Inspired by Nature: The 3‐Halo‐4,5‐dihydroisoxazole Moiety as a Novel Molecular Warhead for the Design of Covalent Inhibitors

Abstract

Over the past few decades, there has been an increasing interest in the development of covalent enzyme inhibitors. As it was recently re-emphasized, the selective, covalent binding of a drug to the desired target can increase efficiency and lower the inhibitor concentration required to achieve a therapeutic effect. In this context, the naturally occurring antibiotic acivicin, and in particular its 3-chloro-4,5-dihydroisoxazole scaffold, has provided a wealth of inspiration to medicinal chemists and chemical biologists alike. In this Concept, to underline the great potentiality that the 3-halo-4,5-dihydroisoxazole warhead has in drug discovery, we present a number of examples, grouped by their potential biological activity and targets, in which this scaffold has been fruitfully used to develop novel biologically active compounds. Through these examples, we show that the 3-halo-4,5-dihydroisoxazole moiety represents an outstanding warhead with high potential for the design of novel covalent enzyme inhibitors.

An Improved Model of the Trypanosoma brucei CTP Synthetase Glutaminase Domain–Acivicin Complex

“…Acivicin (Figure ), a fermentation product of Streptomyces sviceus, inhibits enzymes like CTP synthetase that catalyze amido transfers from l ‐glutamine. This natural product displays potent anticancer activities, however, it has not progressed beyond phase 1 clinical trials due to neurotoxicity . Nevertheless, the compound displays antitrypanosomatid activity and as such the structure of a CTP synthetase complex with a lead compound is potentially valuable.…”

“…This natural product displays potent anticancera ctivities, however,i th as not progressed beyond phase 1c linicalt rials due to neurotoxicity. [6] Nevertheless,t he compound displays antitrypanosomatid activity and as such the structure of aC TP synthetase complex with al ead compoundi sp otentially valuable. Indeed, the SGC model has been used for docking calculationsw hich formedt he basis for studies reportedi nChemMedChem where researchers sought to designa civicin analogues as more potent T. brucei CTP synthetase inhibitors.…”

Bicyclic Pyrrolidine-Isoxazoline γ Amino Acid: A Constrained Scaffold for Stabilizing α-Turn Conformation in Isolated Peptides

“…Furthermore, the presence of the isoxazoline ring, a core often found in biologically active compounds, could be particularly useful for future applications in the pharmaceutical field. In fact, isoxazoline derivatives are important scaffolds found in many naturally occurring and biologically active compounds possessing a wide range of bioactivities, such as antibacterial, antifungal, antiparasitic (Conti et al, 2011 ; Bruno et al, 2014 ; Pinto et al, 2016a ), anticancer (Castellano et al, 2011 ; Kaur et al, 2014 ), anti-inflammatory and anticonvulsant activity (Sperry and Wright, 2005 ; Pinto et al, 2011 , 2016b ). Isoxazolines are also considered to be important precursors for the synthesis of β-hydroxyketones (Kozikowski and Park, 1990 ; Tsantali et al, 2007 ), β-aminoalcohols (Fuller et al, 2005 ), isoxazolidines (Itoh et al, 2002 ), and many other valuable compounds.…”

Effects of 3‐Bromo‐4,5‐dihydroisoxazole Derivatives on Nrf2 Activation and Heme Oxygenase‐1 Expression

“…The 3‐halo‐4,5‐dihydroisoxazole warhead can be considered a rare electrophile in therapeutics since it reacts solely with cysteine residues activated by surrounding amino acid residues present in the catalytic site of a number of enzymes. Such a peculiarity has already been used to design efficacious inhibitors of different enzymatic targets, ranging from parasitic and bacterial enzymes to human targets involved in the modulation of neuronal metabolic pathways or in tumor cell metabolism . In this context, we tested different isoxazoline‐based electrophiles (Figure ) to examine their effect on the Nrf2/HO‐1 axis.…”