezil, respectively. was also found to effectively inhibit AChE activity in rat brain (AChE = 1.266 ng/mL) compared to tacrine (AChE = 1.137 ng/ml). An assessment of the ADMET properties revealed that compounds and are drug-like and can penetrate blood-brain barrier. Findings presented here showcase highly potential cholinergic agents, with expected partial agonist activity towards glycine binding pocket of NMDAR which could lead to development and optimisation of novel nootropic drugs.