Synthesis and activity‐detection of photoswitchable ligands with fipronil to insect

Abstract

BACKGROUND: Ionotropic γ-aminobutyric acid (GABA) receptor (GABAR) in an insect is the major inhibitory receptor and is one of the most important targets for insecticides. Due to the high spatiotemporal resolution of GABAR, the photopharmacological ligands acting on it in vertebrates but not insect have been developed. RESULTS: In this study, two types of photochromic ligands (PCLs) including DTFIPs (DTFIP1 and DTFIP2) and ABFIPs (p-, m-, and o-ABFIP) were synthesized by incorporating photoswitch azobenzene or dithienylethene into fipronil (FIP), which is the antagonist of insect GABAR. Their photomodulation was measured by mosquito larval behavior, and their potential action mechanism was explored by the two-electrode voltage clamp (TEVC) technique in vitro. DTFIP1 and m-ABFIP exhibited the most significant difference of insecticidal activity by about 90-and 5-fold to mosquito larvae between non-irradiated and irradiated formation, respectively, and allowed for optical control of mosquito swimming activity. TEVC assay results indicated that m-ABFIP and DTFIP1 enable optical control over the homomeric LsRDL-type GABAR, which is achieved by regulating the chloride channel of resistance to dieldrin (RDL)-type GABAR by photoisomerization. CONCLUSION: Our results suggested that PCLs synthesized from fipronil provide an alternative and precise tool for studying insect ionotropic GABARs and GABA-dependent behavior.

Design, Synthesis, and Bioactivity of Trifluoroethylthio-Substituted Phenylpyrazole Derivatives

“…N -Phenylpyrazole derivatives have been reported to possess diversiform biological activities in the pharmaceutical and agrochemical fields. − Various molecules containing this motif are successfully developed as insecticides, acaricides, and herbicides in agriculture. In particular, N -phenylpyrazoles bearing a cyanide group on 3 position, a sulfinyl or thioalkyl group on 4 position, and an amino (or substituted amino) on 5 position of the pyrazole ring exhibit potent insecticidal activity. , For instance, fipronil, as the first marketed phenylpyrazole insecticide, has been widely used in crop protection and hygiene pest control for its excellent and broad-spectrum bioactivity, and no cross-resistance with other insecticidal agents. , The proven activity of fipronil is due to the affinity on the gamma-aminobutyric acid receptors (GABARs) and the inhibited influx of chloride ions by blocking the channels enclosed with the TM2 transmembrane helixes, thus causing neurological hyperexcitability and death of pests. − Although fipronil has a high selectivity between insects and mammals, potential toxicity risks to aquatic organisms and bees are also emphasized. − Consequently, the pesticide formulations containing fipronil have been banned in China since 2009, except for sanitary and dry field seed coating use. , Therefore, it is urgently necessary to develop low toxicity and high efficiency, as well as environmentally friendly, pesticide varieties through the modification of fipronil.…”