ML-based prediction to experimental validation: Development of dihydroquinazoline based multi-potent ligands as anti-Alzheimer's agents.

Alzheimer's disease (AD) is a multifactorial neurological disorder accounting for the cognitive decline in the patients. The disease is linked to numerous pathological factors including hyperactivation of acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B), accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles in the brain etc. The single-target medications already available in the market are found to be ineffective and the research focus is shifting towards the development of multitargeting agents. In order to find a multi-potent inhibitor against AChE, MAO-B and Aβ in the present study we employed a machine learning-based tool, PyRMD, to screen an in-house generated library of dihydroquinazoline derivatives. This screening process identified six promising compounds, KV-271, KV-832, KV-968, KV-1131, KV-1159, KV-1234 with dual inhibition potential against AChE and MAO-B enzymes. In the docking studies, these compounds showed good interactions at the active cavity of the AChE and MAO-B comparable to the standard inhibitors donepezil (AChE) and pargyline (MAO-B). To validate these predictions, the six identified compounds were synthesized and subjected to in vitro enzymatic assays. All the six compounds displayed significant inhibitory activity, with IC values below 5 μM for both AChE and MAO-B. Amongst these compounds, KV-1131 and KV-1234 were found to be the most potent inhibitors with IC values of 0.93 μM and 0.85 μM against AChE and IC values of 1.17 μM and 0.79 μM against MAO-B, respectively. In addition, KV-1131 and KV-1234 exhibited inhibitory activity against Aβ self-aggregation inhibition of 34.79 % and 45.70 %, respectively, after 48 h of incubation. Both KV-1131 and KV-1234 were found to be non-toxic up to 10 μM concentration and showed neuroprotective potential against 6-hydroxydopamine induced neurotoxicity in the SHSY-5Y cells. Thus, KV-1131 and KV-1234 were identified as potent leads that can be developed as drug candidates for the treatment of Alzheimer's disease.