Necessity of Merging Dual-Action SDHI and Strobilurin Fungicides with Microbial Bio-Fungicides to Counter Genetic Resistance: A Molecular Docking Study

The increasing prevalence of fungicide-resistant pathogens, exacerbated by global warming and climate-driven changes in forest ecosystems, poses a major threat to agricultural productivity and food security. To address this challenge, we investigated the design of dual-activated fungicides combining SDHI (succinate dehydrogenase inhibitors) and QoI (strobilurin) pharmacophores, alongside microbial bio-fungicides. Novel hybrid structures were generated by merging SDHI and strobilurin moieties and were evaluated through molecular docking simulations against the active sites of fungal plant pathogens. The results demonstrated that the hybrid compounds exhibited more favorable binding energies (more negative ΔG) compared with several commercial fungicides, indicating enhanced inhibitory potential. In parallel, the aromaticity of central rings in the SDHI and strobilurin fragments was quantified using nucleus-independent chemical shift (NICS) calculations, revealing a linear correlation between ring aromaticity and predicted fungicidal activity. This relationship provides a rational framework for predicting the performance of dual-acting fungicides under varying environmental conditions, including temperature, soil pH, and local climate factors. The findings support the central hypothesis that climate-driven increases in fungal resistance can be mitigated by designing dual-activated fungicides with optimized aromaticity, thereby enhancing binding affinity at fungal targets and improving overall inhibitory activity. This approach enables the rational design of climate-adaptive pesticides for fruits and vegetables, combining synthetic and microbial strategies to maintain efficacy against resistant strains while addressing emerging agricultural challenges.