Designed Synthesis of Diversely Substituted Hydantoins and Hydantoin-Based Hybrid Molecules: A Personal Account

Abstract

AbstractHydantoin and its analogues such as thiohydantoin and iminohydantoin have received substantial attention from both a chemical and a biological point of view. Several compounds of this class have shown useful pharmacological activities such as anticonvulsant, antitumor, antiarrhythmic, and herbicidal properties that have led, in some cases, to clinical applications. Because of these broad-spectrum activities, intensive research efforts have been dedicated in industry and academia to the synthesis and structural modifications of hydantoin and its derivatives. Realizing the importance of hydantoin in organic and medicinal chemistry, we also initiated a research program that successfully designed and developed new routes and methods for the formation of hydantoin, thiohydantoin, and iminohydantoin substituted at various positions, particularly at the N-1 position without following a protection–deprotection strategy. Because combinations of two or more pharmacophoric groups can lead to hybrid molecules that display a mixed mechanism of action on biological targets, we extended our developed strategy to the syntheses of new types of hydantoin-based hybrid molecules by combining hydantoin with a triazole, isoxazoline, or phosphate scaffold as a second pharmacophore to exploit their diverse biological functions.1 Introduction2 Chemistry and Properties2.1 Physical Properties2.2 Chemical Properties2.3 Biological Properties3 General Synthetic Methods4 Synthesis of Diversely Substituted Hydantoins5 Synthesis of Diversely Substituted Thiohydantoins6 Synthesis of Diversely Substituted Iminohydantoins7 Fused or Bicyclic (Thio)hydantoins8 Di- or Multivalent (Thio)hydantoins9 Hydantoin-Based Hybrid Molecules9.1 Hydantoin–Isooxazoline Hybrids9.2 Hydantoin–Triazole Hybrids9.3 Hydantoin–Phosphate Hybrids: Phosphorylated Hydantoins10 Summary and Outlook