Pyrazinyl ureas revisited: 1-(3-(Benzyloxy)pyrazin-2-yl)-3-(3,4-dichlorophenyl)urea, a new blocker of Aβ-induced mPTP opening for Alzheimer's disease

• Published in: European journal of medicinal chemistry Vol. 157; pp. 268 - 278
• Main Authors: Elkamhawy, Ahmed, Park, Jung-eun, Hassan, Ahmed H.E., Pae, Ae Nim, Lee, Jiyoun, Paik, Sora, Park, Beoung-Geon, Roh, Eun Joo
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.09.2018; Elsevier
• Subjects: Alzheimer's disease (AD); Aβ-induced neurotoxicity; Chemistry, Medicinal; Cyclophilin D; Life Sciences & Biomedicine; Mitochondrial permeability transition pore (mPTP); Pharmacology & Pharmacy; Science & Technology; Urea; β-amyloid peptide (Aβ); Urea; Alzheimer's disease (AD); Cyclophilin D; β-amyloid peptide (Aβ); Mitochondrial permeability transition pore (mPTP); Aβ-induced neurotoxicity; INDUCED MITOCHONDRIAL DYSFUNCTION; PERMEABILITY TRANSITION PORE; DESIGN; A beta-induced neurotoxicity; MODULATORS; POTENT INHIBITORS; DISCOVERY; CYCLOPHILIN-D; AMYLOID-BETA; beta-amyloid peptide (A beta); DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.07.068

Herein, we report synthesis and evaluation of new twenty-eight pyrazinyl ureas against β amyloid (Aβ)-induced opening of mitochondrial permeability transition pore (mPTP) using JC-1 assay which measures the change of mitochondrial membrane potential (ΔΨm). The neuroprotective effect of seventeen compounds against Aβ-induced mPTP opening was superior to that of the standard Cyclosporin A (CsA). Among them, 1-(3-(benzyloxy)pyrazin-2-yl)-3-(3,4-dichlorophenyl)urea (5) effectively maintained mitochondrial function and cell viabilities on ATP assay and MTT assay. Also, hERG channel assay presented safe cardiotoxicity profile for compound 5. In addition, using CDocker algorithm, a molecular docking model presented a plausible explanation for the elicited differences in efficiencies of the synthesized compounds to reduce the green to red fluorescence as indication of mPTP closure. Hence, this report presents compound 5 as the most promising pyrazinyl urea-based mPTP blocker up to date. [Display omitted] •Biological activity of 17 analogs against Aβ-induced mPTP opening was superior to that of CsA.•Derivative 5 had a safe profile regarding ATP production, cell viability and hERG.•Molecular modeling study predicted plausible binding modes explaining the elicited mPTP blocking activity.•This study suggests compound 5 as potential lead for further development towards AD therapy.