Facile diverted synthesis of pyrrolidinyl triazoles using organotrifluoroborate: discovery of potential mPTP blockers

다국어 초록 (Multilingual Abstract)

<P>This article describes the rapid and diversified synthesis of pyrrolidinyl triazoles for the discovery of mitochondrial permeability transition pore (mPTP) blockers. The 1,3-dipolar cycloaddition of ethynyl trifluoroborate with azidopyrrolidine produced a key intermediate, triazolyl trifluoroborate <B>4</B>, which subsequently underwent a Suzuki–Miyaura coupling reaction to afford a series of 1,4-disubstituted triazoles <B>2</B>. Subsequent biological evaluation of these derivatives indicated <B>2ag</B> and <B>2aj</B> as the most potent mPTP blockers exhibiting excellent cytochrome P450 (CYP) stability when compared to the previously reported oxime analogue <B>1</B>. The present work clearly demonstrates that a 1,2,3-triazole can be used as a stable oxime surrogate. Furthermore, it suggests that late-stage diversification through coupling reactions of organotrifluoroborates is suitable for the rapid discovery of biologically active molecules.</P>

<P>Graphic Abstract</P><P>Pyrrolidinyl triazoles were synthesized <I>via</I> Huisgen 1,3-dipolar cycloadditions of ethynyl trifluoroborate followed by Suzuki–Miyaura coupling reactions and biologically evaluated as potential mPTP blockers.
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