Multiscale mechanistic modeling for the rational design of novel dual-target candidates against acetylcholinesterase and NADPH oxidase: an advanced computational study.

Introduction: Alzheimer's disease is a complex neurodegenerative illness strongly associated with oxidative stress, which requires immediate intervention for therapeutic agents with potent antioxidant properties. Methods: In this work, novel derivatives based on benzofuran and pyrazole scaffolds were designed and assessed for their antioxidant potential and acetylcholinesterase inhibitory activity. The identification of key molecular characteristics that are important for the ability of a compound to scavenge DPPH radicals and AChE cholinesterase and has been accomplished through SAR, then both CoMFA and CoMSIA 3D-QSAR modelling have been used to design fifteen new compounds (D1-D15) which inhibit both DPPH and AChE to a significantly greater extent than the parent compound. Density functional theory calculations at the B3LYP/6-31G (d,p) level revealed that the three most promising candidates (M12, D8, and D9) have quite high electronic and molecular stability. Results and Discussion: The results of pharmacokinetic tests, molecular docking, and 100 ns molecular dynamics experiments confirm that these examined compounds interact favorably with both human acetylcholinesterase and NADPH oxidase enzymes with excellent thermodynamic stability. These results provide further evidence for the potential of the designed compounds to behave as multi-target ligands with AChE inhibition and antioxidant properties that would be effective in the treatment of the complex Alzheimer's disease.