共查询到20条相似文献,搜索用时 15 毫秒
1.
Yin-Lin Zhang Jian-Min Xiao Ji-Li Feng Ke-Wu Yang Lei Feng Li-Sheng Zhou Michael W. Crowder 《Bioorganic & medicinal chemistry letters》2013,23(6):1676-1679
In an effort to prepare a fluorogenic substrate to be used in activity assays with metallo-β-lactamases, (6R,7R)-8-oxo-7-(2-oxo-2H-chromene-3-carboxamido)-3-((4-(2-oxo-2H-chromene-3-carboxamido)-phenylthio)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (CA) was synthesized and characterized. CA exhibited a fluorescence quantum yield (φ) of 0.0059, two fluorescence lifetimes of 3.63 × 10?10 and 5.38 × 10?9 s, and fluorescence intensity that is concentration-dependent. Steady-state kinetic assays revealed that CA is a substrate for metallo-β-lactamases (MβLs) L1 and CcrA, exhibiting Km and kcat values of 18 μM and 5 s?1 and 11 μM and 17 s?1, respectively. 相似文献
2.
《Inorganica chimica acta》2006,359(9):2864-2869
Treatment of 1,3-diphosphinopropane with acetylacetone in the presence of HCl gives the new chiral bis(phosphaadamantyl)propane ligand (bpap) (1) as a mixture of diastereoisomers. Recrystallization from ethanol gives a mixture enriched in rac diastereoisomer (90% rac/10% meso). The enriched mixture reacts with [RuHCl(PPh3)3] in refluxing THF to give [RuHCl(bpap)(PPh3)] (2) in 73% yield. Compound 2 reacts readily with chiral diamines giving octahedral trans-[RuHCl(bpap)(diamine)] complexes 3 (diamine = (1R,2R)-1,2-diaminocyclohexane) and 4 (diamine = (1R,2R)-1,2-diphenylethylenediamine). Compounds 3 and 4 are very active catalysts for H2-hydrogenation of neat acetophenone in the presence of KOtBu as a strong base under mild conditions (room temperature, 3 atm of H2). The low ee values for 1-phenethanol can be attributed to the similar shapes of two terminal adamantoid cages and the flexible backbone of the bpap ligand. The structures of complexes 2 and 3 have been determined by single-crystal X-ray diffraction. 相似文献
3.
Ke Zan Xiao-Qing Chen Xing-Yun Chai Qing Wu Qiang Fu Si-Xiang Zhou Peng-Fei Tu 《Phytochemistry letters》2012,5(2):313-315
Two new eudesmane sesquiterpenoids artanoate (1) and eudesmanomolide (2) were isolated from the aerial parts of Artemisia anomala S. Moore. Their structures were elucidated as methyl (4R, 5S, 6S, 7S, 10R)-1-oxo-4, 6-dihydroxy-eudesma-2, 11 (13)-dien-12-oate (1) and (1R, 5R, 6R, 10R)-3, 13-diacetoxy-1-hydroxy-3, 7(11)-diene-12, 6-olide (2) on the basis of extensive spectroscopic analyses. Compound 1 showed cytotoxicity against HCT-8 cell lines with IC50 value of 9.13 μM, and compound 2 exhibited inhibitory activities against HCT-8 and A549 cell lines with IC50 values of 3.76 and 5.49 μM, respectively. 相似文献
4.
《Bioorganic & medicinal chemistry》2014,22(21):6026-6038
A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT2B and 5-HT7 receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4′,5′-dihydro-3′H-spiro[fluorene-9,2′-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT2B (Ki = 5.1 nM) and 5-HT7 (Ki = 1.7 nM) receptors with high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials. 相似文献
5.
《Bioorganic & medicinal chemistry letters》2014,24(5):1303-1306
A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H3R antagonist. Compound R,S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03–0.3 mg/kg po. 相似文献
6.
David McGowan Origène Nyanguile Maxwell D. Cummings Sandrine Vendeville Koen Vandyck Walter Van den Broeck Carlo W. Boutton Hendrik De Bondt Ludo Quirynen Katie Amssoms Jean-François Bonfanti Stefaan Last Klara Rombauts Abdellah Tahri Lili Hu Frédéric Delouvroy Katrien Vermeiren Geneviève Vandercruyssen Liesbet Van der Helm Erna Cleiren Pierre Raboisson 《Bioorganic & medicinal chemistry letters》2009,19(9):2492-2496
Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent (replicon EC50 = 400 nM and 270 nM, respectively) and selective (CC50 > 20 μM) inhibitors of HCV replication. These data warrant further lead-optimization efforts. 相似文献
7.
Keimei Oh Kazuhiro Yamada Yuko Yoshizawa 《Bioorganic & medicinal chemistry letters》2013,23(24):6915-6919
The four stereoisomers of 2RS,4RS-1-[[2-(2,4-dichlorophenyl)-4-(2-(2-propenyloxy)phenoxymethyl)-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole (YCZ-2013), a novel brassinosteroid biosynthesis inhibitor, were prepared. The diastereomers of 2RS,4R-5 and 2RS,4S-5 were prepared by using the corresponding optically pure R and S toluene-4-sulfonic acid 2,3-dihydroxypropyl ester (R-4,S-4). The enatiomerically and diastereomerically pure acetonide (5) was obtained by a method involving diastereoselective crystallisation of the tosylate salt, followed by re-equilibration with the mother liquor and chromatography. The optical purity of four target compounds (YCZ-2013) was confirmed by chiral high-performance liquid chromatography (HPLC) and NMR. The effects of these stereoisomers on Arabidopsis stem elongation indicated that the cis isomers of 2S,4R-YCZ-2013 and 2R,4S-YCZ-2013 exhibited potent inhibitory activity with IC50 values of approximately 24 ± 3 and 24 ± 2 nM, respectively. The IC50 values of the trans isomers of 2S,4S-YCZ-2013 and 2R,4R-YCZ-2013 are approximately 1510 ± 50 and 3900 ± 332 nM, respectively. Co-application of brassinolide (10 nM), the most potent BR, and GA3 (1 μM) to Arabidopsis seedlings grown in the dark with 2R,4S-YCZ-2013 and 2S,4R-YCZ-2013 revealed that brassinolide recovered the induced dwarfism of Arabidopsis seedlings, whereas GA3 showed no effect. 相似文献
8.
Natalia Szkaradek Anna Rapacz Karolina Pytka Barbara Filipek Agata Siwek Marek Cegła Henryk Marona 《Bioorganic & medicinal chemistry》2013,21(2):514-522
A series of 9 piperazine derivatives of xanthone were synthesized and evaluated for cardiovascular activity. The following pharmacological experiments were conducted: the binding affinity for adrenoceptors, the influence on the normal electrocardiogram, the effect on the arterial blood pressure and prophylactic antiarrhythmic activity in adrenaline induced model of arrhythmia (rats, iv). Three compounds revealed nanomolar affinity for α1-adrenoceptor which was correlated with the strongest cardiovascular (antiarrhythmic and hypotensive) activity in animals’ models. The most promising compound was 4-(3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (12) which revealed antiarrhythmic activity with ED50 value of 0.69 mg/kg in adrenaline induced arrhythmia (rats, iv). Other synthesized xanthone derivatives, that is, (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (10) and (R,S)-4-(2-acetoxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (11) also acted as potential antiarrhythmics in adrenaline induced model of arrhythmia in rats after intravenous injection (ED50 = 0.88 mg/kg and 0.89 mg/kg, respectively). These values were lower than values obtained for reference drugs such as propranolol and urapidil, but not carvedilol.Results were quite promising and suggested that in the group of xanthone derivatives new potential antiarrhythmics and hypotensives might be found. 相似文献
9.
Two new lignans, named (+)-(7′S, 7″S, 8′R, 8″R)-4, 4′, 4″-trihydroxy-3, 5′, 3″-trimethoxy-7-oxo-8-ene [8-3′, 7′-O-9″, 8′-8″, 9′-O-7″] lignoid (1) and (1S)-4-Hydroxy-3-[2-(4-hydroxy-3-methoxy-phenyl)-1-hydroxymethyl-2-oxo-ethyl]-5-methoxy-benzaldehyde (2), along with five known (3–7) ones, have been isolated from the 95% ethanol extract of the seeds of Herpetospermum caudigerum Wall. The structures of the new compounds, including the absolute configurations, were elucidated by spectroscopic and CD analysis. Compounds 1, 2, and 7 displayed inhibitory activities on HBsAg secretion with IC50 values of 20.5, 0.34, and 4.89 μM, while 1, 2, and 7 displayed inhibitory activities on HBeAg secretion with IC50 values of 3.54, 4.83 × 10−4, and 8.02 μM, and cytotoxicity on HepG 2.2.15 cells with CC50 values of 12.7, 2.96 × 105, and 11.4 μM, respectively. 相似文献
10.
Chemical investigation of the ethanol extract of the stalks and infructescence of Sibiraea leavigata led to the isolation of two new monoterpenes named (4R)-2-(2-hydroxy-4-methyl-3-pentenyl)furan-2(5H)-one (1) and (2R,4R)-2-(2-hydroxyethyl)-4-(2-methyl-1-propenyl)furan-5H-2-one (2) along with eight known phenylpropanoids (3–10). Their structures were established on the basis of the interpretation of spectroscopic data and electronic circular dichroism (ECD) calculations. In addition, all of these isolates were evaluated for their cytotoxic activity. The results showed that compound 3 displayed moderate cytotoxicity with IC50 values ranging from 10.8 to 49.2 μg mL−1 against five cell lines. While 1 showed selective promotion effects on proliferation of gastric cancer MGC803 and RSC96 cell lines. 相似文献
11.
Catalin Maxim Traian D. Pasatoiu Victor Ch. Kravtsov Sergiu Shova Christopher A. Muryn Richard E.P. Winpenny Floriana Tuna Marius Andruh 《Inorganica chimica acta》2008,361(14-15):3903-3911
The following Schiff bases were employed as ligands in synthesizing copper(II) and zinc(II) complexes: N-[(2-pyridyl)-methyl]-salicylimine (Hsalampy), N-[2-(N,N-dimethyl-amino)-ethyl]-salicylimine (Hsaldmen), and N-[(2-pyridyl)-methyl]-3-methoxy-salicylimine (Hvalampy). The first two ligands were obtained by reacting salicylaldehyde with 2-aminomethyl-pyridyne and N,N-dimethylethylene diamine, respectively, while the third one results from the condensation of 3-methoxysalicylaldehyde with 2-aminomethyl-pyridine. Four new coordination compounds were synthesized and structurally characterized: [Cu(salampy)(H2O)(ClO4)] 1, [Cu2(salampy)2(H2trim)2] 2 (H2trim? = the monoanion of the trimescic acid), [Cu4(valampy)4](ClO4)4 · 2CH3CN 3, and [Zn3(saldmen)3(OH)](ClO4)2 · 0.25H2O 4. The crystal structure of 1 consists of supramolecular dimers resulted from hydrogen bond interactions established between mononuclear [Cu(salampy)(H2O)(ClO4)] complexes. Compound 2 is a binuclear complex with the copper ions connected by two monoatomic carboxylato bridges arising from two molecules of monodeprotonated trimesic acid. The crystal structure of 3 consists of tetranuclear cations with a heterocubane {Cu4O4} core, and perchlorate ions. Compound 4 is a trinuclear complex with a defective heterocubane structure. The magnetic properties of complexes 1–3 have been investigated. Compound 4 exhibits solid-state photoluminescence at room temperature. 相似文献
12.
Martina Blunder Eva M. Pferschy-Wenzig Walter M.F. Fabian Antje Hüfner Olaf Kunert Robert Saf Wolfgang Schühly Rudolf Bauer 《Bioorganic & medicinal chemistry》2010,18(7):2809-2815
Four derivatives of schisandrin, a major dibenzo[a,c]cyclooctadiene lignan of Schisandra chinensis (Turcz.) Baillon were synthesized and structurally characterized by means of NMR and mass spectroscopy. Furthermore, axial chirality of the biphenyl system was determined by comparison of calculated with measured circular dichroism (CD) spectra. Three of the obtained derivatives showed a ring contraction during chemical modification. While the original lignans were inactive on the performed bioassays, the compounds which showed the cycloheptadiene skeleton revealed remarkable activities. For the inhibition of LTB4 production the IC50 values of aR-6,7-dihydro-6-(1′-hydroxyethyl)-3,9-dimethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,10,11-tetraol (6) and aR-6-(1′-iodoethyl)-1,2,3,9,10,11-hexamethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene (8) were 4.2 ± 0.3 μM and 4.5 ± 0.2 μM, respectively. aR-6,7-Dihydro-6-(1′-hydroxyethyl)-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,3,9,10,11-hexaol (5) revealed dual inhibition on COX-2 (IC50 32.1 ± 2.5 μM) and on LTB4 production (37.3 ± 5.5% inhibition at 50 μM). 相似文献
13.
Hiroshi Enomoto Yuko Morikawa Yurika Miyake Fumio Tsuji Maki Mizuchi Hiroshi Suhara Ken-ichi Fujimura Masato Horiuchi Masakazu Ban 《Bioorganic & medicinal chemistry letters》2009,19(2):442-446
We studied synthetic modifications of N-mercaptoacylamino acid derivatives to develop a new class of leukotriene A4 (LTA4) hydrolase inhibitors. S-(4-Dimethylamino)benzyl-l-cysteine derivative 2a (SA6541) showed inhibitory activity against LTA4 hydrolase (IC50, 270 nM) and selectivity over other metallopeptidases except angiotensin-converting enzyme (ACE, IC50, 520 nM). Modification at the para-substituent of the phenyl ring of compound 2a improved LTA4 hydrolase inhibitory activity as well as selectivity over ACE. Finally, we obtained S-(4-cyclohexyl)benzy-l-cysteine derivatives 11l and 16i as potent and selective LTA4 hydrolase inhibitors. 相似文献
14.
《Inorganica chimica acta》2006,359(9):2896-2909
[RuCl3(NO)(P–P)], [P–P = R2P(CH2)nPR2 (n = 1–3) and R2P(CH2)POR2, PR2–CHCH–PR2, R = Ph and (C6H11)2P-(CH2)2-P(C6H11)2] were obtained and characterized by 31P {1H} NMR, IR spectroscopies and cyclic voltammetry. The structures of fac-[RuCl3(NO)(P–P)], P–P = dppm (1), dppe (2), c-dppen (3) and dppp (4), mer-[RuCl3(NO)(dcpe)] (6a) and mer-[RuCl3(NO)(dppmO)] (7) have been determined by X-ray diffraction. Photochemical isomerization of fac- to mer-[RuCl3(NO)(P–P)] was observed under white light in a CH2Cl2 solution and in solid state. The isomerization processes were followed by IR and 31P {1H} spectra. The mer-[RuCl3(15NO)(dppb)] isomer was used for the definition of the phosphorus atoms in the structure of the complex in solution. The electrochemical study shows that the oxidation/reduction processes observed in these complexes are dependent on both the isomer (fac or mer) and the solvent. In CH2Cl2, the NO+ reduction potentials are less negative for the mer-isomers than for the fac ones, while in CH3CN solvent these potentials are, in general, very close for both isomers. 相似文献
15.
Katrin Döring Deeb Taher Bernhard Walfort Martin Lutz Anthony L. Spek Gerard P.M. van Klink Gerard van Koten Heinrich Lang 《Inorganica chimica acta》2008,361(9-10):2731-2739
The synthesis and characterization of homobimetallic palladium and platinum complexes of type [(Me(O)CS-4-NCN–M ← N∩N → M–NCN-4-SC(O)Me](OTf)2 (Me(O)CS-4-NCN = [C6H2(CH2NMe2)2-2,6-SC(O)Me-4]?; N∩N = 4,4′-bipyridine (bipy); M = Pd, 12; M = Pt, 13) is reported. The required bifunctional thio-acetyl NCN pincer starting compound NC(Br)N-4-SC(O)Me (2) has been synthesized by the consecutive reactions of NC(Br)N–I (I-1-C6H2(CH2NMe2)2-3,5-Br-4) (1) with tBuLi, S8 and Me(O)CCl, respectively. Chemoselective metallation at the Caryl–Br bond was achieved by the reaction of 2 with the palladium(0) source [Pd2(dba)3] (3) (dba = dibenzylidene acetone). Treatment of thus formed [Pd(NCN-4-SC(O)Me)(Br)] (4) with [AgOTf] (8) (OTf = triflate, OSO2CF3) gave [Pd(NCN-4-SC(O)Me)(H2O)][OTf] (9) which was further reacted with 0.5 equiv. of 4,4′-bipyridine (11a) to afford rigid-rod structured 12. When [Pt(tol)2(SEt2)]2 (5) (tol = 4-tolyl) was used instead of 3, then 13 was produced via the in situ formation of [PtBr(NCN-4-SC(O)Me)] (7) and [Pt(NCN-4-SC(O)Me)(H2O)][OTf] (10). Another possibility to synthesize 7 relied upon the subsequent reaction of 1 with 0.5 equiv. of 5 to give [PtBr(NCN-4-I)] (6) which further reacted with tBuLi, 1/8 S8 and Me(O)CCl to afford 7. The cyclic voltammograms of 2, 7, and 13 are discussed.Complex 7 was structurally characterized by single crystal X-ray crystallography. Organometallic 7 crystallizes with three independent molecules in the asymmetric unit and displays a monomeric structure as commonly encountered in d8-metal pincer chemistry. 相似文献
16.
《Inorganica chimica acta》2006,359(5):1650-1658
A series of nickel(II) and palladium(II) complexes containing one or two pentafluorophenyl ligands and the phosphino-amides o-Ph2PC6H4CONHR [R = iPr (a), Ph (b)] displaying different coordination modes have been synthesised. The chelating ability of these ligands and the influence of both coligands and the metal centre in their potential hemilabile behaviour have been explored. The crystal structure of (b) has been determined and reveals N–H⋯O intermolecular hydrogen bonding. Bis-pentafluorophenyl derivatives [M(C6F5)2(o-Ph2PC6H4CO-NHR)] [M = Ni; R = iPr (1a); R = Ph (1b); M = Pd; R = iPr (2a); R = Ph (2b)] in which (a) and (b) act as rigid P, O-chelating ligands were readily prepared from the labile precursors cis-[M(C6F5)2(PhCN)2]. X-ray structures of (1a), (1b) and (2a) have been established, allowing an interesting comparative structural discussion. Dinuclear [{Pd(C6F5)(tht)(μ-Cl)}2] reacted with (a) and (b) yielding the monopentafluorophenyl complexes [Pd(C6F5)Cl{PPh2(C6H4–CONH–R)}] (R = iPr (3a), Ph (3b)) that showed a P, O-chelating behaviour of the ligands, confirmed by the crystal structure determination of (3a). New cationic palladium(II) complexes in which (a) and (b) behave as P-monodentate ligands have been synthesised by reacting them with [{Pd(C6F5)(tht)(μ-Cl)}2], stoichiometric Ag(O3SCF3) and external chelating reagents such as cod [Pd(C6F5)(cod){PPh2(C6H4-CONH-R)}](O3SCF3)(R = iPr (4a), Ph (4b)) and 2,2′-bipy [Pd(C6F5)(bipy){PPh2(C6H4-CONH-R)}](O3SCF3) (R = iPr (5a), Ph (5b)). When chloride abstraction in [{Pd(C6F5)(tht)(μ-Cl)}2] is promoted by means of a dithioanionic salt as dimethyl dithiophospate in the presence of (a) or (b), the corresponding neutral complexes [Pd(C6F5){S(S)P(OMe)2}{PPh2(C6H4-CONH-R)}] (R = iPr (6a), Ph (6b)) were obtained. 相似文献
17.
《Bioorganic & medicinal chemistry letters》2014,24(22):5219-5223
Herein we report the identification of (+)-N-(2-((1H-pyrazol-1-yl)methyl)-3-((1R,3r,5S)-6′-fluoro-8-azaspiro[bicyclo[3.2.1]octane-3,1′-isochroman]-8-yl)propyl)-N-[3H]-methylacetamide {[3H]PF-7191 [(+)-11]} as a promising radiotracer for the nociceptin opioid peptide (NOP) receptor. (+)-11 demonstrated high NOP binding affinity (Ki = 0.1 nM), excellent selectivity over other opioid receptors (>1000×) and good brain permeability in rats (Cb,u/Cp,u = 0.29). Subsequent characterization of [3H](+)-11 showed a high level of specific binding and a brain bio-distribution pattern consistent with known NOP receptor expression. Furthermore, the in vivo brain binding of [3H](+)-11 in rats was inhibited by a selective NOP receptor antagonist in a dose–responsive manner. This overall favorable profile indicated that [3H](+)-11 is a robust radiotracer for pre-clinical in vivo receptor occupancy (RO) measurements and a possible substrate for carbon-11 labeling for positron emission tomography (PET) imaging in higher species. 相似文献
18.
Om P. Mishra Nicholas Simmons Sonia Tyagi Ralph Pietrofesa Vladimir V. Shuvaev Roman A. Valiulin Philipp Heretsch K.C. Nicolaou Melpo Christofidou-Solomidou 《Bioorganic & medicinal chemistry letters》2013,23(19):5325-5328
Secoisolariciresinol diglucosides (SDGs) (S,S)-SDG-1 (major isomer in flaxseed) and (R,R)-SDG-2 (minor isomer in flaxseed) were synthesized from vanillin via secoisolariciresinol (6) and glucosyl donor 7 through a concise route that involved chromatographic separation of diastereomeric diglucoside derivatives (S,S)-8 and (R,R)-9. Synthetic (S,S)-SDG-1 and (R,R)-SDG-2 exhibited potent antioxidant properties (EC50 = 292.17 ± 27.71 μM and 331.94 ± 21.21 μM, respectively), which compared well with that of natural (S,S)-SDG-1 (EC50 = 275.24 ± 13.15 μM). These values are significantly lower than those of ascorbic acid (EC50 = 1129.32 ± 88.79 μM) and α-tocopherol (EC50 = 944.62 ± 148.00 μM). Compounds (S,S)-SDG-1 and (R,R)-SDG-2 also demonstrated powerful scavenging activities against hydroxyl [natural (S,S)-SDG-1: 3.68 ± 0.27; synthetic (S,S)-SDG-1: 2.09 ± 0.16; synthetic (R,R)-SDG-2: 1.96 ± 0.27], peroxyl [natural (S,S)-SDG-1: 2.55 ± 0.11; synthetic (S,S)-SDG-1: 2.20 ± 0.10; synthetic (R,R)-SDG-2: 3.03 ± 0.04] and DPPH [natural (S,S)-SDG-1: EC50 = 83.94 ± 2.80 μM; synthetic (S,S)-SDG-1: EC50 = 157.54 ± 21.30 μM; synthetic (R,R)-SDG-2: EC50 = 123.63 ± 8.67 μM] radicals. These results confirm previous studies with naturally occurring (S,S)-SDG-1 and establish both (S,S)-SDG-1 and (R,R)-SDG-2 as potent antioxidants and free radical scavengers for potential in vivo use. 相似文献
19.
In continuation of our previous efforts directed towards the development of potent and selective inhibitors of aldose reductase (ALR2), and to control the diabetes mellitus (DM), a chronic metabolic disease, we synthesized novel coumarin-thiazole 6(a–o) and coumarin-oxadiazole 11(a–h) hybrids and screened for their inhibitory activity against aldose reductase (ALR2), for the selectivity against aldehyde reductase (ALR1). Compounds were also screened against ALR1. Among the newly designed compounds, 6c, 11d, and 11g were selective inhibitors of ALR2. Whereas, (E)-3-(2-(2-(2-bromobenzylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one 6c yielded the lowest IC50 value of 0.16 ± 0.06 μM for ALR2. Moreover, compounds (E)-3-(2-(2-benzylidenehydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6a; IC50 = 2.94 ± 1.23 μM for ARL1 and 0.12 ± 0.05 μM for ARL2) and (E)-3-(2-(2-(1-(4-bromophenyl)ethylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6e; IC50 = 1.71 ± 0.01 μM for ARL1 and 0.11 ± 0.001 μM for ARL2) were confirmed as dual inhibitors. Furthermore, compounds 6i, 6k, 6m, and 11b were found to be selective inhibitors for ALR1, among which (E)-3-(2-(2-((2-amino-4-chlorophenyl)(phenyl)methylene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6m) was most potent (IC50 = 0.459 ± 0.001 μM). Docking studies performed using X-ray structures of ALR1 and ALR2 with the given synthesized inhibitors showed that coumarinyl thiazole series lacks the carboxylate function that could interact with the anionic binding site being a common ALR1/ALR2 inhibitors trait. Molecular docking study with dual inhibitor 6e also suggested plausible binding modes for the ALR1 and ALR2 enzymes. Hence, the results of this study revealed that coumarinyl thiazole and oxadiazole derivatives could act as potential ALR1/ALR2 inhibitors. 相似文献
20.
《Bioorganic & medicinal chemistry》2016,24(21):5462-5480
Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson’s disease are, among others, the A2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A1 ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure–activity-relationships. Several compounds blocked human and rat A1 and A2AARs at similar concentrations representing dual A1/A2A antagonists with high selectivity versus the other AR subtypes. Among the best dual A1/A2AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, Ki human A1: 65.5 nM, A2A: 230 nM; Ki rat A1: 352 nM, A2A: 316 nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, Ki human A1: 642 nM, A2A: 203 nM; Ki rat A1: 166 nM, A2A: 121 nM). Compound 57 was found to be well water-soluble (0.7 mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A1 and A2AARs and at MAO-B (Ki human A1: 393 nM, human A2A: 595 nM, IC50 human MAO-B: 210 nM) thus allowing future in vivo explorations of the intended multi-target approach. 相似文献