An ionic liquid promoted approach to bitriazolyl compounds as succinate–ubiquinone oxidoreductase inhibitors

Abstract

The respiratory chain succinate–ubiquinone oxidoreductase (SQR or complex II) is a promising target for fungicide discovery. As a continuation of our research work on the development of new fungicides, a series of bitriazolyl compounds were designed and synthesized in excellent yields by an ionic liquid promoted 1,3-dipolar Huisgen cycloaddition reaction of azides and akynes. These newly synthesized compounds were characterized by ¹H NMR, ¹³C NMR and HR-MS spectroscopy. The in vitro assay indicated that several compounds displayed good inhibitory effects against porcine succinate–cyctochrome reductase (SCR) with IC₅₀ values ranging from 2.89 to 61.19 μM. Compound 1b with an IC₅₀ value of 2.89 μM, comparable to the commercial control penthiopyrad, was identified as the most promising inhibitor. Further evaluation of the representative compounds against respective SQR and cyt bc₁ indicated that their inhibitory potency against SQR was much higher than that against cyt bc₁, suggesting that SQR might be a potential target of these inhibitors. Furthermore, molecular docking studies suggested that strong hydrogen bonding and π–π stacking interactions might be responsible for a higher SQR inhibitory effect of compound 1b as compared to that of compounds 1d and 2b. Consequently, bitriazolyl compounds, a totally new skeleton that is distinct from the existing commercial SQR-inhibiting fungicides, were discovered, which could potentially be a new lead for further development of SQR inhibitors.