Structural Modification, , , , and Exploration of Pyrimidine and Pyrrolidine Cores for Targeting Enzymes Associated with Neuroinflammation and Cholinergic Deficit in Alzheimer's Disease.

To obtain a multipotent framework that can target simultaneously COX-2, 5-LOX, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) to treat neuroinflammation, a series of derivatives containing pyrimidine and pyrrolidine cores were rationally synthesized and evaluated. Pyrazoline-pyrimidine hybrid (), (3-acetylcoumarin derivative of pyrrolidin-1-yl)benzenesulfonamide (), and tacrine derivatives of (pyrrolidin-1-yl)benzenesulfonamide (, ) displayed excellent COX-2 inhibition having IC value in the nanomolar range. Tacrine-pyrrolidine hybrids and , and tacrine-pyrimidine hybrid () emerged as the most potent AChE inhibitors with IC values of 23, 16, and 2 nM, respectively. However, compounds , , and possessed excellent simultaneous and balanced inhibitory activity against all of the four tested targets and thus emerged as optimal multipotent hybrid compounds among all of the synthesized series of the compounds. In the , transgenic animal models treated with compounds and displayed a significant decline in both AChE and BChE potentials in the hippocampus and cortical tissues. In anti-inflammatory activities, animals treated with compounds and displayed a significant % inhibition of edema induced by carrageenan and arachidonic acid. Biochemical analysis and histopathological examination of mice liver indicate that tacrine derivatives are devoid of hepatotoxicity and neurotoxicity against SH-SY5Y neuroblastoma cell lines. acute toxicity study showed the safety of synthesized compounds up to 1000 mg/kg dose. The inhibitory manner of interaction of these potent drugs on all of the studied targets was confirmed by molecular docking investigations.