Dihydropiperazine neonicotinoid compounds. Synthesis and insecticidal activity

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Agrochemical Research

Background:

• Neonicotinoid insecticides often contain an imidazolidine ring.
• Developing effective bioisosteric replacements is crucial for insecticide innovation.
• Piperazine derivatives offer a potential alternative scaffold.

Purpose of the Study:

• To explore the synthesis of novel dihydropiperazine derivatives.
• To evaluate their potential as bioisosteric replacements for neonicotinoid imidazolidine rings.
• To understand structure-activity relationships influencing bioisosterism.

Main Methods:

• Regioselective monothionation of N-substituted piperazinediones.
• Synthesis of unsymmetrical piperazinedione precursors from diamines.
• Comparative analysis of synthesized compounds and neonicotinoids (e.g., imidacloprid).

Main Results:

• Successful synthesis of various isomeric dihydropiperazines.
• Compounds 4 and 25 demonstrated suitable bioisosterism with neonicotinoids.
• Altered substitution patterns (compounds 3a, 5, 6) significantly reduced bioisosterism and activity.
• Dihydropiperazine ring provided molecular rigidity compared to acyclic analogs.

Conclusions:

• Regioselective monothionation is an effective strategy for synthesizing dihydropiperazine analogs.
• The dihydropiperazine scaffold can serve as a rigid bioisostere for imidazolidine rings in neonicotinoid-like structures.
• Specific placement of functional groups is critical for maintaining bioisosteric properties and potential activity.