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- 저자 : Dhorma, Lama Prema (검색결과 1 건)
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Venkanna, Arramshetti,Cho, Kyo Hee,Dhorma, Lama Prema,Kumar, Duddukuri Nandan,Hah, Jung Mi,Park, Hyeung-geun,Kim, Sun Yeou,Kim, Mi-hyun Elsevier 2019 European journal of medicinal chemistry Vol.163 No.-
<P><B>Abstract</B></P> <P>Here we first time report an unprecedented and unnatural six-membered 1,5-oxaza spiroquinone scaffold with structural novelty, a convenient and efficient synthetic route was developed for the synthesis of new 1,5-oxaza spiroquinone derivatives (<B>1a-1r)</B> in high yields from readily available starting materials. The logic of the present work consists of (1) the identification of a promising unprecedented scaffold from privileged scaffolds of biological active molecules through our ‘Chemistry-oriented Synthesis’ (ChOS) approach, a compensatory strategy for target-based drug discovery, (2) the positioning of the identified 1,5-oxaza spiroquinone scaffold on neuroinflammation and neurodegenerative disease through nitric oxide (NO) inhibitory activity without cytotoxicity in hyper-activated microglia (IC<SUB>50</SUB> of NO production: 0.07–1.82 μM) to establish structure–activity relationship (SAR), (3) the investigation on the possibility as a selective kinase inhibitor related to neurodegenerative diseases (eg. JNK1, CDK2, DAPK1) through kinase full panel screening of the most potent compound <B>1n</B>, and (4) the evaluation on <I>in vivo</I> efficacy of the compound <B>1n</B> through Y-maze test.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Designed unprecedented 1,5-oxaza spiroquinone core with our ‘Chemistry-oriented Synthesis’ (ChOS) approach and synthetic route was developed for six-membered 1,5-oxaza spiroquinone core. </LI> <LI> Eighteen derivatives were synthesised, characterized and evaluated their neuroprotective effect. </LI> <LI> Compound <B>1n</B> displayed excellent effect on NO (Nitic Oxide) inhibition in BV-2 Cell lines with IC<SUB>50</SUB> values <B>0.07 ± 0.01</B> μM. </LI> <LI> Kinase screening and Molecular docking studies were performed with potent compound <B>1n</B> to explore kinase inhibition activity and its potential binding mechanisms. </LI> <LI> Compound <B>1n</B> could prevent spatial short-term memory deficits induced by scopolamine. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
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