Synthesis and evaluation of novel dihydropyrimidine–oxadiazole hybrid scaffolds as anticholinesterase agents: SAR and in-silico studies

Alzheimer's disease (AD) is the most prevalent form of dementia all around the globe and currently poses a significant challenge to the healthcare system. Currently, available drugs only slow the progression of this disease rather than provide a proper cure for it. Acetylcholinesterase (AChE) enzyme is mainly responsible for the progression of AD, and its management can be done by developing its inhibitors, such as anticholinesterases. We have synthesized a series of novel dihydropyrimidine–oxadiazole hybrids (8a–8ad) via one-pot economic Biginelli reaction using cobalt perchlorate catalyst. The synthesized compounds were subjected to anticholinesterase activity, which showed promising inhibition of the AChE enzyme. Among all the compounds, 8u (IC₅₀ = 0.050 ± 0.007 μM) and 8v (IC₅₀ = 0.057 ± 0.004 μM) were found to be the most potent. Furthermore, molecular docking and molecular dynamics simulations were employed to gain deeper insights into the interactions at the enzyme's active site. The results demonstrated that the compound exhibited conformational stability similar to the reference inhibitor, donepezil.