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

Abstract

Hydantoin and its analogs such as thiohydantoin and iminohydantoin have received substantial attention both from a chemical and biological point of view. Several compounds of this class have shown useful pharmacological activities such as anticonvulsant, antitumor, antiarrhythmic, herbicidal, and others that lead in some cases to clinical applications. Because of 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 to successfully design and develop the new routes/methods resulting in the formation of hydantoin, thiohydantoin, and iminohydantoin substituted at different positions particularly at the N-1 position without following protection-deprotection strategy. Given the fact that the combination of two or more pharmacophoric groups may lead to hybrid molecules which result in a mixed mechanism of action on the biological target. We, therefore, further extended the developed strategy for the synthesis of new types of hydantoin-based hybrid molecules by combining hydantoin with a triazole, isoxazoline, and phosphate scaffolds as another pharmacophoric group to exploit diverse biological functions.

Biologically Oriented Hybrids of Indole and Hydantoin Derivatives

“…The hydantoin or glycolylurea (imidazolidin-2,4-one) is an important nitrogen-containing heterocyclic moiety in which two nitrogen atoms are located in a five-membered ring. Hydantoin and its derivatives are common bioactive molecules, so synthetic and pharmacological interest in them is constantly growing [ 1 , 2 , 3 , 4 ]. In addition, neuroprotective [ 5 ], anticonvulsant [ 6 ], antibacterial [ 7 , 8 ], anti-inflammatory [ 5 , 9 ], and anti-cancer [ 10 , 11 ] properties of imidazolidin-2,4-one derivatives are known.…”

Regio‐ and Chemoselectivity of Tandem N‐Ketoalkylation/Cyclization of 2‐Thioxoimidazoline‐4‐One

“…Usually, that is, in the presence of bases, alkylation of hydantoins and thiohydantoins proceeds as N3‐alkylation due to a higher acidity of the NH‐3 group favoring the formation of the corresponding amide anion [39] . In our case, in the absence of added base, its role is played by DMSO used as the solvent and capable of forming the amide anion.…”

“…Usually, that is, in the presence of bases, alkylation of hydantoins and thiohydantoins proceeds as N3-alkylation due to a higher acidity of the NH-3 group favoring the formation of the corresponding amide anion. [39] In our case, in the absence of added base, its role is played by DMSO used as the solvent and capable of forming the amide anion. To investigate this issue theoretically, we performed calculations of the two isomeric N-1 and N-3 anions of thiohydantoin in the gas phase and in solution using PCM model and DMSO as the solvent at the MP2/cc-pVTZ level of theory.…”

Synthesis of hydantoins from N‐Boc protected amino acid derived amides using polymer‐supported PPh3/CBr4 as a reagent

“…Known for more than a century, hydantoin is a valuable chemical entity continually attracting the attention of scientific community. It is a widely explored pharmacophore in medicinal chemistry, present in compound with various biological properties [1][2][3][4][5][6]. Hydantoin core is constitutive part of several drugs such as dantrolene 1, nilutamide 2 or fosphenytoin 3, to mention just a few [3] (see Figure 1).…”