Synthesis of Novel 3,4-Chloroisothiazole-Based Imidazoles as Fungicides and Evaluation of Their Mode of Action

A molecular
design approach was used in our laboratory to guide
the development of imidazole-based fungicides. Based on homology modeling
and molecular docking studies targeting the cytochrome P450-dependent
sterol 14α-demethylase, 3,4-dichloroisothiazole-based imidazoles
showed great potential. Several such compounds were then rationally
designed, synthesized, characterized, and their antifungal activities
were evaluated. Bioassay results showed that compounds such as (R)-11, (R)-12, and (S)-11 have commendable, broad-spectrum
antifungal activities that are comparable to those of commercial products.
Based on Q-PCR testing and microscopy observations, the imidazole
derivatives affect fungal cell wall formation through the inhibition
of the BcCYP51 expression system. These findings
strongly suggest that the mode of action of these imidazole compounds
is similar to that of tioconazole and imazalil. This report indicates
that this molecular design strategy is not only practical but productive.