Small molecules as arthropod kinin receptor antagonists, feeding modulators, or novel mosquitocidal agents

Aedes aegypti and Culex quinquefasciatus mosquitoes are primary vectors for numerous human and animal pathogens and each pose significant global health threats. The worldwide problem of insecticide resistance prompted the search for novel targets and “lead” insecticidal chemistries. Herein, small molecules identified in a screen of a 20,000-compound random library as antagonists of the tick kinin receptor were investigated for activity against mosquitoes through a multipronged approach. This included an Aedes kinin receptor-based screen for potential antagonists and their structure-activity relationships. Out of the 88 small molecules screened, ten kinin receptor antagonists were identified, among which one small molecule showed myoinhibitory activity on mosquito hindgut contraction, increased female sugar-feeding behavior, and potentiated mortality by malathion, all consistent with antagonism of the kinin system. Two identified structurally related molecules that were not kinin receptor antagonists but were adulticidal for both mosquito species at sub-micromolar levels when applied topically, and disrupted feeding when applied at the LC25. The activity of these small molecules, and their likely novel mode of action, offer a promising pathway for developing feeding stimulants for attractive targeted sugar baits and are chemical leads for future insecticide development.