Halichonine B Inspired Design and Divergent Optimization of Drimanyl Amine for Novel Antimicrobial Leads

Structurally unique halichonine B is promising for the design of pharmaceutical leads, while function-oriented optimization is unknown in agrochemical science. Our recent practical synthesis offers a great chance for the discovery of antimicrobial leads. "Linker plus replaceable substituents" is exerted, in which up to 9 unique linkers together with diverse substituents from a wide chemical space are investigated for optimization of the readily available drimanyl amine. The diamine- or amino amide-related C₂- or C₃-linker is preferred for increasing the bioactive potency. <i>N</i>,<i>N</i>'-bis(substituted) ethylenediamine <b>5a</b> exhibited significant activity against <i>Phytophthora capsici</i> with the effective concentration (EC₅₀) value of 9.91 μM. 2-Amino-drimanylacetamides <b>3n</b> (EC₅₀ = 7.27 μM) and <b>3s</b> (EC₅₀ = 6.42 μM) are selected as leads against <i>Sclerotinia sclerotiorum</i>. Compounds <b>3t</b> and <b>4i</b> were highly potent against fungal, oomycete, and bacterial plant pathogens and bacterial foodborne pathogens in vitro. The EC₅₀ value of <b>4i</b> was 5.31 μM against <i>Ralstonia solanacearum</i>, demonstrating >18-fold improvement over that of the commercial antibacterial agent thiodiazole-copper. It demonstrated a pronounced inhibitory effect on the swarming motility and biofilm formation of <i>R. solanacearum</i>. Beneficial properties are acquired for promising leads <b>4i</b>, <b>3n</b>, and <b>5a</b> through cheminformatics analysis. Synthetically tractable optimization of linkers could augment lead identification and may play an extraordinary role in optimizing and expanding the chemical space of drimanyl amine, further enhancing its impact on lead discovery.