Ligand-Based Scaffold Hopping of VU730 Identifies Natural Product-Inspired Analogs with Insecticidal and Antifeedant Activity against Asian Citrus Psyllid, Diaphorina citri

Huanglongbing (HLB), caused by the phloem-restricted bacterium Candidatus Liberibacter (CLas) vectored by the Asian Citrus Psyllid (Hemiptera: Psyllidae; ACP), has led to billion-dollar losses in the global citrus industry. Pharmacological inhibition of inward rectifier potassium (Kir) channels leads to acute mortality and inhibits CLas acquisition by ACP through salivary gland-directed antifeedant activity. Here, we designed a series of analogs that shifted synthetic Kir inhibitors toward a more biogenic chemical space through systematic modification of VU730 (C17H19N3O2). Analog 7c, which contains a benzimidazole core as the northern fragment, caused ∼50% morbidity at 10 ng/cm2 48 h after tarsal contact exposure and had greater efficacy to feeding disruption than VU730. These data define tractable structural features for identification of natural Kir inhibitors that may possess toxic and antifeedant properties and identify VU730 and 7c as priorities for development of novel mechanism insecticides for HLB prevention.