Antioxidant activity and low toxicity of (E)-1-(1-(methylthio)-1-(selenopheny) hept-1-en-2-yl) pyrrolidin-2-one

The aim of the present study was to evaluate the potential pharmacological and toxicological properties of (E)-1-(1-(methylthio)-1-(selenopheny) hept-1-en-2-yl) pyrrolidin-2-one (compound 1), an organoselenium compound. In vitro experiments showed that compound 1 presented a reduction in the lipid peroxidation induced by Fe2? in thiobarbituric acid-reactive species (TBARS) production, and in the generation of reactive species caused by Fe2?/malonate in DCFH-DA oxidation. The high dose (500 mg/kg) induced an increase on ALT but not on AST activity. Hepatic, but not cerebral, δ-ALA-D activity from mice treated with 500 mg/kg presented a significant inhibition. Brain catalase activity was significantly inhibited by 100 mg/kg whereas hepatic catalase activity showed a significant increase at all doses. Hepatic lipid peroxidation was diminished only at lowest dose (100 mg/kg) whereas for brain tissue, all doses induced a significant reduction in TBARS levels. Brain and liver ascorbic acid contents were increased only at highest dose of compound 1. Urea and creatinine levels were not significantly altered by treatments. This is a promising compound with antioxidant activity and low toxicity, suggesting the potential beneficial activity of compound 1 against oxidative damage in many parameters studied in rats and mice.     

1-(4-Methane(amino)sulfonylphenyl)-3-(4-substituted-phenyl)-5-(4-trifluoromethylphenyl)-1H-2-pyrazolines/pyrazoles as potential anti-inflammatory agents

2-Pyrazolins 14a–l and pyrazoles 15a–l were designed as celecoxib analogs for the evaluation of their in vitro COX-1/COX-2 inhibitory activity and the in vivo anti-inflammatory activity. Compounds 14i, 15a, 15d and 15f were the most COX-2 selective derivatives (S.I. = 5.93, 6.08, 5.03 and 5.27 respectively) while the pyrazoline derivatives 14g and 14i exhibited the highest AI activity (ED₅₀ = 190.5 and 160.1 μmol/kg po, respectively).     

Anti-resorptive activity and pharmacokinetic study of N(1),N(1)-diisopropyl-N(2)-(diphenylphosphoryl)-2-(4-nitrophenyl)acetamidine

In vitro anti-resorptive activity, mechanism of action, pharmacokinetic profile and in vivo anti-resorptive activity of N¹,N¹-diisopropyl-N²-(diphenylphosphoryl)-2-(4-nitrophenyl)acetamidine (1) were evaluated.     

NMR structural characterization of cecropin A(1-8) - magainin 2(1-12) and cecropin A (1-8) - melittin (1-12) hybrid peptides.

In order to elucidate the structure-antibiotic activity relationships of the peptides, the three-dimensional structures of two hybrid peptides, CA(1-8) - MA(1-12) and CA(1-8) - ME(1-12) in trifluoroethanol-containing aqueous solution were investigated by NMR spectroscopy. Both CA(1-8) - MA(1-12) and CA(1-8) - ME(1-12) have strong antibacterial activity but only CA(1-8) - ME(1-12) has hemolytic activity against human erythrocytes. CA(1-8) - MA(1-12) has a hydrophobic 310-helix of only two turns combined with one short helix in the N-terminus with a flexible hinge section in between. CA(1-8) - MA(1-12) has a severely bent structure in the middle of the peptide. These structural features as well as the low hydrophobicity of CA(1-8) - MA(1-12) seem to be crucial for the selective lysis against the membrane of prokaryotic cells. CA(1-8) - ME(1-12) has an alpha-helical structure of about three turns in the melittin domain and a flexible structure with one turn in the cecropin domain connected with a flexible hinge section in between, and these might be the structural features required for membrane disruption against prokaryotic and eukaryotic cells. The central hinge region (Gly9-Ile10-Gly11) in an amphipathic antibacterial peptide is considered to play an important role in providing the conformational flexibility required for ion channel formation of the C-terminal hydrophobic alpha-helix on cell membrane.     

Multitarget Effect of 2-(4-(Methylthio)phenyl)-3-(3-(piperidin-1-yl)propyl)thiazolidin-4-one in a Scopolamine-Induced Amnesic Rat Model

Neurochemical Research - Cholinergic system dysfunction, oxidative damage, and alterations in ion pump activity have been associated with memory loss and cognitive deficits in Alzheimer’s...     

The Synthesis and Antiviral Activity of (E)-5-(2-Nitrovinyl)uridine and (E)-5-(2-Nitrovinyl)-2′-deoxyuridine

Abstract

The protection of the sugar moiety of a 5-formyluracil nucleoside with acid-labile protecting groups allows for the deprotection of the sugar of a subsequently formed nucleoside possessing a 5-nitrovinyl side-chain. The synthesis and antiviral activity of (E) -5-(2-nitrovinyl)-uridine and (E)-5-(2-nitrovinyl)-2′-deoxyuridine are reported.     

Synthesis and Biological Properties of (+) and (-)-(E)-5-(2-bronovinyl)-21 -deoxy-11 a-Carbauridine

Abstract

Carbocyclic (+)- and (-)-(E)-5- (2-bromovinyl)-2′-deoxyuridlne have been prepared from (+)- and (-)-endo-norborn-5-en-2-y1 butyrate. In cell cultures both (+)- and (-)-C-BVDU showed activity against herpes simplex virus types 1 and 2, (+)-C-BVDU being only slightly less active than BVDU itself. (-)-C-BVDU gave a smaller but still significant antiviral effect. A nomenclature for carbocyclic nucleosides is proposed.     

Novel (E)-1-(4-methyl-2-(alkylamino)thiazol-5-yl)-3-arylprop-2-en-1-ones as potent antimicrobial agents

New (E)-1-(4-methyl-2-(alkylamino)thiazol-5-yl)-3-arylprop-2-en-1-ones, unsubstituted or carrying fluoro, bromo, methoxy, nitro, methyl and chloro groups on the benzene ring, were synthesized and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria and fungi. The compounds were very potent towards all tested microorganisms and in most cases their activity was better than that of reference drugs.     

Design, synthesis and anticonvulsant activities of novel 1-(substituted/unsubstituted benzylidene)-4-(4-(6,8-dibromo-2-(methyl/phenyl)-4-oxoquinazolin-3(4H)-yl)phenyl) semicarbazide derivatives

Novel quinazolinone derivatives 5a-5n were designed, synthesized and screened for antiepileptic activity using MES and scPTZ seizures tests. Neurotoxicity study was performed by rotorod test. Compounds 5c, 5d, 5g, 5j and 5k were found active in the preliminary screening in MES model and/or scPTZ model. Further all these five compounds were administered to rats, 5c and 5d showed better activity than Phenytoin in oral route. Among all the title compounds tested, the most active one was 5c that revealed protection in MES at a dose of 30 mg/kg (ip) after 0.5 and 4h. This molecule also provided protection in the scPTZ at a dose of 100mg/kg (0.5h) and 300 mg/kg (4h).     

Enhancement in antimicrobial activity of 2-(phenyl)-3-(2-butyl-4-chloro-1H-imidazolyl)-5-butylate isoxazolidine

The trans rich isomer, 2-(phenyl)-3-(2-butyl-4-chloro-1H-imidazolyl)-5-butylate isoxazolidine A (>96% ee) was synthesized by the condensation of E isomer rich nitrone 4 (>98% ee) with butyl acrylate in an inert solvent. Obtained isoxazolidine was screened for its antifungal activity against Aspergillus niger, Cephalosporium acremonium, Fusarium moniliforme by using Nystatin as positive control. It was also tested for its antibacterial activity against Bacillus subtilis, Escherichia coli, and Staphylococcus aureus by using Streptomycin as positive control. Enhanced antifungal activity was observed in isoxazolidine of >96% ee compared to the isoxazolidine of >69% ee (B), and enhancement was not observed in antibacterial activity.     

The L-DOPA-sparing effect of R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane hydrochloride [(-)-BPAP] in reserpine-pretreated rats

R-(-)-1-(Benzofuran-2-yl)-2-propylaminopentane hydrochloride [(-)-BPAP], a highly potent enhancer of impulse propagation-mediated release of catecholamines and serotonin in the brain, and significantly increased the locomotor activity of normal rats at the doses of 0.3 and 1 mg/kg s.c. (P < 0.05), while L-DOPA (200 and 400 mg/kg i.p.) had no significant effect. The locomotor activity of rats simultaneously administered L-DOPA and (-)-BPAP was significantly higher than with (-)-BPAP alone (P < 0.05). In rats pretreated with reserpine (1 mg/kg i.v.), the hypolocomotion was significantly reversed by 400 mg/kg i.p. L-DOPA, or 1 or 3 mg/kg s.c. (-)-BPAP (P < 0.05). Furthermore, the combined administration of subthreshold doses of 200 mg/kg i.p. L-DOPA and 0.3 mg/kg s.c. (-)-BPAP highly potentiated the locomotor activity in the reserpine-pretreated rats. However, (-)-BPAP failed to reverse the hypolocomotion in rats pretreated with reserpine + alpha-methyl-DL-p-tyrosine. Thus, (-)-BPAP was demonstrated to possess the L-DOPA-sparing effect in normal and reserpine-pretreated rats.     

Synthesis and antipicornavirus activity of (R)- and (S)-1-[5-(4'-chlorobiphenyl-4-yloxy)-3-methylpentyl]-3-pyridin-4-yl-imidazolidin-2-one

The new pyridyl imidazolidinone derivative, 1-[5-(4'-chlorobiphenyl-4-yloxy)-3-methylpentyl]-3-pyridin-4-yl-imidazolidin-2-one (+/-)-1a, was synthesized and found to have an excellent antiviral activity against EV71 (IC50 = 0.009 microM). Therefore, both the enantiomers, (S)-(+)-1a and (R)-(-)-1a, have been prepared starting from readily available monomethyl (R)-3-methylglutarate (7) as a useful chiral building block and their antiviral activity was evaluated in a plaque reduction assay. Interestingly, we observed that the enantiomer (S)-(+)-1a was 10-fold more active against enterovirus71 (EV71) (IC50 = 0.003 microM) than the corresponding enantiomer (R)-(-)-1a (IC50 = 0.033 microM). Similar results were found against all five strains (1743, 2086, 2231, 4643, and BrCr) of EV71 tested. This demonstrated that the absolute configuration of the chiral carbon atom at the 3-position of the alkyl linker considerably influenced the anti-EV71 activity of these pyridyl imidazolidinones.     

Identification of a novel 1'-[5-((3,5-dichlorobenzoyl)methylamino)-3-(3,4-dichlorophenyl)-4-(methoxyimino)pentyl]-2-oxo-(1,4'-bipiperidine) as a dual NK(1)/NK(2) antagonist

A novel series of dual NK(1)/NK(2) receptor antagonists, based on the 2-oxo-(1,4'-bipiperidine) template, has been prepared. Compound 10R is a potent dual NK(1)/NK(2) antagonist and demonstrates excellent in vivo activity and good oral plasma levels in the dog.     

Synthesis of N2-(substituted benzyl)-3-(4-methylphenyl)indazoles as novel anti-angiogenic agents

To search for novel compounds with potent anti-angiogenic activity, a series of N(1)-(substituted benzyl)-3-(4-methylphenyl)-1H-indazoles (16, 18, 20, 22, 24, 26, 28, 30, 32) and N(2)-(substituted benzyl)-3-(4-methylphenyl)-2H-indazoles (17, 19, 21, 23, 25, 27, 29, 31, and 33) were synthesized. The structures of these regioisomers were established by IR, UV, and NMR spectral data. 3-(4-Methylphenyl)-1H-indazole (6) and the N(2)-substituted derivatives (17, 19, 21, 23, 25, 29, 31, 33) were evaluated for their anti-angiogenic activity. Most of them showed more prominent activity than ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3). Among these tested compounds, 2-(4-chlorobenzyl)-3-(4-methylphenyl)-2H-indazole (19), 2-(4-methylbenzyl)-3-(4-methylphenyl)-2H-indazole (25), and 2-(4-methoxybenzyl)-3-(4-methylphenyl)-2H-indazole (31) showed significant anti-angiogenic activity and are worthy of further investigation.     

S-(2-(acylamino)phenyl) 2,2-dimethylpropanethioates as CETP inhibitors

Studies on the relationship between the structure of the benzene moiety of S-(2-(acylamino)phenyl) 2,2-dimethylpropanethioates and CETP inhibitory activity were performed. Substituents on the benzene moiety influenced CETP inhibitory activity in a type and position dependent manner, and electron-withdrawing groups at the 4- or 5-position increased the activity. The most potent compound showed 50% inhibition of CETP activity in human plasma at a concentration of 2 microM.     

Beta-L-(-)-dioxolane Cytidine (β-L-(-)-OddC) as a Potent Compound for the Treatment of Cancer

Abstract

L-(-)-OddC is the first nucleoside analog with the unnatural L-configuration and the first chain-terminator shown to have anti-cancer activity. This compound was found to be highly active against solid tumor growth in several human xenograft models. L-(-)-OddC exerts its activity be terminating DNA chain elongation after its incorporation.     

(R)-2-(4-Phenylbutyl)dihydrobenzofuran derivatives as melatoninergic agents

(R)-2-(4-Phenylbutyl)dihydrobenzofuran derivatives (e.g., 3 and 4) were synthesized as novel melatoninergic ligands with significantly lower vasoconstrictive activity in vitro in the rat tail artery. Binding affinity assays were performed on cloned human MT1 and MT2 receptors stably expressed in NIH3T3 cells.     

Novel P450(17alpha) inhibitors: 17-(2'-oxazolyl)- and 17-(2'-thiazolyl)-androstene derivatives

Twelve 17-(2'-oxazolyl)- and 17-(2'-thiazolyl)-androsta-5,16-diene derivatives were designed and synthesized from 3 beta-acetoxy-pregna-5,16-dien-20-one (1b) as inhibitors of 17 alpha-hydroxylase-C(17,20)-lyase (P450(17 alpha)). Potent inhibitors of this enzyme could be of value as treatment of prostate cancer. Two substituents (methyl and phenyl) were introduced either at their 4'- or 5'-position in order to investigate their structure-activity relationship. Due to the 16,17-double bond, 17-thiazoles were generally obtained in low yield. The pharmacological results showed that the compounds containing 17-(2'-oxazolyl) (14c) and 17-(2'-thiazolyl) (8c) (41.5%) demonstrated reasonable inhibition against P450(17 alpha). Their 3-acetate (13c and 7c) were less potent than their 3-OH counterparts. The introduction of a phenyl or methyl group generally decreased inhibitory activity. Surprisingly, 17-(5'-methyl-2'-thiazolyl) (12a) was the most potent compound in this series and was almost as potent as L-39, which has good antitumor activity.     

Synthesis and histamine H3 receptor activity of 4-(n-alkyl)-1H-imidazoles and 4-(omega-phenylalkyl)-1H-imidazoles

The influence of lipophilic moieties attached to a 4-1H-imidazole ring on the histamine H₃ receptor activity was systematically investigated. Series of 4-(n-alkyl)-1H-imidazoles and 4-(ω-phenylalkyl)-1H-imidazoles were prepared, with an alkyl chain varying from 2–9 methylene groups and from 1–9 methylene groups, respectively. The compounds were tested for their activity on the H₃ receptor under in vitro conditions. For the 4-(n-alkyl)-1H-imidazoles the activity is proportional to chain length, ranging from a pA₂ value of 6.3±0.2 for 4-(n-propyl)-1H-imidazole to a pA₂ value of 7.2±0.1 for 4-(n-decyl)-1H-imidazole. For the series 4-(ω-phenylalkyl)-4H-imidazoles an optimum in H₃ activity was found for the pentylene spacer: 4-(ω-phenylpentyl)-1H-imidazole has a pA₂ value of 7.8±0.1.     

1-(2-((Z)-6-(2-(Trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one as a new potent apoptosis agent

Compounds 4a–f, 5a–f and 6–9, showed significant growth inhibition activity against human tumor cell lines. Of these compounds, 1-(2-((Z)-6-(2-(trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one (8) displayed the most potent growth inhibition activity. Compound 8 also arrested cancer cells in G2/M phase and induced apoptosis via activation of caspase-3 and -9. According to western-blotting analysis, compound 8 can up-regulate Bax, down-regulate Bcl-2 and XIAP, as well as promote cytochrome c release.