Design, Synthesis, and Evaluation of Novel 4‑Chloropyrazole-Based Pyridines as Potent Fungicide Candidates

A rational molecular design approach was developed in
our laboratory
to guide the discovery of novel sterol biosynthesis inhibitors. Based
on the application of bioactivities of heterocyclic rings and molecular
docking targeting the sterol biosynthesis 14α-demethylase, a
series of 4-chloropyrazole-based pyridine derivatives were rationally
designed, synthesized, and characterized and their fungicidal activities
were also evaluated. Bioassay results showed that 7e, 7f, and 7m exhibited commendable, diverse antifungal
actions that are comparable to those of the positive controls imazalil
and triadimefon. The active compounds’ mode of action was further
studied by microscopy observations, Q-PCR, and enzyme inhibition assay
and discovered that target compounds affect fungal sterol biosynthesis
via disturbing RcCYP51 enzyme system. These findings
support that their fungicidal mode of action still targets the cytochrome
P450-dependent 14α-demethylase as the molecular design did at
first. The above results strongly suggest that our rational molecular
design protocol is not only practical but also efficient.