Computationally Guided Design and Biological Evaluation of New Benzoxazole Bridged thiazole based 1,3-Oxazole Conjugates as Potential Anti-Alzheimer's Agents: Molecular Docking, DFT and sADMET Studies

Abstract

Alzheimer's disease (AD) remains one of the most devastating neurodegenerative disorders, characterized by progressive cognitive impairment associated with cholinergic dysfunction. In pursuit of potent dual cholinesterase inhibitors, a series of structurally diverse benzoxazole linked thiazole based 1,3-oxazole molecular hybrids were rationally designed, synthesized, and biologically evaluated as multifunctional anti-Alzheimer agents. The target compounds were synthesized in satisfactory yields, and their chemical structures were unequivocally established by 1 H-NMR, 13 C-NMR, and high-resolution electron ionization mass spectrometry (HREI-MS) analyses. The synthesized hybrids exhibited promising inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), with IC 50 values ranging from 0.64 ± 0.38 to 8.34 ± 0.45 μM and 1.32 ± 0.45 to 10.53 ± 0.35 μM, respectively. Among the synthesized series, compounds 6, 7, 9, 12 and 13 emerged as the most potent dual cholinesterase inhibitors to display sub-micromolar to low- micromolar inhibition against AChE (IC 50 = 1.07 ± 0.65, 0.64 ± 0.38, 1.18 ± 0.98, 1.30 ± 0.70 and 0.90 ± 0.64 μM) and BuChE (IC 50 = 1.60 ± 0.40, 1.32 ± 0.45, 1.90 ± 0.40, 2.10 ± 0.97 and 1.55 ± 1.38 μM), with inhibitory potencies comparable to or exceeding that of the reference inhibitor donepezil (1.51 ± 0.12 and 2.30 ± 0.96 μM) respectively for AChE and BuChE. Preliminary structure-activity relationship (SAR) analysis revealed that both the nature and spatial orientation of the substituents on the benzoxazole-oxazole framework play a critical role in modulating dual cholinesterase inhibition. To gain molecular-level insights into ligand-target recognition, molecular docking studies were performed using the most active analogues that reveal favorable binding conformations and key non-covalent interactions within the catalytic gorge of both cholinesterase enzymes. The computational findings were in excellent agreement with the biological results and provided a plausible structural basis for the observed inhibitory activities. Hence, these findings identify benzoxazole-oxazole linked thiazole molecular hybrids as promising lead scaffolds for the development of next-generation multifunctional therapeutics for the treatment of Alzheimer's disease.