Novel isoxazole and pyrazole analogs based on natural biphenyl-neolignan honokiol were synthesized and evaluated for their inhibitory activities against nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells. The isoxazole skeleton was constructed via nitrile oxide cycloaddition from oxime 3 and pyrazole was generated by condensation of 4-chromone and alkyl hydrazine. Following, we synthesized a series of 17 isoxazole and 18 pyrazole derivatives and evaluated their inhibitory effects on NO production in LPS-activated BV-2 cells. Among the prepared compounds, 13b and 14a inhibited NO production in LPS-activated BV-2 cells by suppressing iNOS and COX-2 expression. The pyrazole analog 14a was the most potent inhibitor. These findings provide insight into the structural features influencing biological activities of this class of compounds and provide a foundation for further studies of analog design. Recently, retinoid X receptor was studied as the only binding protein of honokiol derivatives, although the various biological activities of honokiol were well known. Our synthetic and medicinal chemistry work would be exploited to design photoaffinity probes for target identification using a forward chemical genetic approach. Further analysis of the mode of action and biological activity in vivo of these pyrazole analogs as well as their potential as novel drug candidates is under way.

Synthesis and anti-neuroinflammatory activity of N-heterocyclic analogs based on natural biphenyl-neolignan honokiol

2019 Fall National Meeting

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