Design, Synthesis, Insecticidal Evaluation and Modeling Studies on 1,4,6,7- tetrahydropyrazolo[3,4-d][1,3]oxazine Derivatives: An Application of Scaffold Hopping Strategy on Fipronil

Abstract

Background:: As the first phenylpyrazole pesticide, fipronil has been widely used in crop protection and public hygiene. In the low energy conformation of fipronil, a pseudo-six-membered ring is observed through an intramolecular hydrogen bond. Methods: : A scaffold hopping strategy was applied to mimic the pseudo-six-membered ring of fipronil by non-aromatic ring. All compounds were synthesized with a proper synthetic route and characterized by 1H NMR, 13C NMR and high-resolution mass spectra. Insecticidal activities of all target compounds against Plutella xylostella were assessed by a professional organization. Physicochemical property prediction and docking study of these compounds with GABA receptor were also performed. Results:: A series of 1,4,6,7-tetrahydropyrazolo[3,4-d][1,3]oxazine derivatives containing twenty-five compounds were designed, synthesized and evaluated. Several compounds exhibited moderate activities against Plutella xylostella. The strong electron-withdrawing groups are conducive to improve activities of this series of compounds against Plutella xylostella. Docking study showed that the most active compound 10 with nitro group could bind within the TM2 domain of GABA receptor, in which a hydrogen bond was observed with residue 6’Thr. The activity of 10 was weaker than fipronil due to the differences in physicochemical properties. Conclusion: : More attention should be paid to physicochemical properties during novel pesticide hit or lead design through scaffold hopping.

4‐Oxo‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐d]pyrimidine Derivatives: Design, Synthesis, Insecticidal Assay and Binding Mode Studies

“…For agrichemical fipronil, a N−H⋅⋅⋅O intramolecular hydrogen bond can be observed in the low energy conformation [22] . In our previous studies, as shown in Figure 2, two series compounds including aromatic and aliphatic rings mimic the pseudo six‐member ring conformed by intramolecular hydrogen bond (H‐Bond) in fipronil [10,23] . However, the insecticidal activities of these two series of compounds were inferior because of the losing of the amino hydrogen, which is a vital hydrogen bond donor in the binding mode of fipronil.…”

“…[22] In our previous studies, as shown in Figure 2, two series compounds including aromatic and aliphatic rings mimic the pseudo six-member ring conformed by intramolecular hydrogen bond (H-Bond) in fipronil. [10,23] However, the insecticidal activities of these two series of compounds were inferior because of the losing of the amino hydrogen, which is a vital hydrogen bond donor in the binding mode of fipronil. Considering the balance of toxicity and activities, there is a need for developing the phenylpyrazole insecticide leads preserving at least one amino hydrogen.…”

“… Previous scaffold hopping works of mimicking the intramolecular H‐bond and molecule design strategy in this work based on the low energy conformation of fipronil [10,23] …”