Introduction

Hydantoin, imidazolidine-2,4-dione, is a non-aromatic five-membered heterocycle, which is considered a valuable, privileged scaffold in medicinal chemistry. The importance of the hydantoin scaffold in drug discovery has been reinforced by several medicines in clinical use, such as phenytoin, nitrofurantoin, and enzalutamide. Hydantoin has five potential substituent sites, including two hydrogen bond acceptors and two hydrogen bond donors. Two additional attractive features of hydantoin scaffolds are their synthetic feasibility for core scaffolds via established cyclization reactions and their ease of accepting various substituents. Because of these characteristics, many hydantoin derivatives with different substituents have been designed and synthesized and exhibit a broad spectrum of biological and pharmacological activities against, for example, cancers, microbial infections, metabolic diseases, and epilepsy. In this review, recent contributions of hydantoin, thiohydantoin, and selenohydantoin scaffolds to medicinal chemistry are described; some major compounds are presented to emphasize their importance, and their structure-activity relationships (SARs) are briefly addressed. Major discussions are devoted to the structural features or novelty of each scaffold and its SAR.[1]

Recent pharmacological applications of hydantoin

Hydantoins with antiproliferative activity

In 2013, Azizmohammadi and coworkers reported a novel series of hydantoin-chromene hybrids with antiproliferative activity. The hybrids, as 5-alkylidenehydantoin species, were synthesized by condensation of (thio)hydantoins and substituted chromene-3-aldehydes, the latter of which were prepared from o-hydroxybenzaldehydes and acrolein or 2-butenal. The synthesized compounds were screened for antiproliferative activity by using five cancer cell lines, MOLT-4, MCF-7, K562, A549, and NIH/3T3. The selected screening data are summarized, which indicate that the hydantoin-chromene hybrids exhibited mild to good anticancer activities. Among them, compounds exhibited the best cytotoxic profile compared to that of cisplatin, a clinical anticancer drug.

In 2013, a study reported on a series of 3-aminoalkyl/benzyl phenytoins and 3-(4-piperidino/piperazino/morpholino) phenacyl phenytoins. These hydantoin derivatives were designed with inspiration from known hydantoin or oxazolinone anticancer agents, which feature phenyl group-bearing substituents at positions N1 and N3. Notably, compound 18 and its derivatives were found to possess anticancer activity by inhibiting epidermal growth factor receptor (EGFR) kinase activity. Building on these known leads and keeping the hydantoin moiety as the core structure, two substituents with phenyl groups were introduced at N1 and N3. Phenytoin-based derivatives were synthesized and tested for their ability to inhibit cell proliferation using an NCI 60 cancer cell line panel assay. Interestingly, N3-(4-piperidinylphenacyl)-5,5-diphenylhydantoin exhibited moderate to good activity. Furthermore, the researchers conducted a molecular docking study of compound A to predict its binding modes with the V600E-B-RAF kinase domain, which is a potential target for this compound.[2]

In 2016, a series of novel N3-benzyloxyhydantoins were reported as cytotoxic agents against several cancer cell lines by Liu et al. These hydantoins were prepared using one-step condensations of 4-nitrophenyl (benzyloxy)carbamates with various amino acid methyl esters. In that study, twenty-eight 3-benzyloxyhydantoins were synthesized and evaluated for cytotoxicity against murine leukemia (L1210), human leukemia (K562), and human laryngeal carcinoma (HEP-2) cell lines. Among the compounds, several exhibited moderate to good cytotoxicity against these cells. In particular, three derivatives, showed high activity against the HEP-2?cell line with submicromolar IC50 activities (i.e., IC50?=?0.15, 0.04, and 0.07, respectively;  From the results, a partial SAR revealed that halogen substitutions such as chloride and bromide on the phenyl ring enhance antiproliferative activity, and elevated hydrophobicity by C5 substitution of hydantoin also provides better activity. In addition, the authors investigated the binding energies and binding modes of potent derivatives against a potential target, ribonucleotide reductase (RR), which suggested the importance of C5 hydrophobic substituents in binding with the active site of RR.

Hydantoins as sirtuin inhibitors

Sirtuins (SIRTs) are a class of proteins that have several catalytic activities such as deacetylase, depalmitoylase, desuccinylase, and demalonylase activities; they regulate a wide range of biological processes such as aging, apoptosis, transcription, inflammation, and energy efficiency. Recently, the inhibition of SIRTs was suggested to be a promising pharmacological target for cancer chemotherapy and neurodegenerative diseases. In this regard, Sacconnay et al. reported new 5-benzylidenehydantoins as SIRT inhibitors. They identified 5-benzylidenehydantoins by conducting structure-based virtual screening and cell-based assays, in which their inhibitory activity was compared with that of sirtinol, a pan-SIRT inhibitor. The derivatives possess 3-benzyl-5-benzylidenehydantoin scaffolds, in which the N3 and C3 positions of hydantoin are substituted, and three compounds exhibited good inhibitor activity against SIRT1 and SIRT2. Simultaneous inhibition of SIRT 1 and 2 is known to be a promising therapeutic strategy for cancer treatment. Further investigation revealed that compound was a non-selective SIRT inhibitor, absorbed by passive diffusion and showing low cytotoxicity.

Discovery of hydantoin-based LXR agonists.

In the same year, Kuora and coworkers reported 1,3-bistrifluoromethylcarbinol-hydantoin hybrids as selective LXRβ agonists. This study was performed starting from the previously developed agonist, the 2-oxo-8-n-propyl-4-trifluoromethylchromene-5-methoxyphenyl-5-methylhydantoin hybrid. The major progress in this study is that 2-oxo-4-trifluoromethylchromene was transformed to bistrifluoromethylcarbinol, and the substituents on the 5-phenyl in hydantoin were thoroughly optimized with 32 analogs. Finally, the authors identified 1,1-bistrifluoromethylcarbinol-5-isopropoxyphenylhydantoin hybrids as novel LXRβ-selective agonists that showed the best profiles in this series in terms of agonistic potency, selectivity, and decrease in total cholesterol (LXRα EC50 (Emax): 1.1?μM (26%); LXRβ EC50 (Emax): 1.2?μM (146%)). However, these compounds did not meet the requirements for human therapeutic use because of issues of potency, selectivity, and pharmacokinetic profiles. One year later, Kuora et al. reported 2-hydroxyacetophenone-tethered bistrifluoromethylcarbinol-hydantoin hybrids. Some issues of the 1,3-bistrifluoromethylcarbinol-hydantoin hybrids were their insufficient potency and selectivity and their susceptibility to metabolism. The metabolic site and major metabolite were identified. To ameliorate these properties, the authors changed the alkyl linker to various unsaturated alkyl or benzene ring-containing linkers and replaced the 5-phenyl in hydantoin with a pyridinyl ring. The results showed that the incorporation of a 2-hydroxyacetophenone linker improved β-selectivity and potency 20-fold compared to that of the previous compound.

Cardiac arrhythmia is considered to be the leading cause of sudden cardiac death (SCD). Although several drug targets that modulate heart rhythm are available, the search for new therapeutic targets to treat cardiac arrhythmias is a matter of great interest in medicinal chemistry. In this regard, in 2012, Handzlik et al. attempted to discover new antagonists targeting the α1-adrenoceptor and published two subsequent articles that addressed the synthesis and α1-adrenoceptor antagonistic activity of two series of phenylpiperazine hydantoin derivatives and 5-arylidenehydantoin derivatives . Based on Barbaro's pharmacophore model, they proposed two novel scaffolds of phenylpiperazine-tethered diphenylhydantoin and 5-arylidenehydantoin, in which the 2-oxo group and one of the phenyl groups on the hydantoin were expected to contribute substantially to receptor binding. In the first study, Handzlik et al. synthesized phenylpiperazine-tethered diphenylhydantoins, in which the phenylpiperazines were linked to N1 of the hydantoin ring. Next, they evaluated α1-adrenoceptor affinities by using a radioligand binding assay and revealed partial SARs where (1) the hydroxyl group at R3 was not necessary for binding, (2) the methoxy substituent at R2 was optimal despite the limited number of examples, (3) the chain length had remarkable influence on binding affinity, and (4) a smaller substituent at R1 enhanced the binding affinity.[3]

Hydantoins as α1-adrenoreceptor antagonists

Cardiac arrhythmia is considered to be the leading cause of sudden cardiac death (SCD). Although several drug targets that modulate heart rhythm are available, the search for new therapeutic targets to treat cardiac arrhythmias is a matter of great interest in medicinal chemistry. In this regard, in 2012, Handzlik et al. attempted to discover new antagonists targeting the α1-adrenoceptor and published two subsequent articles that addressed the synthesis and α1-adrenoceptor antagonistic activity of two series of phenylpiperazine hydantoin derivatives and 5-arylidenehydantoin derivatives. Based on Barbaro's pharmacophore model, they proposed two novel scaffolds of phenylpiperazine-tethered diphenylhydantoin and 5-arylidenehydantoin, in which the 2-oxo group and one of the phenyl groups on the hydantoin were expected to contribute substantially to receptor binding.

References

[1] Kavitha, C. V., Nambiar, M., Kumar, C. S. A., Choudhary, B., Muniyappa, K., Rangappa, K. S., & Raghavan, S. C. (2009). Novel derivatives of spirohydantoin induce growth inhibition followed by apoptosis in leukemia cells. Biochemical Pharmacology, 77(4), 348-363.

[2] Suzen, S., & Buyukbingol, E. (2000). Anti-cancer activity studies of indolalthiohydantoin (PIT) on certain cancer cell lines. Il Farmaco, 55(5), 246-248.

[3] Carmi, C., Cavazzoni, A., Zuliani, V., Lodola, A., Bordi, F., Plazzi, P. V., Alfieri, R. R., Petronini, P. G., & Mor, M. (2006). 5-Benzylidene-hydantoins as new EGFR inhibitors with antiproliferative activity. Bioorganic & Medicinal Chemistry Letters, 16(9), 4021-4025.