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A labeling technique was developed for the imidazoline I 2 receptor ligand 2-(3-fluoro-tolyl)-4, 5-dihydro-1H-imidazole (FTIMD) using Pd(0)-mediated 11 C-carbomethoxylation with [ 11 C]CO, followed by imidazoline ring formation with ethylenediamine-trimethylaluminium (EDA-AlMe 3 ). To achieve this, [ 11 C]CO was passed through a methanol (MeOH) solution containing 3-fluoro-4-methylphenylboronic acid (1), palladium (II) acetate (Pd [OAc] 2 ), triphenylphosphine (PPh 3 ), and p-benzoquinone (PBQ). The mixture was then heated at 65°C for 5 min. EDA was introduced into the reaction mixture, and MeOH was completely evaporated at temperatures exceeding 100°C. The dried reaction mixture was combined with an EDA-AlMe (1:1) toluene solution and heated at 145°C for 10 min. Portions of the reaction mixture were analyzed through high-performance liquid chromatography, resulting in [ 11 C]FTIMD with 26% (n = 2) decay-corrected radiochemical yield (RCY). This method could be utilized for various arylborons to produce [2- 11 C]imidazolines 4a-h with RCYs ranging from low to moderate. Notably, [2- 11 C]benazoline was obtained with a moderate RCY of 65%. The proposed technique serves as an alternative to the Grignard method, which uses [ 11 C]CO to generate a [2- 11 C]-labeled imidazoline ring., (© 2023 John Wiley & Sons Ltd.)

A series of substituted imidazoline derivatives were synthesized and characterized. Compounds were tested in-vivo for their antihypertensive, analgesic, antiaggressive, depressant, antidepressant, and ALD 50 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 ALD 50  > 500 mg/kg with maximum in 4a and 5a (>1000 mg/kg)., (Copyright © 2020. Published by Elsevier Ltd.)

The first enantio- and diastereoselective synthesis of Tepe's human proteasome modulator is described. Routes to this and other highly substituted chiral imidazolines generally produce racemic material. Key to the route disclosed here is a gram-scale anti -selective aza-Henry reaction of an α-alkyl α-nitro ester nucleophile, catalyzed by a Bis(Amidine) [BAM] chiral proton complex, delivering the key intermediate in high yield as a single stereoisomer. The adduct is reduced to the amino ester and converted to an imidazoline.

Imidazoline derivatives with different exocyclic substituents were simply prepared from common starting materials. The procedures were carried out in an eco-friendly manner. The antioxidant activity of these derivatives was explored by different experimental assays, such as ABTS .+ and DPPH . scavenging assay, as well as reducing power assay. The structural differences are discussed in terms of the results. Sulfur analogs showed higher antioxidant activity than their oxygenated counterparts. The same tendency was observed in microbiological studies, in which the same imidazoline compounds were assayed for light-mediated activity against of Staphylococcus aureus and Escherichia coli strains. A light-enhanced activity was observed for almost all the sulfated imidazolines after exposure to UV-A (400-320 nm) light., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Epimeric series of aryl-substituted glucopyranosylidene-spiro-imidazolinones, an unprecedented new ring system, were synthesized from the corresponding Schiff bases of O -perbenzoylated (gluculopyranosylamine)onamides by intramolecular ring closure of the aldimine moieties with the carboxamide group elicited by N -bromosuccinimide in pyridine. Test compounds were obtained by Zemplén O -debenzoylation. Stereochemistry and ring tautomers of the new compounds were investigated by NMR, time-dependent density functional theory (TDDFT)-electronic circular dichroism, and DFT-NMR methods. Kinetic studies with rabbit muscle and human liver glycogen phosphorylases showed that the ( R )-imidazolinones were 14-216 times more potent than the ( S ) epimers. The 2-naphthyl-substituted ( R )-imidazolinone was the best inhibitor of the human enzyme ( K i 1.7 μM) and also acted on HepG2 cells (IC 50 177 μM). X-ray crystallography revealed that only the ( R ) epimers bound in the crystal. Their inhibitory efficacy is based on the hydrogen-bonding interactions of the carbonyl oxygen and the NH of the imidazolinone ring.

The modification of Chan-Lam-Evans cross-coupling reaction for the selective Se-arylation of 2-selenohydantoins under base-free mild conditions via aryl boronic acids is described herein. This approach was used to synthesize novel 5-arylidene-3-substituted-2-(arylselanyl)-imidazoline-4-ones with high yields. The anticancer activity of the final compounds was evaluated in vitro against different cancer cells, and thus, the possibility of 5-arylidene-3-substituted-2-(arylselanyl)-imidazoline-4-ones successful application as cytotoxic agents was demonstrated.

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 (IC 50  = 0.14, 0.14, 0.056, 0.14, 0.13 and 0.14 μM, respectively) compared to sorafenib (IC 50  = 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 K i values of 95.0, 0.83, 6.90 and 12.4 nM, respectively compared to acetazolamide with K i values 250, 12.1, 74 and 12.8 nM, respectively. Therefore, compound 4a can be considered as a potent dual p38αMAPK/CA inhibitor., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A novel chemotype topologically similar to known influenza virus PA endonuclease inhibitors has been designed. It was aimed to reproduce the extended topology of the known metal-chelating ligands with a p-phenylidene-linked bis-imidazoline scaffold. It was envisioned that aromatic groups introduced to this scaffolds via metal-catalyzed N-arylation (Buchwald-Hartwig or Chan-Evans-Lam) would contribute to lipophilic binding to the target and one of the imidazoline nitrogen atoms would ensure non-chelating coordination to the prosthetic divalent metal ion. The compounds displayed appreciable anti-influenza activity in vitro and substantial concentration window from the general cytotoxicity range. Docking analysis of low-energy poses of the most active compound (as well as their comparison to the binding of an inactive compound) revealed that these compounds reproduced similar binding components to a known PA endonuclease inhibitor and displayed similar binding pose and desired monodentate metal coordination, as was initially envisioned. These findings warrant further investigation of the mechanism of action of the newly discovered series., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

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.

Biologically and chemically useful hydrazinoimidazolines were evaluated as antioxidant and antihaemolytic agents. 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH • ), galvinoxyl radical (GOR), nitric oxide (NO) and hydrogen peroxide (H 2 O 2 ) scavenging assays, ferric ions reducing power assay, and ex vivo model of rat erythrocytes exposed to 2,2'-azobis(2-methylpropionamidine)dihydrochloride (AAPH) or H 2 O 2 were used. The most potent DPPH • scavengers proved to be hydrazinoimidazolines 3, 2, and 4, revealing excellent antiradical effects - superior or comparable to that of all antioxidant standards used. Moreover, these molecules showed strong NO neutralising potencies - better to that of ascorbic acid (AA) (3), 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) (3 and 2), butylated hydroxytoluene (BHT) (3 and 2), and butylated hydroxyanisole (BHA) (3, 2, and 4). Compound 4 was also effective in GOR scavenging. The excellent scavenger of GOR, NO, and H 2 O 2 proved to be structure 5, with the potency superior or comparable to the majority of antioxidant standards used. In turn, compound 9 was effective in H 2 O 2 and GOR neutralisation. All hydrazinoimidazolines revealed the reducing power that is higher than BHT. Moreover, the protective effects of most test compounds on oxidatively stressed erythrocytes were observed. Some structure-activity relationships were disclosed. A significance of the primary hydrazino group on antioxidant effects was confirmed. The most likely DPPH • and GOR scavenging mechanisms for test compounds were propound. Among all the investigated molecules, hydrazinoimidazolines 5, 3, 2, 4, and 9, due to their excellent or good antiradical activities, can represent promising antioxidant candidates with prospective utility for prevention of diseases related to reactive oxygen/nitrogen species.

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.

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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)., (© 2017 Deutsche Pharmazeutische Gesellschaft.)

The imidazoline I 2 receptors (I 2 -IRs) are widely distributed in the brain, and I 2 -IR ligands may have therapeutic potential as neuroprotective agents. Since structural data for I 2 -IR remains unknown, the discovery of selective I 2 -IR ligands devoid of α 2 -adrenoceptor (α 2 -AR) affinity is likely to provide valuable tools in defining the pharmacological characterization of these receptors. We report the pharmacological characterization of a new family of (2-imidazolin-4-yl)phosphonates. Radioligand binding studies showed that they displayed a higher affinity for I 2 -IRs than idazoxan, and high I 2 /α 2 selectivity. In vivo studies in mice showed that acute treatments with 1b and 2c significantly increased p-FADD/FADD ratio (an index of cell survival) in the hippocampus when compared with vehicle-treated controls. Additionally, acute and repeated treatments with 2c, but not with 1b, markedly reduced hippocampal p35 cleavage into neurotoxic p25. The present results indicate a neuroprotective potential of (2-imidazolin-4-yl)phosphonates acting at I 2 -IRs.

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., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Parasitic diseases caused by protozoan parasites of the genus Trypanosoma and Plasmodium cause some of the deadliest and disabling human infections in tropical and subtropical areas. Diphenyl-based bis(2-phenylimino)imidazolidines and bisguanidines are extremely potent antiparasitic agents against Trypanosoma brucei (etiological agent of African trypanosomiasis) and Plasmodium falciparum (etiological agent of severe malaria). Many of these compounds are also curative in mouse models of stage 1 African trypanosomiasis representing promising leads for the development of antitrypanosomal drugs. In addition, different classes of bis(2-iminoimidazolidines) and bisguanidines have been shown to have antimicrobial activity against other pathogens (e.g. bacteria, fungi, parasitic worms). Due to their structural and physicochemical properties, these dibasic compounds, which are dications at physiological pH, are prone to bind to the minor groove of DNA at AT-rich sites. In several cases, such interaction is thought to be responsible for their antimicrobial activity., Results: In this review, we give a comprehensive view of the synthetic methods used to introduce the 2-aminoimidazoline scaffold in a molecule. Synthetic routes that give access to these cyclic guanidines (i.e. unsubstituted, 1-, 4-, and 5-substituted 2-aminoimidazolines) are detailed. The in vitro and in vivo antiprotozoal activity of bis(2-aminoimidazolines) and bisguanidines against kinetoplastid parasites (T. brucei, T. cruzi, Leishmania), Plasmodium spp. and other pathogens (e.g. ESKAPE bacteria, Candida spp., M. tuberculosis, E. multilocularia) is also reviewed. Finally, the targets that are involved in the antimicrobial activity (e.g. DNA) or other biological activities (e.g. α-adrenergic receptors, imidazoline binding sites, kinases) of this class of dicationic compounds are discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Five neutral mononuclear copper(I) halide complexes containing 2,2,5,5-tetramethylimidazolidine-4-thione (tmimdtH) and triphenylphosphane (PPh3) or tri-o-tolylphosphane (totp) have been prepared and structurally characterized by X-ray single-crystal analysis. The complexes containing PPh3 adopt the usual distorted tetrahedral geometry, while the presence of the bulkier totp forces the formation of three-coordinated trigonal planar species. The interaction of the compounds with calf-thymus DNA was monitored directly via UV-vis spectroscopy, DNA-viscosity measurements and indirectly via its competition with ethidium bromide for DNA studied by fluorescence emission spectroscopy. Intercalation was revealed as the most possible mode of binding. Furthermore, luminescent properties and thermal stabilities of the complexes were investigated., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The involvement of the serotonin 5-HT 1A receptor (5-HT 1A -R) in the antidepressant effect of allyphenyline and its analogues indicates that ligands bearing the 2-substituted imidazoline nucleus as a structural motif interact with 5-HT 1A -R. Therefore, we examined the 5-HT 1A -R profile of several imidazoline molecules endowed with a common scaffold consisting of an aromatic moiety linked to the 2-position of an imidazoline nucleus by a biatomic bridge. Our aim was to discover other ligands targeting 5-HT 1A -R and to identify the structural features favoring 5-HT 1A -R interaction. Structure-activity relationships, supported by modeling studies, suggested that some structural cliché such as a polar function and a methyl group in the bridge, as well as proper steric hindrance in the aromatic area of the above scaffold, favored 5-HT 1A -R recognition and activation. We also highlighted the potent antidepressant-like effect (mouse forced swimming test) of (S)-(+)-19 [(S)-(+)-naphtyline] at very low dose (0.01 mg kg -1 ). This effect was clearly mediated by 5-HT 1A , as it was significantly reduced by pretreatment with the 5-HT 1A antagonist WAY100635., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.

Over the years, the 2-substituted imidazoline nucleus has been demonstrated to be a bioversatile structural motif. In this study, novel imidazoline derivatives bearing a 3- and/or 4-hydroxy- or methoxy-substituted phenyl ring, linked by an ethylene bridge to position 2 of an N-benzyl- or N-phenethyl-substituted imidazoline nucleus, were prepared and studied against D2 -like receptor subtypes. Binding studies highlighted that a set of N-phenethylimidazoline compounds are selective for D4 over D2 and D3 receptors. In functional assays, the 3-methoxy-substituted derivative, endowed with the highest D4 affinity value, and its 3-hydroxy analogue behaved as partial agonists with low intrinsic efficacy and as competitive D4 antagonists when tested in the presence of the D2 -like receptor agonist quinpirole. Molecular docking analysis, performed using a homology model of the human D4 receptor developed using the X-ray crystal structure of the antagonist-bound human D3 receptor as a template, was in accordance with the binding results and provided useful information for the design of novel imidazoline D4 receptor ligands based on this new scaffold., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Synthesis and hypotensive properties of centrally acting imidazoline agents: 1-[(imidazolidin-2-yl)imino]-1H-indazole (Marsanidine) and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indazole (TCS-80) were tested in rats. We have recently synthesized two novel Marsanidine analogues which decrease blood pressure and heart rate in rats: 1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-54), and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-213). Among all these analogues, compound TCS-80 exhibits the highest affinity to I1-imidazoline receptors and the lowest α2/I1 selectivity ratio. The observed cardiovascular effects of the compounds might be mediated through α2-adrenergic and I1-imidazoline receptors and subsequent decrease of the symphathetic nerve activity. The present studies were performed to determine whether α2-adrenergic and/or I1-imidazoline receptors are involved in the decrease of blood pressure and heart rate induced by Marsanidine, TCS-54, TCS-80, and TCS-213 in rats., Methods: Anesthetized rats were infused iv with the tested compounds and selective α2-adrenoceptor antagonist, RX821002, or nonselective α2-adrenergic/I1-imidazoline receptor antagonist, Efaroxan. The mean arterial blood pressure and heart rate were monitored directly and continuously throughout the experiment., Results: Efaroxan inhibited the hypotensive effect of TCS-80 stronger than RX821002. The degree of inhibition of the hypotensive effect of the remaining compounds was similar for both antagonists. The presence of Efaroxan and RX821002 diminished the heart rate decrease induced by all compounds administration, though the influence on the maximal chronotropic effect was attenuated significantly in the TCS-80 and TCS-213 treated animals only., Conclusion: Our results indicate that hypotensive and negative chronotropic activities of all tested compounds are mediated by both the α2-adrenergic and I1-imidazoline receptors. Moreover, the circulatory effect of TCS-80 might be mediated to relatively higher degree by the I1-imidazoline receptors than by the α2-adrenergic ones., (Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

In the aim of identifying new privileged structures, we describe the 5-steps synthesis of cyclic guanidine compounds "tetrahydroisoquinoline-iminoimidazolines" derived from tetrahydroisoquinoline-hydantoin core. In order to evaluate this new minimal structure and the impact of replacing a carbonyle by a guanidine moiety, their affinity towards adenosine receptor A2A was evaluated and compared to those of tetrahydroisoquinoline-hydantoin compounds., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

A library of star-shaped 2H-imidazolines has been synthesized via Debus-Radziszewski condensation from 1,2-diketones and ketone starting materials. Selective reduction of one imine group of the 2H-imidazole intermediate with LiAlH4 or catalytic flow hydrogenation furnished 2H-imidazolines, which could be conveniently diversified by reacting the amine N with electrophiles, resulting in a set of 21 amide-, carbamate-, urea-, and allylamine-containing products. In total, five points of diversification could be used, which allow the production of a set of functionally diverse compounds. The synthesis of acylated 2H-imidazolidines resulted in intrinsically labile compounds, which spontaneously degraded to acyclic derivatives, as shown for the reaction of 2H-imidazolidine with hexylisocyanate.

A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide 15k gave respective IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of 15k. 2-Aminoimidazolinyl, 2-thioimidazolinyl, and 2-aminooxazolinyl units were shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)-benzamides previously reported, but the 2-aminooxazolinyl unit was the most potent in inhibiting HDAC3-NCoR2. Many of the new HDAC inhibitors showed higher solubilities and lower binding to human serum albumin than that of Mocetinostat. Increases in histone H3K9 acetylation in the human cell lines U937 and PC-3 was observed for all three oxazolinyl inhibitors evaluated; those HDAC inhibitors also lowered cyclin E expression in U937 cells but not in PC-3 cells, indicating underlying differences in the mechanisms of action of the inhibitors on those two cell lines.

Diphenyl-based bis(2-iminoimidazolidines) are promising antiprotozoal agents that are curative in mouse models of stage 1 trypanosomiasis but devoid of activity in the late-stage disease, possibly due to poor brain penetration caused by their dicationic nature. We present here a strategy consisting in reducing the pKa of the basic 2-iminoimidazolidine groups though the introduction of chlorophenyl, fluorophenyl and pyridyl ring in the structure of the trypanocidal lead 4-(imidazolidin-2-ylideneamino)-N-(4-(imidazolidin-2-ylideneamino)phenyl)benzamide (1). The new compounds showed reduced pKa values (in the range 1-3 pKa units) for the imidazolidine group linked to the substituted phenyl ring. In vitro activities (EC50) against wild type and resistant strains of T. b. brucei (s427 and B48, respectively) were in the submicromolar range with four compounds being more active and selective than 1 (SI > 340). In particular, the two most potent compounds (3b and 5a) acted approximately 6-times faster than 1 to kill trypanosomes in vitro. No cross-resistance with the diamidine and melaminophenyl class of trypanocides was observed indicating that these compounds represent interesting leads for further in vivo studies., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

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.

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.

With the help of pharmacophore analysis and docking investigation, 15 novel 1-(4,4,5,5-tetramethyl-2-(3-nitrophenyl)-4,5-dihydroimidazol-1-yl)-oxyacetyl-L-amino acids (6a-o) were designed, synthesized, and assayed. On tail-flick and xylene-induced ear edema models, 10 μmol/kg 6a-o exhibited excellent oral anti-inflammation and analgesic activity. The dose-dependent assay of their representative 6f indicates that the effective dose should be 3.3 μmol/kg. The correlation of the three-dimensional quantitative structure-activity relationship with the docking analysis provides a basis for the rational design of drugs to treat inflammatory pain.

A broccoli-like bismuth sulfide (bBi2S3) was synthesized via a solvothermal method using a self-made imidazoline derivative of 2-undecyl-1-dithioureido-ethyl-imidazoline as the soft template. The morphology and chemical constitution of the product were characterized by scanning electron microscope (SEM), transmission electron microscope (TEM) and X-ray diffraction (XRD). Electrochemical characterization experiments show that the bBi2S3 has the higher specific surface area and standard heterogeneous electron transfer rate constant than the rod-like Bi2S3 (rBi2S3). Hemoglobin (Hb) was then chosen as a protein model to investigate the electrocatalytic property of the synthesized bBi2S3. The results show that Hb entrapped in the composite film of chitosan and bBi2S3 displays an excellent direct electrochemistry, and retains its biocatalytic activity toward the electro-reduction of hydrogen peroxide. The current response in the amperometry shows a linear response to H2O2 concentrations in the range from 0.4 to 4.8µM with high sensitivity (444µAmM(-1)) and low detection limit (0.096µM). The Michaelis-Menten constant (KM(app)) of the fabricated bioelectrode for H2O2 was determined as low as 1µM. These results demonstrate that the synthesized bBi2S3 offers a new path for the immobilization of redox-active protein and the construction of the third-generation biosensors., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The synthesis of new 1,2,4-trisubstituted imidazolinone derivatives was described. The new compounds were designed as dual p38αMAPK and ERK1/2 inhibitors through hybridization of pharmacophoric elements associated with inhibition of these kinases. The kinase inhibition assay revealed excellent activity in the nanomolar range; especially compounds 6d and 7h which seemed promising candidates for such dual activity with IC50 values of 4.5 and 4.7 nM against p38αMAP, 25.0 and 24.0 nM against ERK1, and 3.2 and 3.5 nM against ERK2, respectively. These compounds were further tested for their antiproliferative activity against nine cancer cell lines, where they elicited high activity in the sub-micromolar range against breast, prostate and melanoma cells., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

We have previously identified phenylguanidine and phenyl-2-aminoimidazoline compounds as high affinity ligands with conflicting functional activity at the α2-adrenoceptor, a G-protein-coupled receptor with relevance in several neuropsychiatric conditions. In this paper we describe the design, synthesis, and pharmacological evaluation of a new series of pyridine derivatives [para substituted 2- and 3-guanidino and 2- and 3-(2-aminoimidazolino)pyridines, disubstituted 2-guanidinopyridines and N-substituted-2-amino-1,4-dihydroquinazolines] that were found to be antagonists/inverse agonists of the α2-adrenoceptor. Furthermore, the compounds exert their effects at the α2-adrenoceptor both in vitro in human prefrontal cortex tissue and in vivo in rat brain as shown by microdialysis experiments. We also provide a docking study at the α2A- and α2C-adrenoceptor subtypes demonstrating the structural features required for high affinity binding to the receptor.

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.

NIS-mediated aminoamidiniumation has been developed for the syntheses of bicyclic imidazolidinium salts, which could be readily converted into cyclic vicinal diamines.

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.

The proteasome has emerged as the primary target for the treatment of multiple myeloma. Unfortunately, nearly all patients develop resistance to competitive-type proteasome inhibitors such as bortezomib. Herein, we describe the optimization of noncompetitive proteasome inhibitors to yield derivatives that exhibit nanomolar potency (compound 49, IC50 130 nM) toward proteasome inhibition and overcome bortezomib resistance. These studies illustrate the feasibility of the development of noncompetitive proteasome inhibitors as additives and/or alternatives to competitive proteasome inhibitors.

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The silver carbonate promoted reaction of [60]fullerene with (Z)-N-arylbenzamidines afforded the unprecedented C60-fused imidazoline derivatives in high yields. Substrates with both electron-donating and -withdrawing groups on aromatic rings could be employed. In addition, the electrochemistry and further selective functionalization of the obtained C60-fused imidazolines were investigated.

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.

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.

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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

An organocatalytic enantioselective Mannich-type reaction of isocyanoacetate with N-sulfonylimines catalyzed by chiral thioureas derived from quinine yielded 2-imidazolines with high diastereo- and enantioselectivities (up to >99:1 dr. and 96% ee). This reaction provided a convenient route to access various imidazolines and related α,β-diamino acids having a quaternary carbon center in high enantiomeric purities.

A series of 1,2,4-trisubstituted 5-imidazolinone derivatives were synthesized by Erlenmeyer condensation of benzoylglycine (hippuric acid) with different aldehydes in the presence of sodium acetate and acetic anhydride. The derivatives of the compounds were prepared by condensation of some known sulpha drugs with 5-oxazolone derivatives. The anticonvulsant activity of the compounds was determined by the protection of pentylenetetrazole-induced convulsions that was ranged from 10 to 60%. The compounds with p-OCH₃, p-OH and o-Cl substitutions in the phenyl ring on 4(th) position of the imidazolinone ring exhibited good anticonvulsant activity. In silico metabolic and toxicity studies showed that all the compounds in the series are not likely to exhibit toxicity except the compounds IIIa, IIIb, VIa and VIb, that is predicted to show 29% mutagenicity and 53% irritation in comparison to the other compounds. The predicted lethal effect and hERG toxicity of the compounds showed that IIa, IVa, Va and Vb might be toxic at higher concentrations. The results successfully establish the synthesized imidazolinone derivatives as novel compounds with anticonvulsant properties, low predicted cardiotoxicity and lethal effects thus can be promising leads for further development as novel anticonvulsants.

The bradykinin (BK) B1 receptor is an attractive target for the treatment of chronic pain and inflammation. Starting from a dual B1 and B2 antagonist, novel antagonists were designed that display low-nanomolar affinity for human B1 receptor and selectivity over B2. Initially, potent imidazoline derivatives were studied, but these compounds suffered from low bioavailability. This issue could be overcome by the use of less basic amino derivatives leading to orally active compounds.

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 β-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.

A series of novel N1-amino-acid substituted 2,4,5-triphenyl imidazoline derivatives was designed and synthesized based on our previous studies. All synthesized target compounds were screened for their p53-MDM2 binding inhibitory activities and anti-proliferative activities against five cancer cell lines. Among them, twelve compounds displayed improved binding inhibitory activities and most compounds showed higher cell growth inhibition activities with IC(50) values in the low micromolar range. Compound 6c exhibited marked p53-MDM2 binding inhibitory activity (IC(50)=0.59 μM) which was eightfold more potent than that of Nutlin-1 (IC(50)=4.78 μM). CoMFA analysis was performed based on obtained biological data and resulted in a statistically significant CoMFA model with high predict abilities (q(2)=0.645, r(2)=0.979)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A high yielding three-step procedure was applied for the synthesis of N-(imidazolidin-2-ylidene)-1-arylmethanamine oxides 3 (α-aminonitrones) starting from the easily accessible imidazolidin-2-one O-benzyl oxime 1. The α-aminonitrone-α-iminohydroxyloamine tautomerism of these products was studied theoretically and the structures of the synthesised compounds were confirmed by single crystal X-ray crystallographic analysis. The compounds were evaluated in vitro for their binding affinities to α(1) and α(2) adrenoceptors as well as imidazoline I(1) and I(2) receptors. The highest potencies at the α(2) adrenergic receptors were observed for compounds bearing biphenyl (4h, K(i)  = 9 nM) and naphthyl (4i, K(i)  = 92 nM) moieties. Compounds 4h and 4i were further tested in vivo for their cardiovascular and sedative-hypnotic effects in rats., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A series of 2-[(heteroaryl)methyl]imidazolines was synthesized and tested for their activities at α(1)- and α(2)-adrenoceptors and imidazoline I(1) and I(2) receptors. The most active 2-[(indazol-1-yl)methyl]imidazolines showed high or moderate affinities for α(1)- and α(2)-adrenoceptors. However, their intrinsic activities at α(2A)-adrenoceptors proved to be negligible. A selected 7-chloro derivative behaved as a potent α(1)-adrenoceptor antagonist and exhibited peripherally mediated hypotensive effects in rats., (Copyright © 2011 Elsevier Ltd. All rights reserved.)