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Elkamhawy, Ahmed,Park, Jung-eun,Hassan, Ahmed H.E.,Ra, Hyunhwa,Pae, Ae Nim,Lee, Jiyoun,Park, Beoung-Geon,Moon, Bongjin,Park, Hyun-Mee,Roh, Eun Joo Elsevier 2017 European journal of medicinal chemistry Vol.128 No.-
<P><B>Abstract</B></P> <P>Herein, we report a new series of aliphatic substituted pyridyl-urea small molecules synthesized as potential modulators for amyloid beta (Aβ) induced mitochondrial dysfunction. Their blocking activities against Aβ-induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measures the change of mitochondrial membrane potential (ΔΨm). The inhibitory activity of sixteen compounds against Aβ-induced mPTP opening was superior or almost similar to that of the standard Cyclosporin A (CsA). Among them, 1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl)ethyl)urea (<B>5x</B>) effectively maintained mitochondrial function and cell viabilities on ATP assay, MTT assay, and ROS assay. Using CDocker algorithm, a molecular docking model presented a plausible binding mode for <B>5x</B> with cyclophilin D (CypD) receptor as a major component of mPTP. Moreover, hERG and BBB-PAMPA assays presented safe cardiotoxicity and high CNS bioavailability profiles for <B>5x</B>. Taken as a whole, this report presents compound <B>5x</B> as a new nonpeptidyl mPTP blocker may hold a promise for further development of Alzheimer's disease (AD) therapeutics.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Biological activity of sixteen compounds against Aβ-induced mPTP opening was superior to that of Cyclosporin A. </LI> <LI> Compound <B>5x</B> effectively maintained mitochondrial function and cell viabilities. </LI> <LI> Molecular docking studies presented a plausible binding mode for <B>5x</B> with cyclophilin D. </LI> <LI> hERG assay presented a safe cardiotoxicity profile of <B>5x.</B> </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Elkamhawy Ahmed,Mohammad M. Al-Sanea,송치만,심태보,노은주 대한화학회 2015 Bulletin of the Korean Chemical Society Vol.36 No.7
A new series possessing [1,2,3]triazolo[4,5-d]pyrimidine scaffold was synthesized and biologically evaluated for potential antiproliferative activity. Fourteen compounds were selected for in vitro anticancer assay over a panel of 60 cell lines at National Cancer Institute (NCI), USA. The most sensitive cell lines to the synthesized compounds were leukemia (K-562 and SR), nonsmall cell lung cancer HOP-92, and melanoma MDA-MB-435. Compounds 12 and 24 exerted broad spectrum activity against most cell panel, while compounds 14, 21, and 23 exhibited effectiveness toward specific cell lines belong to different tumor subpanels. Accordingly, SAR, COMPARE analyses, and in silico ADME profiling were discussed for the target compounds. In addition, compounds 11 and 22 exerted good FGFR3 inhibitory activity with 58.8 and 46.7% at 100 μM, respectively. Taken as a whole, the present study revealed that the new series can be considered as promising lead for further development of more potent anticancer agents as well as FGFR3 kinase potential inhibitors.