Application of Molecular-Modeling, Scaffold-Hopping, and Bioisosteric Approaches to the Discovery of New Heterocyclic Picolinamides

Macrocyclic natural products and their derivatives are a valuable source for biologically active crop protection products and have had significant impact on the development of conventional agrochemicals. However, they can be challenging starting points for lead-generation efforts because of their size, structural complexity, and developability. Using molecular modeling and electrostatic analysis, alternative bicyclic isosteres were identified as replacements for the antifungal nine-membered macrocycle UK-2A. By application of a structure-based conformational approach, a series of heterocyclic replacements were derivatized to deliver promising fungicidal activity and scaffold bioisosteres were further diversified to investigate structure-activity relationships.

Automated summary

Macrocyclic natural products and their derivatives are valuable sources for biologically active crop protection products. However, finding suitable starting points for lead generation can be challenging due to their size and structural complexity. In this study, alternative bicyclic isosteres were identified as replacements for the antifungal nine-membered macrocycle UK-2A using molecular modeling and electrostatic analysis. Structure-based conformational approach was then used to derivatize a series of heterocyclic replacements, resulting in promising fungicidal activity and exploration of structure-activity relationships.