Ametoctradin is a Potent Qo Site Inhibitor of the Mitochondrial Respiration Complex III

Article abstract of DOI:10.1021/acs.jafc.5b00228

Ametoctradin is a new Oomycete-specific fungicide under development by BASF. It is a potent inhibitor of the bc₁ complex in mitochondrial respiration. However, its detailed action mechanism remains unknown. In the present work, the binding mode of ametoctradin was first uncovered by integrating molecular docking, MD simulations, and MM/PBSA calculations, which showed that ametoctradin should be a Q_o site inhibitor of bc₁ complex. Subsequently, a series of new 1,2,4-triazolo[1,5-a]pyrimidine derivatives were designed and synthesized to further understand the substituent effects on the 5- and 6-position of 1,2,4-triazolo[1,5-a]pyrimidine. The calculated binding free energies (ΔG_cal) of newly synthesized analogues as Q_o site inhibitors correlated very well (R² = 0.96) with their experimental binding free energies (ΔG_exp). Two compounds (4a and 4c) with higher inhibitory activity against porcine SQR than ametoctradin were successfully identified. The structural and mechanistic insights obtained from the present study will provide a valuable clue for future designing of a new promising bc₁ inhibitor.