In Vitro and In Silico Kinetic Studies of Patented 1,7-diEthyl and 1,7-diMethyl Aminoalkanol Derivatives as New Inhibitors of Acetylcholinesterase

Two aminoalkanol derivatives of 1,7-diEthyl-8,9-diphenyl-4azatricyclo (5.2.1.02.6) dec-8-ene-3,5,10-trione and two derivatives of 1,7-diMethyl-8,9-diphenyl-4-azatricyclo (5.2.1.02.6) dec-8-ene-3,5,10-trione were evaluated in vitro for their inhibition efficacy of acetylcholinesterase. The Km, Vmax, slope angles of Lineweaver–Burk plots, Ki and IC₅₀ values showed that all four aminoalkanol derivatives are competitive inhibitors of acetylcholinesterase whose inhibitory potency depends, to a varying extent, on the nature of the four different substituents present in the main compound structure. Studies have shown that the most potent acetylcholinesterase inhibitors are derivatives containing isopropylamine and/or methyl substituents in their structure. In contrast, dimethylamine and/or ethyl substituents seem to have a weaker, albeit visible, effect on the inhibitory potency of acetylcholinesterase. Additionally, docking studies suggest that studied compounds binds with the peripheral anionic site and not enter into the catalytic pocket due to the presence of the sterically extended substituent.     

Catalase Inhibition by Aminoalkanol Derivatives with Potential Anti-Cancer Activity—In Vitro and In Silico Studies Using Capillary Electrophoresis Method

In this work, the investigation of type and inhibitory strength of catalase by two pairs of aminoalkanol derivatives (1,7 diEthyl- and 1,7-diMethyl-8,9-diphenyl-4-azatricyclo (5.2.1.02.6) dec-8-ene- 3,5,10-trione) has been presented. The obtained results allowed for the determination of all kinetic parameters (Km, Vmax, slope angles of Lineweaver–Burk plots, Ki and IC₅₀) on the basis of which it was shown that all four aminoalkanol derivatives are competitive inhibitors of catalase. However, the strength of action of each of them depends on the type of substituents present in the main structure of the molecule. Subtle differences in the potency of individual derivatives were possible to detect thanks to the developed, sensitive method of capillary electrophoresis, which allowed simultaneous monitoring of the mutual changes in the concentrations of substrates and products of the reaction catalyzed by the enzyme. Detailed values of kinetic parameters showed that all derivatives are weak inhibitors of catalase, which in this case is a big advantage because each inhibition of catalase activity is associated with a greater amount of accumulated, harmful reactive oxygen species. The results of docking studies also show the convergence of the binding energies values of individual inhibitors with all kinetic parameters of the investigated catalase inhibition and thus additionally confirm the weak inhibitory strength of all four aminoalkanol derivatives.     

新型杀螨剂螺螨酯的合成

以环己酮为起始原料,经过加成、酰化、酯化、环合等反应制备得到螺螨酯中间体3-（2,4-二氯苯基）-2-氧代-1-氧杂螺[4．5-癸-3-烯4-醇,其与2,2-二甲基丁酰氯反应制得3-（2,4-二氯苯基）-2-氧代-1-氧杂螺[4．5]癸-3-烯4-基-2,2-二甲基丁酸酯即为螺螨酯。工艺路线适合产业化生产螺螨酯,5步反应总收率达到35．3％。     

Reactions with β-ketodianilides. I. New synthesis of Pyrido[3,4-c]pyridine Derivatives

Acetonedicarboxylic acid dianiline reacted with malononitrile, ethyl cyanoacetate or benzoylacetonitrile to give (6-amino-5-cyano-1,2-dihydro-2-oxo-1-phenylpyrid-4-yl)-acetanilide ( 3 ), (3-cyano-2,6-dioxo-1-phenyl-1,2,5,6-tetrahydropyrid-4-yl)acetanilide ( 8 ) or (3-cyano-1,6-dihydro-1,2-diphenyl-6-oxopyrid-4-yl)acetanilide ( 9 ). Compounds 3 and 8 could be cyclised into 8-amino-1,6-diphenyl-1,2,4,5,6,7-hexahydro-7-iminopyrido[3,4-c]pyridine-2,5-dione ( 4 ) and 7-amino-1,2,3,5,6,8-hexahydro-1,6-diphenylpyrido[3,4-c]pyridine-2,5,8-trione ( 10 ) respectively by heating their solutions in dimethylformamide in the presence of triethylamine. Each of 3 and 4 coupled with arenediazonium chlorides to give the corresponding arylhydrazone derivatives ( 5a–d ) and ( 6a–c ), respectively. Condensation of 4 with p-nitrosodimethylaniline yielded 8-amino-4- (p-dimethylaminophenylimino)-1,6-diphenyl-1,2,4,5,6,7-hexahydro-7-iminopyrido[3,4-c]pyridine2,5-dione ( 7 ).     

Convenient synthesis of perhydroindene derivatives from 2,7-dimethyl-1,3,7-octatriene

Several perhydroindene derivatives were prepared from 2,7-dimethyl-1,3,7-octatriene ( I ) via Diels Alder reaction followed by cyclisation. For example, the Diels Alder reaction between I and methyl vinyl ketone ( II ) in the presence of Lewis acid afforded 4-acetyl-3-(3-methylbut-3-enyl)-1-methylcyclohexene ( IIIa ), which, upon treatment with phosphoric acid, was converted to a mixture of 2-acetyl-5,7,7-trimethyl-bicyclo [4,3,0]-non-1-(6)-ene ( IV ), 2-acetyl-5,7,7-trimethylbicyclo[4,3,0]-non-1-ene ( VI ) and 2-isopropyl-3,6-dimethylindene ( V ).     

一类新型三唑并嘧啶联噻二唑杂环化合物的合成及杀菌活性

以5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶-2-甲酰肼为原料,设计合成了8个新型的2-(5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶)-1,3,4-噻二唑.5.硫醚类化合物.通过1HNMR、MS和元素分析对所合成的化合物进行了结构表征.初步的生物活性测试结果表明,所合成的化合物均具有较好的杀菌活性.     

Synthesen von C-Nucleosiden und C-Nucleosidanaloga. I. Darstellung von 1-(D-galacto-2,3,4,5,6-Pentakisacetoxyhexanoyl)-3-alkyl- oder arylamino-6,6-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-4-onen

Syntheses of C-Nucleosides and Analogs of C-Nucleosides. I. Preparation of 1-(D-galacto-2,3,4,5,6-Pentakisacetoxy-hexanoyl)-3-alkyl-or arylamino-6,6-dimethyl-4,5,6,7-tetrahydro-benzo[c] thiophene-4-ones 2-(Alkyl- or Arylamino-mercapto-methylen)-5,5-dimethyl-cyclohexane-1,3-diones 1 react in alkaline medium with 3,4,5,6,7-penta-O-acetyl-1-bromo-1-deoxy-D-galacto-heptulose 2b to give the title compounds 6d-g .     

Insights into the mode of action of the anti-Candida activity of 1,10-phenanthroline and its metal chelates

Metal complexes of malonie acid (metal = Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Ag(I)) were prepared and only the Ag(I) complex inhibited the growth of Candida albicans. Malonate complexes incorporating the chelating 1,10-phenanthroline (1,10-phen) ligand showed a range of activities: good (Mn(II), Cu(II), Ag(I)); moderate (Zn(II)); poor (Co(II), Ni(II)). Metal-free 1,10-phen and Ag(CH(3)CO(2)) were also highly active. The metal-free non-chelating ligands 1,7- phenanthroline and 4,7-phenanthroline were inactive and the Cu(II), Mn(II) and Zn(II) complexs of 1,7-phen displayed only marginal activity. Whereas the Cu(II) malonate/1,10-phen complex induces significant cellular oxidative stress the Zn(II) analogue does not.     

hERG Optimization of Benzofuro−Pyridine and Pyrazino−Indole Derivatives as MCHR1 Antagonists

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the antagonists of melanin concentrating hormone receptor 1 (MCHR1). The design, synthesis, and biological studies of novel MCHR1 antagonists based on benzofuro−pyridine and pyrazino−indole scaffold was performed. We confirmed that fine-tuning lipophilicity and basic pK_a by modifying the benzyl group and introducing different substituents on the aliphatic nitrogen sidechain decreases both hERG inhibition and metabolic clearance. We have succeeded to develop excellent in vitro parameters in the case of compounds 17 (4-[(5-chloropyridin-2-yl)methoxy]-1-[4-(2-hydroxyethyl)-8-oxa-4-azatricyclo[7.4.0.0²,⁷]trideca-1(13),2(7),9,11-tetraen-11-yl]-1,2-dihydropyridin-2-one monohydrochloride) and 23 g (4-[(5-chloropyridin-2-yl)methoxy]-1-(1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)pyridin-2(1H)-one monohydrochloride), which can be considered as valuable tools for further pharmacological investigation.     

Synthesis of some new 3-mercapto-5-substituted-1,2,4-triazine-s-triazoles for evaluation as antimicrobial agents

The synthesis of several S- and N-substituted derivatives of 5-[(5,6-diphenyl-1,2,4-triazin-3-yl)oxymethyl]-s-triazole-3-thiol, 2-[(5,6-diphenyl-1,2,4-triazin-3-yl)-oxymethyl]-5,6-dihydrothiazolo-[3,2-b]-s-briazole, 2-[(5,6-diphenyl-1, 2,4-triazin-3-yl)oxymethyl]-5H,6,7-dihydro-s-triazolo-[3,2-b]-1,3-thiazine, 2-[(5,6-diphenyl-1,2,4-triazin-3-yl)oxymethyl]-5,6-dihydrothiazolo-[3,2-b]-s-triazol-5-one and 2-[(5,6-diphenyl-1,2,4-triazin-3-yl)oxymethyl]-6-phenylthiazolo-[3,2-b]-s-triazole is reported. All the novel compounds have been screened for antimicrobial activity and one of them showed noteworthy activity.     

Novel derivatives of methyl hexahydro-3-methyl-6-thioxo-1,2,4,5-tetrazine-3-nonanoate

Methyl hexahydro-3-methyl-6-thioxo-1,2,4,5-tetrazine-3-nonanoate (I) on treatment with reagents such as chloroacetic acid, 1,2-dibromoethane and 2-mercaptoethanol under different reaction conditions afforded methyl 3,4,6,7-tetrahydro-3-methyl-6-oxo-2H-thiazolo[3,2-b]-1,2,4,5-tetrazine-3-nonanoate (II), methyl 3,4,6,7-tetrahydro-3-methyl-2H-thiazolo[3,2-b]-1,2,4,5-tetrazine-3-nonanoate (III) and methyl 8-methyl-1-oxa-4-thia-6,7,9,10-tetraazaspiro-[4.5]-decane-8-nonanoate (IV) in good yields. The structures of compounds II–IV were established by elemental analysis, infrared (IR), nuclear magnetic resonance (NMR), and mass spectral data.     

5-[(4-氨基苯基)二氮烯基]嘧啶-2,4,6(1H,3H,5H)-三酮的合成

以对硝基苯胺和巴比妥酸为原料,通过重氮化及偶合反应合成了5-[(4-硝基苯基)二氮烯基]嘧啶-2,4,6(1H,3H,5H)-三酮(A),化合物A经硫化物还原,得到单偶氮化合物5-[(4-氨基苯基)二氮烯基]嘧啶-2,4,6(1H,3H,5H)-三酮(B),该化合物可作为重氮组分与一些具有活泼氢的偶合组分反应,从而制备出酰胺键多、对称性高及稳定性强的双偶氮化合物。考察了还原剂用量、反应时间及反应温度对化合物B收率的影响,结果表明:投料比n(A)∶n(Na2S)=1∶1.7,105℃下回流48h,化合物B的收率为84.6%。利用1H NMR、FT-IR及元素分析对产物的结构进行了表征。     

Effect of some tripodal bipyrazolic compounds on C38 steel corrosion in hydrochloric acid solution

The corrosion inhibition of C38 steel in molar HCl by N,N-bis[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]buthylamine (P1) and 5-{N,N-bis[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl] amino} pentanol (P2) has been investigated at 308 K using electrochemical and weight loss measurements. Measurements show that these compounds act as good inhibitors without changing the mechanism of the corrosion process. Moreover, the inhibiting efficiency increases with the increase in concentration of the studied inhibitors. Compound P2 showed better protection properties even at relatively higher temperatures when compared to P1. The associated activation corrosion and free adsorption energies have been determined. P1 and P2 are adsorbed on the C38 steel surface according to a Langmuir isotherm adsorption model.     

Discovery of potent inhibitors of PapG adhesins from uropathogenic Escherichia coli through synthesis and evaluation of galabiose derivatives

The synthesis of two galabioside (Galalpha1-4Gal) collections based on diversification at the O-1 and O-3' atoms is reported. The galabiosides were evaluated as inhibitors of hemagglutination of human erythrocytes by two strains of Escherichia coli that expressed the class I and class II PapG adhesins, respectively. The class I adhesin was found to prefer aromatic substituents both at the O-1 and the O-3' position of the galabiose disaccharide. One galabioside, p-methoxyphenyl [3-O-(m-nitrobenzyl)-alpha-D-galactopyranosyl]-(1-4)-beta-D-galactopyranoside], had an IC(50) value of 4.1 microM, which is the best inhibition of the class I adhesin to date. In the case of the class II adhesin, one inhibitor, 2-[(S)-2-methoxycarbonyl-2-acetamido-ethylthio]ethyl (3-O-3-[2-(methoxycarbonylphenylthio)propyl]-alpha-D-galactopyranosyl)-(1-4)-alpha-D-galactopyranoside, was found to have an IC(50) value of 68 microM, which is the best artificial inhibition of the class II adhesin reported so far with an affinity for the adhesin comparable to that of the natural tetrasaccharide ligand globotetraose.     

Evaluation of Interactions of Selected Olivacine Derivatives with DNA and Topoisomerase II

Olivacine and ellipticine are model anticancer drugs acting as topoisomerase II inhibitors. Here, we present investigations performed on four olivacine derivatives in light of their antitumor activity. The aim of this study was to identify the best antitumor compound among the four tested olivacine derivatives. The study was performed using CCRF/CEM and MCF-7 cell lines. Comet assay, polarography, inhibition of topoisomerase II activity, histone acetylation, and molecular docking studies were performed. Each tested compound displayed interaction with DNA and topoisomerase II, but did not cause histone acetylation. Compound 2 (9-methoxy-5,6-dimethyl-1-({[1-hydroxy-2-(hydroxymethyl)butan-2-yl]amino}methyl)-6H-pyrido[4,3-b]carbazole) was found to be the best candidate as an anticancer drug because it had the highest affinity for topoisomerase II and caused the least genotoxic damage in cells.     

New Insight into Dearomatization and Decarbonylation of Antitubercular 4H-Benzo[e][1,3]thiazinones: Stable 5H- and 7H-Benzo[e][1,3]thiazines

8-Nitro-4H-benzo[e][1,3]thiazinones (BTZs) are potent in vitro antimycobacterial agents. New chemical transformations, viz. dearomatization and decarbonylation, of two BTZs and their influence on the compounds’ antimycobacterial properties are described. Reactions of 8-nitro-2-(piperidin-1-yl)-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazin-4-one and the clinical drug candidate BTZ043 with the Grignard reagent CH₃MgBr afford the corresponding dearomatized stable 4,5-dimethyl-5H- and 4,7-dimethyl-7H-benzo[e][1,3]thiazines. These methine compounds are structurally characterized by X-ray crystallography for the first time. Reduction of the BTZ carbonyl group, leading to the corresponding markedly non-planar 4H-benzo[e][1,3]thiazine systems, is achieved using the reducing agent (CH₃)₂S ⋅ BH₃. Double methylation with dearomatization and decarbonylation renders the two BTZs studied inactive against Mycobacterium tuberculosis and Mycobacterium smegmatis, as proven by in vitro growth inhibition assays.     

Studies on the Vilsmeier-haack reaction. Part XIII: Novel heterocyclo-substituted 4,4′-bi-pyrazolyl dithiocarbamate derivatives

5-Imino-3-methyl-l-phenyl-2-pyrazoline-4-dithiocarbamic acid (I) underwent simultaneous formylation and dimerization reactions with the Vilsmeier reagent giving 4-[5′-imino-3-(1″-formyl-2″-dimethylaminoethenyl)-3′-methyl-1′-phenyl-1′H-pyrazolo-4′-dithiocarbamyl-2,4-dihydro-3-imino-5-methyl-2-phenyl-1-pyrazoline]dithiocarbamate (II) which hydrolysed with sodium hydroxide to give 4-[3′-(1″-formyl-2″-hydroxyethenyl)-3′-methyl-1-phenyl-1′-H-pyrazolo-4′-dithiocarbamyl-1′-pyrazoline]dithiocarbamate-5,5′-dione (IV). Treatment of II and/or IV with morpholine, piperidine, piperazine, hydroxylamine, hydrazine hydrate or phenylhydrazine afforded the corresponding dipyrazolo-4,4′-dithiocarbamate derivatives with different heterocyclic systems at the 3-position. The structures of these compounds were confirmed by microanalysis data, IR and ¹H-NMR spectrometry. All synthesized compounds have been screened in vitro against Gram-positive and Gram-negative bacteria, and fungi.     

Ureidosulfocoumarin Derivatives As Selective and Potent Carbonic Anhydrase IX and XII Inhibitors

Owing to severe allergic reactions (anaphylaxis) and resistance exhibited by sulfonamide-based carbonic anhydrase (CA) inhibitors, non-classical or non-sulfonamide CA inhibitors are gaining increased attention by medicinal chemists. In this context, we report the design and synthesis of 30 new non-sulfonamide sulfocoumarin derivatives as CA inhibitors. They were investigated against hCA I and II (cytosolic isozymes) as well as hCA IX and XII (transmembrane, tumor-associated enzymes). All compounds showed prominent selectivity for the tumor-associated isoenzymes hCA IX and XII over the cytosolic isoenzymes hCA I and II. Among all synthesized compounds, 1-(2,2-dioxidobenzo[e][1,2]oxathiin-6-yl)-3-(o-tolyl)urea( 5 j )and1-(3-fluorophenyl)-3-(8-methoxy-2,2-dioxidobenzo[e][1,2]oxathiin-6-yl)urea( 5 q )were found to be more potent and to have better inhibition constant values against hCA IX than the standard acetazolamide (AAZ), with K_i values of 23.6 and 23.3 nM, respectively. All other compounds were found to be active under K_i=920 nM against hCA IX and XII.This study provides a new perspective for the future development of non-sulfonamide derivatives as selective CA inhibitors.     

Coronanden mit 1,2-Dithio-ethen-Einheiten. II. Kristallstrukturen der beiden Thiakronenether 8,9-Dicyan-8,9-didehydro-7,10-dithia[12]krone-4 und 11,12-Dicyan-11,12-didehydro-10,13-dithia[15]krone-5

Coronands with 1,2-Dithio-ethene Units. II. Crystal Structures of the Two Crown Thioethers 8,9-Dicyano-8,9-didehydro-7,10-dithia-[12]crown-4 and 11,12-Dicyano-11,12-didehydro-10,13-dithia[15]crown-5 The structures of the title compounds have been determined by X-ray analysis. Both thioethers crystallize in the monoclinic system with the following crystal data. Dithia-[12]crown-4: a = 751.7(1), b = 1010.4(1), c = 1639.8(2) pm, β = 95.08(1)°, Z = 4, space group P2₁/n; dithia[12]crown-5: a = 1169.9(3), b = 916.7(3), c = 1414.1(4)pm, β = 92.51(2)°, Z = 4, space group P2₁/c. The structures were refined to final R = 0.048 (R_w = 0.031) and 0.040 (0.046), respectively. They are characterized by their structural parameters (bond lengths and angles, torsion angles, l.s. planes) and discussed in special consideration of the ring conformation and the geometric arrangement of the donor atoms.     

Influence of an Alkoxy Group on Bis-Triazinyl-Pyridines for Selective Extraction of Americium(III)

The extraction of americium(III), curium(III), and lanthanides(III) from nitric acid by 2,6-bis-(5,6-dimethyl-[1,2,4]-triazin-3-yl)-pyridine and 2,6-bis-(5,6-dimethyl-[1,2,4]-triazin-3-yl)-4-methoxypyridine was studied. The physico-chemical properties of these ligands, such as the protonation and complexation constants, were also determined to describe the influence of different substituent groups. The selectivity of substituted-BTP was confirmed both in complexation and in solvent extraction experiments. The presence of an alkoxy-group in position 4 of the pyridine decreases the BTP selectivity. Influence of a long alkyl chain on protonation and complexation constants was also studied with 2,6-bis-(5,6-dimethyl-[1,2,4]-triazin-3-yl)-4-dodecyloxypyridine.