A Pyrazole-Amide-Azobenzene scaffold for the photocontrollable modulation of succinate dehydrogenase: synthesis, photophysical and biological properties.
Aiming to resolve the issues resulting from the widespread use of antifungal in agricultural production, a series of novel Pyrazole-Amides-Azobenzenes (PAAs) has been designed and synthesized by incorporating the photochromic azobenzene moiety into the pharmacophore, endowing them with both antifungal and photoswitching properties. The majority of compounds (especially target compounds A3 and A4) achieved visible light-induced transition from the trans-isomer to cis-isomer. In addition, the in vitro inhibitory activity of compound A3 against Phytophthora capsici increased from an initial 64.2% (trans-isomer) to 89.2% (cis-isomer enriched) with irradiation of 410 nm light. Following the combined enzyme inhibition assays, molecular docking simulations, and molecular dynamics simulation (MD) indicate that these compounds function as ligands targeting succinate dehydrogenase (SDH), exhibiting pronounced differences in enzyme inhibition efficacy between the cis- and trans-isomers. Notably, compounds A3 and A4 exhibited moderate SDH inhibition and low toxicity (against HK-2) in the absence of light irradiation, whereas their inhibitory activity against SDH and toxicity (against HK-2) were significantly enhanced upon irradiation at 410 nm. In addition, zebrafish embryo hatching research have demonstrated that both the trans and cis isomers of compound A4 exhibit low toxicity. Consequently, this light-controlled pharmacological behavior provides practical evidence supporting the application of the PAAs scaffold as a targeted succinate dehydrogenase inhibitor (SDHI) in agricultural production.