Applications of Isosteres of Piperazine in the Design of Biologically Active Compounds: Part 1.

Piperazine and homopiperazine are well-studied heterocycles in drug design that have found gainful application as scaffolds and terminal elements and for enhancing the aqueous solubility of a molecule. The optimization of drug candidates that incorporate these heterocycles in an effort to refine potency, selectivity, and developability properties has stimulated the design and evaluation of a wide range of bioisosteres that can offer advantage. In this review, we summarize the design and application of bioisosteres of piperazine and homopiperazine that have almost exclusively been in the drug design arena. While there are ∼100 approved drugs that incorporate a piperazine ring, only a single marketed agricultural product is built on this heterocycle. As part of the review, we discuss some of the potential reasons underlying the relatively low level of importance of this heterocycle to the design of agrochemicals and highlight the potential opportunities for their use in contemporary research programs.