Inspired by Nature: The 3‐Halo‐4, 5‐dihydroisoxazole Moiety as a Novel Molecular Warhead for the Design of Covalent Inhibitors. Issue 1 (26th November 2015)

• Record Type: Journal Article
• Authors: Pinto, Andrea; Tamborini, Lucia; Cullia, Gregorio; Conti, Paola; De Micheli, Carlo
• Is Part Of: ChemMedChem. Volume 11:Issue 1(2016)
• Page Start: 10
• Page End: 14
• Publication Date: 2015-11-26
• Subjects: covalent inhibitors -- 4, 5-dihydroisoxazoles -- electrophiles -- natural products -- drug warheads; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500496
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : A hint from Nature : 3‐Halo‐4, 5‐dihydroisoxazole, a component of the naturally occurring antibiotic acivicin, is a powerful warhead for the covalent inhibition of target enzymes. Here, we describe the use of this moiety in medicinal chemistry to develop covalent inhibitors of parasitic and bacterial enzymes, and human targets involved in the modulation of neuronal metabolic pathways or tumor cell metabolism.