Multiscale Model-Driven Discovery of Insecticides for Sustainable Agriculture: A Demonstration of Product-by-Design Approach

Discovering high-performance molecules and processes to produce them relies on expert knowledge and intuition, often requiring extensive laboratory work with many failures. Being able to predict the chemical properties of new molecules while considering the full cycle from design to environmental fate, early in the discovery phase, would streamline the process significantly. Synthetic insecticides, while effective at enhancing crop yields, pose significant risks such as biodiversity loss, pest resistance, and environmental persistence. This underscores the need for a sustainable agricultural framework, one exemplified by environmentally friendly insecticides that balance efficacy with ecological safety. This study employs a structure-directed molecular design approach to predict carbamate insecticide structures derived from renewable platform molecules. We generated and identified potential furan-based carbamates with predicted reduced ecological impact using computational tools and predictive ecological frameworks. We then utilized reaction patterns to systematically explore chemical space and generate novel bioactive structures and found that hydrogenated furan derivatives possess an improved sustainability profile. We next synthesized and evaluated ten of these molecules. Among them, methyl N-[(furan-2-yl)methyl] carbamate and methyl N-{[5-(methoxymethyl)oxolan-2-yl]methyl} carbamate exhibited high insecticidal activity against lesser mealworm beetle (Alphitobius diaperinus) with reduced ecological impact, demonstrating a sweet spot between potency and biodegradability. Our methodology paves the way for accelerated and targeted discovery of next-generation sustainable pest management solutions and, more generally, for designing innovative biobased chemicals.