Structural Modification, In Vitro, In Vivo, Ex Vivo, and In Silico Exploration of Pyrimidine and Pyrrolidine Cores for Targeting Enzymes Associated with Neuroinflammation and Cholinergic Deficit in Alzheimer’s Disease

Abstract

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 (23g), (3-acetylcoumarin derivative of pyrrolidin-1-yl)­benzenesulfonamide (27), and tacrine derivatives of (pyrrolidin-1-yl)­benzenesulfonamide (31, 38) displayed excellent in vitro COX-2 inhibition having IC50 value in the nanomolar range. Tacrine–pyrrolidine hybrids 36 and 38, and tacrine–pyrimidine hybrid (46) emerged as the most potent eeAChE inhibitors with IC50 values of 23, 16, and 2 nM, respectively. However, compounds 27, 31, and 38 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 ex vivo, transgenic animal models treated with compounds 36 and 46 displayed a significant decline in both AChE and BChE potentials in the hippocampus and cortical tissues. In anti-inflammatory activities, animals treated with compounds 36 and 46 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. In vivo 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 in vitro targets was confirmed by molecular docking investigations.

Antioxidant Molecules Isolated from Edible Prostrate Knotweed: Rational Derivatization to Produce More Potent Molecules

“…The cell or tissue damage is autoprotected from viral, microbial, chemical, or physical injury by the process of inflammation [ 22 ]. In inflammation, blood vessel dilation occurs which increases the intracellular space [ 23 ]. The arachidonic acid pathway plays a vital role in the mechanism of inflammation.…”

Design, Synthesis, and Bioevaluation of Indole Core Containing 2-Arylidine Derivatives of Thiazolopyrimidine as Multitarget Inhibitors of Cholinesterases and Monoamine Oxidase A/B for the Treatment of Alzheimer Disease

“…To determine the neurotoxicity of our synthesized compounds, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was performed on neuroblastoma SHSY5Y cells according to our previously reported procedure. 44 Cell viability was determined at concentration ranges of 1, 10, 20, and 40 μM. Donepezil was used as positive control.…”

3-(((1S,3S)-3-((R)-Hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-oxocyclohexyl)methyl)pentane-2,4-dione: Design and Synthesis of New Stereopure Multi-Target Antidiabetic Agent

“…The medicinal chemists used two major approaches for the discovery of new potential drugs, i.e., natural or synthetic approaches [ 39 , 40 , 41 , 42 ]. Natural products are one of the safest sources for effective drug discovery [ 43 , 44 ].…”