| Summary: | A large number of studies have shown that matrine (<b>MA</b>) possesses various pharmacological activities and is one of the few natural, plant-derived pesticides with the highest prospects for promotion and application. Fifty-eight <b>MA</b> derivatives were prepared, including 10 intermediates and 48 target compounds in 3 series, to develop novel mosquitocidal agents. Compounds <b>4b</b>, <b>4e</b>, <b>4f</b>, <b>4m</b>, <b>4n</b>, <b>6e</b>, <b>6k</b>, <b>6m</b>, and <b>6o</b> showed good larvicidal activity against <i>Aedes albopictus</i>, which is both a highly aggressive mosquito and an important viral vector that can transmit a wide range of pathogens. Dipping methods and a bottle bioassay were used for insecticidal activity evaluation. The LC<sub>50</sub> values of <b>4e</b>, <b>4m</b>, and <b>6m</b> reached 147.65, 140.08, and 205.79 μg/mL, respectively, whereas the LC<sub>50</sub> value of <b>MA</b> was 659.34 μg/mL. Structure–activity relationship analysis demonstrated that larvicidal activity could be improved by the unsaturated heterocyclic groups introduced into the carboxyl group after opening the D ring. The <b>MA</b> derivatives with oxidized N-1 lost their mosquitocidal activities, indicating that the bareness of N-1 is crucial to maintain their anti-mosquito activity. However, the activity was not greatly influenced by introducing a cyan group at C-6 or a benzene sulfonyl group at N-16. Additionally, compounds <b>4e</b> and <b>4m</b> exhibited good inhibitory activities against acetylcholinesterase with inhibitory rates of 59.12% and 54.30%, respectively, at a concentration of 250 μg/mL, whereas the inhibitory rate of <b>MA</b> was 9.88%. Therefore, the structural modification and mosquitocidal activity of <b>MA</b> and its derivatives obtained here pave the way for those seeking strong mosquitocidal agents of plant origin.
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