title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli, 25, 20133, Milano, Italy.
authors.forename: Andrea
authors.identifier: http://orcid.org/0000-0002-2501-3348
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli, 25, 20133, Milano, Italy.
authors.forename: Lucia
authors.identifier: http://orcid.org/0000-0002-9755-7846
authors.initials: L
authors.lastname: Tamborini
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli, 25, 20133, Milano, Italy.
authors.forename: Gregorio
authors.initials: G
authors.lastname: Cullia
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli, 25, 20133, Milano, Italy.
authors.forename: Paola
authors.identifier: http://orcid.org/0000-0003-2140-0567
authors.initials: P
authors.lastname: Conti
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli, 25, 20133, Milano, Italy. carlo.demicheli@unimi.it.
authors.forename: Carlo
authors.identifier: http://orcid.org/0000-0003-3549-4365
authors.initials: C
authors.lastname: De Micheli
mesh_terms: D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057056:Cysteine Proteases / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation
chemical_list: D004791:Enzyme Inhibitors; D007555:Isoxazoles; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D057056:Cysteine Proteases; D019731:Carbon-Nitrogen Ligases; C006303:acivicin
keywords: 4,5-dihydroisoxazoles; covalent inhibitors; drug warheads; electrophiles; natural products