Synthesis, molecular docking studies, and larvicidal activity evaluation of new fluorinated neonicotinoids against Anopheles darlingi larvae

Anopheles darlingi is the main vector of malaria in Brazil, characterized by a high level of
anthropophilia and endophagy. Imidacloprid, thiacloprid, and acetamiprid are the most wide-
spread insecticides of the neonicotinoid group. However, they produce adverse effects on
the non-target insects. Flupyradifurone has been marketed as an alternative to non-fluori-
nated neonicotinoids. Neonicotinoids containing trifluoroacethyl substituent reveal
increased insecticidal activity due to higher hydrophobicity and metabolic stability.
We synthesized novel neonicotinoid insecticides containing fluorinated acceptor groups
and their interactions were estimated with the nicotinic acetylcholine receptor (nAChR) bind-
ing site by molecular docking studies, to evaluate their larvicidal activity against A. darlingi,
and to assess their outdoor photodegradation behavior. New neonicotinoid analogues were
prepared and characterized by NMR and mass-spectrometry. The synthesized molecules
were modelled by time-dependent density functional theory and analyzed, their interaction
with nAChR was investigated by molecular docking. Their insecticide activity was tested on
Anopheles larvae collected in suburban area of Manaus, Brazil. Four new fluorinated neoni-
cotinoid analogs were prepared and tested against 3rd instars larvae of A. darlingi showing
high larvicidal activity. Docking studies reveal binding modes of the synthesized compounds
and suggest that their insecticidal potency is governed by specific interactions with the
receptor binding site and enhanced lipophilicity. 2-Chloro-5-(2-trifluoromethyl-pyrrolidin-1-
ylmethyl)pyridine 5 showed fast degradation in water maintaining high larvicidal activity. All
obtained substances possessed high larvicidal activity in low concentrations in 48 hours of
exposure, compared to commercial flupyradifurone. Such activity is connected to a unique
binding pattern of the synthesized compounds to insect’s nAChR and to their enhanced bio-
availability owing to introduction of fluorinated amino-moieties. Therefore, the compounds in
question have a high potential for application as control agents for insects transmitting tropi-
cal diseases, and they will be less persistent in the environment.