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

Abstract

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.

Applications of Isosteres of Piperazine in the Design of Biologically Active Compounds: Part 2

“…The substituted heterocycles pyrrolidin-3-amine ( 1 ) and pyrrolidin-3-ylmethanamine ( 2 ) present as diamines with enhanced conformational mobility and a potentially useful chiral center compared to piperazine that can be of value in structure–activity relationship (SAR) optimization. For example, pyrrolidin-3-amine ( 1 ) functioned as an effective piperazine mimic in a series of antagonists of the C–X–C chemokine receptor type 4 (CCXR4, fusin) receptor . An example where compound 2 was probed as a potential piperazine mimetic was in the context of inhibitors of factor Xa, a serine protease that is an enzyme in the coagulation cascade, that were studied for their potential to act as antithrombotic agents .…”

“…The panoply of options discussed offers interesting options to modulate shapes and properties of the mimetics. However, there has not been a similar vein of interest in either piperazine, homopiperazine, or isosteric heterocycles within the agricultural chemistry community, with the commercial use of piperazine derivatives restricted to a single marketed agricultural product, antifungal agent triforine ( 260 ). , This is perhaps surprising within an industry that has pioneered the design and application of a range of interesting structural motifs that have subsequently been recognized and embraced by medicinal chemists, although typically after an interval of a decade or more. For example, the CHF 2 moiety originated in the agricultural arena where its hydrogen-bond donor properties were also recognized in the context of fungicide inpyrfluxam ( 261 ). − While this motif has found extensive application in agricultural chemical design, embedded in the range of structurally interesting constellations compiled in Figure , it was not until 2002 that this moiety was embraced by medicinal chemists. − Since that description, the awareness of the properties and utility of the CHF 2 functionality has increased considerably.…”

“…Against a backdrop in which the agricultural chemistry area has produced many structurally interesting and innovative motifs whose properties are still in the process of being fully elucidated, it is perhaps surprising that piperazines, homopiperazines, and their bioisosteres have not found broader application in the pursuit of agricultural products. The inherent basicity of these heterocycles may have been prejudicial, as discussed above, but that is readily modulated by judicious substitution with an electron-withdrawing element, as in compound 260 and the tropane nitriles 265 and 266 , which are prodrugs used to successfully deliver the active species 267 . , Indeed, many of these motifs offer a broad palette to modulate the physicochemical properties of a molecule in a productive direction, as is often the case in the design of pharmaceuticals that would allow for matching with the complexion of agricultural product physical properties, which is quite different from those in drug molecules. − An example of the subtlety of effects of structural modification on the physicochemical properties of piperazines is provided by a recently matched molecular pair analysis that investigated the effect on the lipophilicity of introducing a one-carbon-atom-bridging element to both piperazine and morpholine . The introduction of bridging elements to piperazines has been demonstrated to be a useful tactic to improve the drug-like properties, exemplified by an analysis of the four motifs in compounds 268 – 271 .…”

“…For example, pyrrolidin-3-amine (1) functioned as an effective piperazine mimic in a series of antagonists of the C−X−C chemokine receptor type 4 (CCXR4, fusin) receptor. 1 An example where compound 2 was probed as a potential piperazine mimetic was in the context of inhibitors of factor Xa, a serine protease that is an enzyme in the coagulation cascade, that were studied for their potential to act as antithrombotic agents. 3 The selection of compound 2 as a structural motif was based on an analysis of the geometry of the active site, in which the prototype inhibitor adopted an L-shaped configuration that projected the chloronaphthalene moiety into the S1 subpocket of the enzyme.…”

“…In the accompanying review (10.1021/acs.jafc.2c00726), we provided a synopsis of applications of piperazine and homopiperazine in the design of bioactive compounds and discussed some applications of these heterocycles and their fused ring homologues while illustrating the potential of 4-fluoro, 4-cyano, and 4-hydroxy piperidines and a sulfoximine-based homologue to act as functional mimetics. 1 In this review, we continue the survey, with a focus on the applications of pyrrolidine and fused pyrrolidine ring systems, azetidines and their stretched and spiro derivatives, and diaminocycloalkanes that are able to functionally recapitulate a piperazine or homopiperazine heterocycle. As with all aspects of bioisosterism, applications of these specific motifs will depend upon the biochemical context under study.…”