Synthesis and evaluation of 2-(3-arylureido)pyridines and 2-(3-arylureido)pyrazines as potential modulators of A beta-induced mitochondrial dysfunction in Alzheimer's disease

Abstract

A series of 2-(3-arylureido)pyridines and 2-(3-benzylureido)pyridines were synthesized and evaluated as potential modulators for amyloid beta (A beta)-induced mitochondrial dysfunction in Alzheimer's disease (AD). The blocking activities of forty one small molecules against A beta-induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measures the change of mitochondrial membrane potential (Delta psi m). The inhibitory activity of twenty five compounds against A beta-induced mPTP opening was superior to that of the standard cyclosporin A (CsA). Six hit compounds have been identified as likely safe in regards to mitochondrial and cellular safety and subjected to assessment for their protective effect against A beta-induced deterioration of ATP production and cytotoxicity. Among them, compound 7fb has been identified as a lead compound protecting neuronal cells against 67% of neurocytotoxicity and 43% of suppression of mitochondrial ATP production induced by 5 mu M concentrations of A beta. Using CDocker algorithm, a molecular docking model presented a plausible binding mode for these compounds with cyclophilin D (CypD) receptor as a major component of mPTP. Hence, this report presents compound 7fb as a new nonpeptidyl mPTP blocker which would be promising for further development of Alzheimer's disease (AD) therapeutics. (C) 2017 Elsevier Masson SAS. All rights reserved.