Synthesis and antitumor activity of bis(arylsulfonyl)dihydroimidazolinone derivatives.

A series of novel bis(arylsulfonyl)dihydroimidazolinones with different aryl substitution patterns were readily synthesized and evaluated for their antitumor activities. Some of the newly synthesized compounds exhibited cytotoxicity at micromolar range against multiple cancer cell lines, including A549, HepG2, HuCCA-1, and MOLT-3. The most potent analogue contained pentafluorobenzenesulfonyl groups, which could be chemically elaborated to serve as a potential pharmacophore.

Synthesis and biological evaluation of imidazoline derivatives as potential CNS and CVS agents.

A series of substituted imidazoline derivatives were synthesized and characterized. Compounds were tested in-vivo for their antihypertensive, analgesic, antiaggressive, depressant, antidepressant, and ALD50 activities. The compounds 3a, 3c, 4c, 5a, and 6c showed cardiovascular as well as central nervous system activities and are potential candidate as drug among all fifteen compounds tested. All these compounds have shown better activity for antihypertensive, analgesic, antiaggressive, and depressant-antidepressant, properties than reference compounds clonidine, morphine, diazepam, and imipramine respectively. Most of the compounds have shown ALD50 > 500 mg/kg with maximum in 4a and 5a (>1000 mg/kg).

2,4,5-Tris(alkoxyaryl)imidazoline derivatives as potent scaffold for novel p53-MDM2 interaction inhibitors: Design, synthesis, and biological evaluation.

Imidazoline-based small molecule inhibitors of p53-MDM2 interaction intended for the treatment of p53 wild-type tumors are the promising structures for design of anticancer drugs. Based on fragment approach we have investigated a key role of substituents in cis-imidazoline core for biological activity of nutlin family compounds. Although the necessity of the substituents in the phenyl rings of cis-imidazoline has been shown, there are no studies in which the replacements of a halogen by other substituents have been investigated. A series of simple cis-imidazoline derivatives containing halogen, hydroxy and alkoxy-substituents were synthesized. The biological activity of the compounds was studied using assays of cytotoxicity (MTT) and p53 level. It was found that the hydroxyl-derivatives were not cytotoxic whereas the alkoxy analogues were the same or more active as halogen-substituted compounds in cell viability test. The synthesized alkoxy derivatives induced an increase of p53 level and did not promote necrotic cell death in the concentration up to 40 µM.

Discovery and structure-activity relationship of imidazolinylindole derivatives as kallikrein 7 inhibitors.

A series of imidazolinylindole derivatives were discovered as novel kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Structure-activity relationship (SAR) studies led to the identification of potent human KLK7 inhibitors. By further modification of the benzenesulfonyl moiety to overcome species differences in inhibitory activity, potent inhibitors against both human and mouse KLK7 were identified. Furthermore, the complex structure of 25 with mouse KLK7 could explain the SAR and the cause of the species differences in inhibitory activity.

1,2,4-Trisubstituted imidazolinones with dual carbonic anhydrase and p38 mitogen-activated protein kinase inhibitory activity.

Various 1,2,4 trisubstituted imidazolin-5-one derivatives were synthesized and evaluated for their inhibitory activity against p38 mitogen-activated protein kinase (p38MAPK) and carbonic anhydrase (CA) enzymes aiming to explore potential dual inhibitors. Results revealed that compounds 3c, 3g, 3h, 4a, 6c and 6d were the most effective derivatives against p38αMAPK (IC50 = 0.14, 0.14, 0.056, 0.14, 0.13 and 0.14 µM, respectively) compared to sorafenib (IC50 = 1.58 µM) as standard drug. On the other hand, compound 4a revealed the best inhibitory activity against all the tested carbonic anhydrase isoforms CA I, II, IV and IX with Ki values of 95.0, 0.83, 6.90 and 12.4 nM, respectively compared to acetazolamide with Ki values 250, 12.1, 74 and 12.8 nM, respectively. Therefore, compound 4a can be considered as a potent dual p38αMAPK/CA inhibitor.

Modulation of Fluorescent Protein Chromophores To Detect Protein Aggregation with Turn-On Fluorescence.

We present a fluorogenic method to visualize misfolding and aggregation of a specific protein-of-interest in live cells using structurally modulated fluorescent protein chromophores. Combining photophysical analysis, X-ray crystallography, and theoretical calculation, we show that fluorescence is triggered by inhibition of twisted-intramolecular charge transfer of these fluorophores in the rigid microenvironment of viscous solvent or protein aggregates. Bioorthogonal conjugation of the fluorophore to Halo-tag fused protein-of-interests allows for fluorogenic detection of both misfolded and aggregated species in live cells. Unlike other methods, our method is capable of detecting previously invisible misfolded soluble proteins. This work provides the first application of fluorescent protein chromophores to detect protein conformational collapse in live cells.

Synthesis and properties of geometrical 4-diarylmethylene analogs of the green fluorescent protein chromophore.

We have developed a novel analog of the GFP chromophore: geo-DAIN. Since geo-DAIN is equipped with an E/Z-photoisomerizable geometrical diarylmethylene moiety instead of benzylidene of the GFP chromophore, different-colored reversible emissions are expected. We synthesized geo-DAIN by a condensation with methyl imidate and N-(diarylmethylene)glycinate. We found the emission from geo-DAIN to be different from that of benzylidene-type analogs; in the powder state, the E- and Z-isomers of geo-DAIN emitted different fluorescence colors.

Synthesis of dihydroimidazole tethered imidazolinethiones and their activity as novel antagonists of the nuclear retinoic acid receptor-related orphan receptors (RORs).

Targeting the transcriptional activity of nuclear hormone receptors has proven an effective strategy to treat certain human diseases, and they have become a major focus point to develop novel therapies for the treatment of cancer, inflammation, autoimmune diseases, metabolic disorders, and others. One family of nuclear receptors that has attracted most interest in recent years is the retinoic acid receptor-related orphan receptors (RORs), in particular RORγ. RORγ is a critical regulator of the immune system and RORγ antagonists have shown activity in animal models of inflammatory autoimmune diseases. Here we present the synthesis and biological evaluation of dihydroimidazole tethered imidazolinethiones. We have identified several dual RORγ/α and pan-ROR antagonists with significant activity in cellular assays that could serve as starting points for future optimization efforts to generate potent and selective RORγ modulators.

Synthesis, antifungal and antitumor activity of two new types of imidazolin-2-ones.

Thirty-six imidazolin-2-ones, including ten pairs of benzimidazolones and sixteen imidazopyridines, were synthesized and subjected for the evaluation of antifungal and antitumor activity. Compounds 4a-01, 6-01, 6-04 and 6-06 could effectively inhibit the spore germination and mycelium growth of Botrytis cinerea. The relationship between structure and antifungal activity revealed that the introducing short-chain aliphatic acyl groups at the moiety of imidazopyridines is favorable for the antifungal activity, whereas aromatic acyl groups are much better than aliphatic acyl groups for the activity of benzimidazolones except for acetyl. Preliminary SRB assay indicated that 6-01 exerted strong antiproliferative effect against Hela and NCM460 cell lines. Further kinases assay revealed that 6-01 could specially inhibit mTOR among 114 human cancer related kinases. Elisa and Western blot analysis testified that 6-01 simultaneously inhibits the phosphorylation of Akt and 4E-BP1, and 6-01 is a novel mTOR inhibitor which targets on both mTORC1 and mTORC2. This investigation provided a valuable chemical structure for the development of antitumor drugs.

Synthesis and Biological Evaluation of New Diarylpyrazole and Triarylimidazoline Derivatives as Selective COX-2 Inhibitors.

New series of diarylpyrazoles 8a-f and triarylimidazoline-5-ones 11a-g were synthesized and evaluated for their in vitro cyclooxygenase-1 (COX-1) and COX-2 inhibitory activity and in vivo anti-inflammatory activity. The synthesized compounds showed good selectivity for COX-2; compounds 8a, 8d, 8f, 11a, and 11c exhibited the highest COX-2 selectivity indexes (SI = 4.77-5.43) compared to the reference drug celecoxib (SI = 7.8). All compounds showed good in vivo anti-inflammatory activity, especially compounds 8a, 8f, 11c, and 11d, which also showed some similarities to the time interval pattern of celecoxib at all different time intervals (1, 3, and 6 h).

Synthesis, antiviral activity and structure-activity relationship of 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorosulfonylureas and products of their cyclization.

Novel 1-(1-aryl-4,5dihydro-1H-imidazoline)-3-chlorosulfonylourea derivatives 3a-3f were synthesized in the reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with chlorosulfonyl isocyanate. The second series of compounds 4a-4f was prepared from the respective 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorsulfonylureas 3a-3f and 1,1'-carbonyldiimidazole (CDI). The selected compounds were tested for their activity against Herpes simplex virus and coxsackievirus B3 (CVB3). It was determined that three derivatives, i.e 3d, 4a and 4d are active against Herpes simplex virus (HSV-1). Compounds 3d and 4c are active against CVB3. Their favorable activity can be primarily attributed to their low lipophilicity values. Moreover, the lack of substituent in the phenyl moiety or 4-methoxy substitution can be considered as the most beneficial for the antiviral activity.

Synthesis, central nervous system activity and structure-activity relationship of N-substituted derivatives of 1-arylimidazolidyn-2-ylideneurea and products of their cyclization.

A series of 20 N-substituted derivatives of 1-arylimidazolidyn-2-ylideneurea and products of their cyclization was designed as compounds having double antinociceptive and serotoninergic activity. Ethyl {[(1-arylimidazolidin-2-ylidene)carbamoyl]amino}acetates were prepared from 1-aryl-4,5-dihydro-1H-imidazol-2-amines and ethyl isocyanatoacetate, and then converted with ammonia solution to 2-{[(1-phenylimidazolidin-2-ylidene)carbamoyl]amino}acetamides. Both series of N-substituted derivatives of 1-arylimidazolidyn-2-ylideneureas were subjected to cyclization to respective imidazo[1,2-a][1,3,5]triazines. Chain and cyclic compounds bearing ester moiety affected spontaneous locomotor activity, body temperature of mice as well as showed antinociceptive and serotoninergic activity. Interestingly, their antinociceptive activity was not reversed by naloxone, thus it is not mediated through the opioid system. Chain and cyclic compounds bearing amide moiety were devoid of central nervous system (CNS) activity which may be attributed to unfavorably low lipophilicity (connected with too high polar surface area and too small molecular volume) and poor blood-brain barrier permeation properties.

Discovery of 5-(5,5-Dimethylbutenolide-3-ethylidene)-2-amino-imidazolinone Derivatives as Fungicidal Agents.

The novel fungicidal agents 5-(5,5-dimethylbutenolide-3-ethylidene)-2-amino-imidazolinone derivatives, were designed and synthesized in moderate to excellent yields in four steps by αa-hydroxyketone and diketene as raw materials and characterized by HR-ESI-MS and 1H-NMR. The preliminary bioassay showed that some of these compounds, such as 4a, 4e and 5g exhibit 94.9%, 92.8% and 81.4% inhibition rates against Sclerotinia scleotiorum at the concentration of 50 µg/mL, respectively. The EC50 values of compounds 4e and 4i were 4.14 and 3.27 µM against Alternaria Solani, and 5g had EC50 value of 3.23 µM against S. scleotiorum. Compounds 4d and 4g displayed 98.0% and 97.8% control of spore germination against Botrytis cinerea at the concentration of 100 µg/mL, respectively.

Synthesis, Structural Studies and Molecular Modelling of a Novel Imidazoline Derivative with Antifungal Activity.

Six novel imidazoline derivatives were synthesized and tested in antifungal assays. One of the compounds, N-cyclohexyl-2-imino-3-(4-nitrophenyl)imidazolidine-1-carboxamide showed moderate activity against several clinical strains of Candida albicans. Its structure was solved by X-ray crystallography and its mode of action was deduced using molecular modelling. It was found to be similar to that of fluconazole. The potential for further optimization including SAR of the compound is briefly discussed.

Diastereoselective one-pot synthesis of tetrafunctionalized 2-imidazolines.

A convenient trans-selective one-pot synthesis of tetrafunctionalized 2-imidazolines is described. Our approach to these valuable heterocyclic scaffolds involves a formal 1,3-dipolar cycloaddition between nitrile ylides or nitrilium triflates and imines. A detailed experimental study in combination with a high-level computational exploration of reaction routes reveals a plausible reaction pathway that accounts for the observed diastereoselectivity.

Copper-catalyzed N-arylation of 2-imidazolines with aryl iodides.

The first copper-catalyzed N-arylation of 2-imidazolines is described. The reaction affords compounds with desirable lead-like characteristics in high yield with practical simplicity under inexpensive, "ligand-free" conditions. The cross coupling was successful with electron-rich and electron-poor aromatic iodides. Substrates bearing halides, esters, nitriles, and free hydroxyls are well tolerated, providing reactive handles for further functionalization, as are pyridines. In addition, the regioselective N-arylation of a 4-substituted imidazoline is reported.

Inhibitors of the p53/hdm2 protein-protein interaction-path to the clinic.

A growing number of the elements identified in intracellular signaling events that affect cell growth and transformation are proteins that physically interact with each other via domains or specifically recognized amino acid sequences. Some of these intracellular protein-protein interactions are attractive targets for anticancer targeted therapy, but progress in this field has been compromised by the paucity of compounds with suitable biological profiles and pharmacological properties. This Letter covers salient achievements in the identification and development of inhibitors of the p53-hdm2 protein-protein interaction, and highlights different screening techniques and structure-based design approaches that may be brought to bear on the discovery and development of inhibitors of other therapeutically relevant intracellular protein-protein interactions.

A diversity-oriented approach to spirocyclic and fused hydantoins via olefin metathesis.

An efficient and general method is reported to prepare a diverse series of 5,5-spirocyclic and 1,5-, 4,5-, and 3,4-fused bicyclic imidazolidinone derivatives based on selective alkylation and ring closing metathesis (RCM) by exploiting the four possible points of diversity in the hydantoin ring. Hydantoins containing trienes and tetraenes undergo selective RCM and cross metathesis to afford functionalized spirohydantoins. A tandem metathesis sequence involving ring closing-ring opening-ring closing and cross metathesis (RC-RO-RC-CM) occurred with a hydantoin triene to give a bicyclic hydantoin dimer in high yield. The fused bicylic dimer could participate in cross metathesis to produce a functionalized fused hydantoin derivative. The methodology establishes novel routes to unnatural amino acids, proline homologues, and cyclic vicinal diamines.

Palladacyclic imidazoline-naphthalene complexes: synthesis and catalytic performance in Pd(II)-catalyzed enantioselective reactions of allylic trichloroacetimidates.

A new family of air- and moisture-stable enantiopure C,N-palladacycles (PIN-acac complexes) were prepared in good overall yield in three steps from 2-iodo-1-naphthoic acid and enantiopure ß-amino alcohols. Three of these PIN complexes were characterized by single-crystal X-ray analysis. As anticipated, the naphthalene and imidazoline rings of PIN-acac complexes 18a and 18b were canted significantly from planarity and projected the imidazoline substituents R(1) and R(2) on opposite faces of the palladium square plane. Fifteen PIN complexes were evaluated as catalysts for the rearrangement of prochiral (E)-allylic trichloroacetimidate 19 (eq 2) and the S(N)2' allylic substitution of acetic acid with prochiral (Z)-allylic trichloroacetimidate 23. Although these complexes were kinetically poor catalysts for the Overman rearrangement, they were good catalysts for the allylic substitution reaction, providing branched allylic esters in high yield. However, enantioselectivities were low to moderate and significantly less than that realized with palladacyclic complexes of the COP family. Computational studies support an anti-acetoxypalladation/syn-deoxypalladation mechanism analogous to that observed with COP catalysts. The computational study further suggests that optimizing steric influence in the vicinity of the carbon ligand of a chiral C,N-palladacycle, rather than near the nitrogen heterocycle, is the direction to pursue in future development of improved enantioselective catalysts of this motif.

Attenuation of collagen-induced arthritis by orally available imidazoline-based NF-κB inhibitors.

The pathogenesis of rheumatoid arthritis is mainly driven by NF-κB-mediated production of cytokines, such as TNF-α. We report herein that the orally available imidazoline-based NF-κB inhibitor, TCH-013, was found to significantly reduce TNF-α signaling and attenuate collagen antibody induced arthritis in BALB/c mice.