Design, synthesis and biological evaluation of novel 5-((substituted quinolin-3-yl/1-naphthyl) methylene)-3-substituted imidazolidin-2,4-dione as HIV-1 fusion inhibitors.

A series of novel 5-(substituted quinolin-3-yl or 1-naphthyl)methylene)-3-substituted imidazolidin-2,4-dione 9-26 was designed and synthesized. The prepared compounds were identified using 1H NMR, 13C NMR as well as elemental analyses. The inhibitory activity of 9-26 on HIV-1IIIB replication in MT-2 cells was evaluated. Some derivatives showed good to excellent anti-HIV activities as compounds 13, 18, 19, 20, 22 and 23. They showed EC50 of 0.148, 0.460, 0.332, 0.50, 0.271 and 0.420 µM respectively being more potent than compound I (EC50 = 0.70 µM) and II ( EC50 = 2.40 µM) as standards. The inhibitory activity of 9-26 on infected primary HIV-1 domain, 92US657 (clade B, R5) was investigated. All the tested compounds consistently inhibited infection of this virus with EC50 from 0.520 to 11.857 µM. Results from SAR studies showed that substitution on ring A with 6/7/8-methyl group resulted in significant increase in the inhibitory activity against HIV-1IIIB infection (5- >300 times) compared to the unsubstituted analog 9. The cytotoxicity of these compounds on MT-2 cells was tested and their CC50 values ranged from 11 to 85 µM with selectivity indexes ranged from 0.53 to 166. The docking study revealed nice fitting of the new compounds into the hydrophobic pocket of HIV-1 gp41 and higher affinity than NB-64. Compound 13, the most active in preventing HIV-1IIIB infection, adopted a similar orientation to compound IV. Molecular docking analysis of the new compounds revealed hydrogen bonding interactions between the imidazolidine-2,4-dione ring and LYS574 which were missed in the weakly active derivatives.

Synthesis of imidazolidine-2,4-dione and 2-thioxoimidazolidin-4-one derivatives as inhibitors of virulence factors production in Pseudomonas aeruginosa.

In an attempt to counteract bacterial pathogenicity, a set of novel imidazolidine-2,4-dione and 2-thioxoimidazolidin-4-one derivatives was synthesized and evaluated as inhibitors of bacterial virulence. The new compounds were characterized and screened for their effects on the expression of virulence factors of Pseudomonas aeruginosa, including protease, hemolysin, and pyocyanin. Imidazolidine-2,4-diones 4c, 4j, and 12a showed complete inhibition of the protease enzyme, and they almost completely inhibited the production of hemolysin at 1/4 MIC (1/4 minimum inhibitory concentration; 1, 0.5, and 0.5 mg/ml, respectively). 2-Thioxoimidazolidin-4-one derivative 7a exhibited the best inhibitory activity (96.4%) against pyocyanin production at 1 mg/ml (1/4 MIC). A docking study was preformed to explore the potential binding interactions with quorum-sensing receptors (LasR and RhlR), which are responsible for the expression of virulence genes.

Synthesis and pharmacological evaluation of novel N-Mannich bases derived from 5,5-diphenyl and 5,5-di(propan-2-yl)imidazolidine-2,4-dione core.

The aim of this study was to design and synthesize two series of N-Mannich bases with imidazolidine-2,4-dione core as a potential anticonvulsant with reduced toxicity and broad antiseizure activity. Preliminary screening revealed that the majority of synthesized compounds were effective in the maximal electroshock seizure (MES) and/or subcutaneous pentylenetetrazole (scPTZ) test. The most active in vivo compound, 18 (3-((4-methylpiperazin-1-yl)methyl)-5,5-diphenylimidazolidine-2,4-dione), exhibited an ED50 value comparable to that of phenytoin in the MES test (38.5 mg/kg vs 28.1 mg/kg), and more importantly, it showed four times higher potency than phenytoin in the 6 Hz test (12.2 mg/kg vs > 60 mg/kg). Additionally, 18 exhibited antiallodynic properties in the von Frey test in neuropathic (oxaliplatin-treated) mice. Compound 18 also demonstrated a broader spectrum of anticonvulsant activity than phenytoin and showed statistically significant antinociceptive properties in selected models of chronic pain.

Design, synthesis and preliminary bioactivity studies of imidazolidine-2,4-dione derivatives as Bcl-2 inhibitors.

Anti-apoptotic B-cell lymphoma-2 (Bcl-2) proteins are promising targets for cancer therapy. In the present study, a series of imidazolidine-2,4-dione derivatives were designed and synthesized to test their inhibitory activities against anti-apoptotic Bcl-2 proteins. Among them, compound 8k had better growth inhibitory effects on K562 and PC-3 cell lines compared to lead compound WL-276.

Novel spirohydantoin derivative as a potent multireceptor-active antipsychotic and antidepressant agent.

A series of novel spirohydantoin derivatives with arylpiperazinylbutyl moiety were synthesized and evaluated for serotonin 5-HT1A, 5-HT2A, 5-HT7 and dopamine D2 receptors. Based on these data, four compounds were selected for further binding affinity assays on dopamine D1, D3, D4, and 5-HT2C, 5-HT6 as well as adrenergic α1 and α2C receptors, which are involved in various CNS diseases such as schizophrenia, anxiety and/or depression. The compound 14, 1-{4-[4-(2-metoxyphe-nyl)piperazin-1-yl]butyl}-3',4'-dihydro-2H,2'H,5H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dione, with the most promising functional profile, mixed 5-HT2A/D2 antagonist and 5-HT1A partial agonist, was selected. In the mouse d-amphetamine-induced locomotor hyperactivity model, compound 14 produced antipsychotic-like activity, which is devoid of cataleptogenic effects and in the forced swim test in mice, it showed a significant antidepressant-like effect unlike the reference drug aripiprazole.

Unravelling the Structural Mechanism of Action of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione in Dual-Targeting Tankyrase 1 and 2: A Novel Avenue in Cancer Therapy.

Tankyrase (TNKS) belonging to the poly(ADPribose) polymerase family, are known for their multi-functioning capabilities, and play an essential role in the Wnt ß-catenin pathway and various other cellular processes. Although showing inhibitory potential at a nanomolar level, the structural dual-inhibitory mechanism of the novel TNKS inhibitor, 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione, remains unexplored. By employing advanced molecular modeling, this study provides these insights. Results of sequence alignments of binding site residues identified conserved residues; GLY1185 and ILE1224 in TNKS-1 and PHE1035 and PRO1034 in TNKS-2 as crucial mediators of the dual binding mechanism of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione, corroborated by high per-residue energy contributions and consistent high-affinity interactions of these residues. Estimation of the binding free energy of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione showed estimated total energy of -43.88 kcal/mol and -30.79 kcal/mol towards TNKS-1 and 2, respectively, indicating favorable analogous dual binding as previously reported. Assessment of the conformational dynamics of TNKS-1 and 2 upon the binding of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione revealed similar structural changes characterized by increased flexibility and solvent assessible surface area of the residues inferring an analogous structural binding mechanism. Insights from this study show that peculiar, conserved residues are the driving force behind the dual inhibitory mechanism of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione and could aid in the design of novel dual inhibitors of TNKS-1 and 2 with improved therapeutic properties.

Synthesis and Antiplasmodial Activity of Novel Bioinspired Imidazolidinedione Derivatives.

Malaria is an enormous threat to public health, due to the emergence of Plasmodium falciparum resistance to widely-used antimalarials, such as chloroquine (CQ). Current antimalarial drugs are aromatic heterocyclic derivatives, most often containing a basic component with an added alkyl chain in their chemical structure. While these drugs are effective, they have many side effects. This paper presents the synthesis and preliminary physicochemical characterisation of novel bioinspired imidazolidinedione derivatives, where the imidazolidinedione core was linked via the alkylene chain and the basic piperazine component to the bicyclic system. These compounds were tested against the asexual stages of two strains of P. falciparum-the chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains. In parallel, in vitro cytotoxicity was investigated on a human keratinocyte cell line, as well as their hemolytic activity. The results demonstrated that the antiplasmodial effects were stronger against the W2 strain (IC50 between 2424.15-5648.07 ng/mL (4.98-11.95 µM)), compared to the D10 strain (6202.00-9659.70 ng/mL (12.75-19.85 µM)). These molecules were also non-hemolytic to human erythrocytes at a concentration active towards the parasite, but with low toxicity to mammalian cell line. The synthetized derivatives, possessing enhanced antimalarial activity against the CQ-resistant strain of P. falciparum, appear to be interesting antimalarial drug candidates.

Recent applications of hydantoin and thiohydantoin in medicinal chemistry.

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. The publications in this review encompass those from 2012 to 2018.

Crystal structures of two hydrogen-bonded compounds of chloranilic acid-ethyl-eneurea (1/1) and chloranilic acid-hydantoin (1/2).

The structures of the hydrogen-bonded 1:1 co-crystal of chloranilic acid (systematic name: 2,5-di-chloro-3,6-dihy-droxy-1,4-benzo-quinone) with ethyl-eneurea (systematic name: imidazolidin-2-one), C6H2Cl2O4·C3H6N2O, (I), and the 1:2 co-crystal of chloranilic acid with hydantoin (systematic name: imidazolidine-2,4-dione), C6H2Cl2O4·2C3H4N2O2, (II), have been determined at 180 K. In the crystals of both compounds, the base mol-ecules are in the lactam form and no acid-base inter-action involving H-atom transfer is observed. The asymmetric unit of (I) consists of two independent half-mol-ecules of chloranilic acid, with each of the acid mol-ecules lying about an inversion centre, and one ethyl-eneurea mol-ecule. The asymmetric unit of (II) consists of one half-mol-ecule of chloranilic acid, which lies about an inversion centre, and one hydantoin mol-ecule. In the crystal of (I), the acid and base mol-ecules are linked via O-H⋯O and N-H⋯O hydrogen bonds, forming an undulating sheet structure parallel to the ab plane. In (II), the base mol-ecules form an inversion dimer via a pair of N-H⋯O hydrogen bonds, and the base dimers are further linked through another N-H⋯O hydrogen bond into a layer structure parallel to (01). The acid mol-ecule and the base mol-ecule are linked via an O-H⋯O hydrogen bond.

Design, synthesis, anticonvulsant, and antiarrhythmic properties of novel N-Mannich base and amide derivatives of ß-tetralinohydantoin.

BACKGROUND: 5,5-Diphenylhydantoin (Phenytoin) is a well-known anticonvulsant and antiarrhythmic drug which may cause unwanted side effects. In order to avoid the adverse effects of phenytoin, especially on the central nervous and cardiovascular systems, two small series of amine derivatives (Mannich bases) and amide ones were designed containing ß-tetralinohydantoin system. In preliminary studies, some of arylpiperazinylmethyl derivatives with a ß-tetralinohydantoin moiety were effective in screening anticonvulsant tests in mice. METHODS: These new amine and amide derivatives of ß-tetralinohydantoin were evaluated in standard anticonvulsant screens (maximal electroshock (MES) or pentylenetetrazole (scPTZ) seizure tests) and their neurotoxicity was assessed in standardized rotarod tests. Additionally, due to structural features (a hydantoin ring), influence on antiarrhythmic activity, electrocardiogram components and blood pressure was tested in rats. RESULTS: The new N-Mannich bases were effective in maximal electroshock or pentylenetetrazole seizures screens; and the most interesting compound 4 (1-{[4-(1-phenyethyl)-piperazin-1-yl]methyl}-3',4'-dihydro-1'H,2H,5H-spiro[imidazolidine-4,2'-naphthalene]-2,5-dione) displayed anticonvulsant activity in both the aforementioned tests. Furthermore, compound 6, an amide derivative of ß-tetralinohydantoin, displayed significant antiarrhythmic activity in a barium chloride-induced arrhythmia model (ED50 16.3mg/kg), but it was devoid of anticonvulsant protection. None of the tested compounds affected the electrocardiogram components or blood pressure in normotensive rats. CONCLUSION: All new N-Mannich bases containing the ß-tetralinohydantoin system and 1-phenylalkylpiperazine were classified to Anticonvulsant Screening Program 1st class. In contrast, our results suggested that the introduction of an amide bond in the alkyl side chain of the ß-tetralinohydantoin system abolished the anticonvulsant activity, but not the antiarrhythmic one. However, further studies are required for a definitive conclusion.

Antinociceptive activity of novel amide derivatives of imidazolidine-2,4-dione in a mouse model of acute pain.

BACKGROUND: Antiepileptic drugs are commonly used in non-epileptic disorders. For example, phenytoin and levetiracetam demonstrate analgesic properties in rodent models of pain. In order to enhance their antinociceptive activity, structural features of phenytoin and levetiracetam, such as imidazolidine-2,4-dione and amide bond in alkyl chain, were combined in one molecule. Furthermore, in preliminary studies, methoxyphenylpiperazinpropyl derivatives of imidazolidine-2,4-dione acted as antinociceptive agents in several rodent models of acute pain. METHODS: The final compounds and the reference drugs - levetiracetam and phenytoin were evaluated in the hot plate test to assess their antinociceptive activity in this acute pain model. Furthermore, for the analgesic active compounds the impact on animals' locomotor activity and motor performance were estimated and the affinity to serotonergic (5-HT1A, 5-HT7) and adrenergic (α1) receptors was determined. RESULTS: Three of the tested compounds: 7, 15 and 18 showed statistically significant antinociceptive properties at the dose of 30mg/kg. Among them, compound 18, 1-methyl-3-[1-(morpholin-4-yl)-1-oxobutan-2-yl]imidazolidine-2,4-dione, exhibited the most significant and long-lasting antinociceptive activity. Noteworthy, this activity was not associated with a negative effect on animals' motor functions. Serotonergic or adrenergic neurotransmission is not involved in this antinociceptive effect. CONCLUSION: Some amide derivatives of imidazolidine-2,4-diones possess antinociceptive properties in mice but further studies are needed to explain their mechanism of action and assess their toxicity.

Synthesis, anti-inflammatory, analgesic and COX-1/2 inhibition activities of anilides based on 5,5-diphenylimidazolidine-2,4-dione scaffold: Molecular docking studies.

The design, synthesis and pharmacological activities of a group of 5,5-diphenylimidazolidine-2,4-dione bearing anilide, phenacyl and benzylidene fragments 2-27 were reported. The prepared 5,5-diphenylimidazolidine-2,4-dione derivatives were evaluated in vivo for anti-inflammatory, analgesic activities and in vitro for COX-1/2 inhibition assay. Among the tested compounds, derivatives 5, 9, 10, 13, and 14 showed significant and potent anti-inflammatory and analgesic activities almost equivalent to reference drug celecoxib. In COX-1/2 inhibition assay, compounds 5, 9, 10 and 14 showed high COX-2 inhibitory activity (IC50 = 0.70 µM, 0.44 µM, 0.61 µM and 0.41 µM; respectively) and selectivity index (SI) range of 142-243 comparable to celecoxib [COX-2 (SI) > 333]. These potent COX-2 inhibitors 9, 10, 13, and 14 were docked into the active site pocket of COX-2 to explore the binding mode and possible interactions of these ligands.

Synthesis, biological evaluation and 3D-QSAR studies of imidazolidine-2,4-dione derivatives as novel protein tyrosine phosphatase 1B inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) plays a vital role in the regulation of insulin sensitivity and dephosphorylation of the insulin receptor, so PTP1B inhibitors may be potential agents to treat type 2 diabetes. In this work, a series of novel imidazolidine-2,4-dione derivatives were designed, synthesized and assayed for their PTP1B inhibitory activities. These compounds exhibited potent activities with IC50 values at 0.57-172 µM. A 3D-QSAR study using CoMFA and CoMSIA techniques was carried out to explore structure activity relationship of these molecules. The CoMSIA model was more predictive with q(2) = 0.777, r(2) = 0.999, SEE = 0.013 and r(2)pred = 0.836, while the CoMFA model gave q(2) = 0.543, r(2) = 0.998, SEE = 0.029 and r(2)pred = 0.754. The contour maps derived from the best CoMFA and CoMSIA models combined with docking analysis provided good insights into the structural features relevant to the bioactivity, and could be used in the molecular design of novel imidazolidine-2,4-dione derivatives.

Synthesis, characterization, hypoglycemic and aldose reductase inhibition activity of arylsulfonylspiro[fluorene-9,5'-imidazolidine]-2',4'-diones.

A series of 3-arylsulfonylspiroimidazolidine-2,4-diones (2a-g) and their corresponding rearranged products, 1-arylsulfonylspiroimidazolidine-2,4-diones (3a-g) were synthesized and evaluated for antidiabetic and aldose reductase inhibition activity. Three of the compounds (2b, 2c and 3c) were found more potent in-vivo hypoglycemic agents than the commercial drug glibenclamide. The free energy of binding (ΔG) values showed that the compounds are active against aldose reductase and aldehyde reductase enzymes, which was also estimated using molecular mechanics Poisson-Boltzmann surface area method. Of the tested compounds, 2b was found to be the most potent in-vitro selective inhibitor of ALR2 possessing an IC50 value of 0.89 µm. Structure activity relationship and molecular docking revealed the importance of substitution features of aryl group of aryllsulfonylimidazolidine-2,4-dione scaffold. It was observed that the substitution with a halogen at para position of the aryl group had a remarkable effect on ALR2 inhibition potency.