The Novel Ketoprofen Amides – Synthesis and Biological Evaluation as Antioxidants,Lipoxygenase Inhibitors and Cytostatic Agents

The novel amides of ketoprofen and its reduced derivatives (5a–f, 4a–n, 6a–g) with aromatic and cycloalkyl amines or hydroxylamines were prepared and screened for their reducing and cytostatic activity as well as for their ability to inhibit soybean lipoxygenase and lipid peroxidation. 1,1-Diphenyl-picrylhydrazyl test for reducing ability revealed that ketoprofen amides were more potent antioxidants than the amides of the reduced ketoprofen derivatives. The most active compound was benzhydryl ketoprofen amide 5f. Lipoxygenase inhibition of the tested compounds varied from strong to very weak. The most potent compound was benzhydryl derivative 6f (IC₅₀ = 20.5 μm ). Aromatic and cycloalkyl amides 4 and 5 were more potent lipoxygenase inhibitors than derivatives with carboxylic group. Aromatic amides of series 4 and 5 showed excellent lipid peroxidation inhibition (92.2–99.9%). On the other hand, the most pronounced cytostatic activity was exerted by O-benzyl derivative 4i, although in general all tested reduced and non-reduced lipophilic derivatives showed similar activity.     

Synthesis and Study of the Analgesic and Antiinflammatory Activity of α-Acetoxyphenylacetic Acid Amides

Pharmaceutical Chemistry Journal -     

Drug Delivery Studies in Caco-2 Monolayers. Synthesis,Hydrolysis, and Transport of O-Cyclopropane Carboxylic Acid Ester Prodrugs of Various β-Blocking Agents

A series of O-cyclopropane carboxylic acid ester prodrugs of various -blocking agents was synthesized. All prodrugs were hydrolyzed to give their parent compounds in aqueous phosphate buffer of pH 7.4 and in 80% human plasma. The half-lives in buffer solutions varied from 4 hours for the timolol prodrug to about 1 day for the prodrug of alprenolol. In human plasma the half-lives were shorter, ranging from 1 to 7 hours. The formation of the O-cyclopropane carboxylic acid ester derivatives significantly increased the lipophilicities of the -blockers as measured by the distribution coefficient between n-octanol and aqueous phosphate buffer of pH 7.4. To characterize the biomembrane permeability characteristics of the -blockers, transport properties across Caco-2 cell monolayers were investigated. An increase in lipophilicity resulted in a higher permeability of the prodrugs as compared to the parent compounds. Hence, acebutolol experienced an increment of a factor 17 on the apparent permeability coefficient, Papp, whereas Papp for the more lipophilic drug propranolol was increased by a factor of only 1.26. Some conversion of the prodrugs to their parent compounds was observed during the transport and appeared to be due to enzymatic intracellular metabolism.Deseaced.     

Synthesis and Biological Evaluation of ��-Aroylpropionic acid based 1,3,4-Oxadiazoles

In the present investigation, two new series, 1-(4-benzylphenyl)-3-(5-substituted-1,3,4-oxadiazol-2-yl)-1-propanone and 1-(4-ethylphenyl)-3-(5-substituted-1,3,4-oxadiazol-2-yl)-1-propanone from β-(4-benzylbenzoyl)propionic acid and β-(4-ethylbenzoyl)propionic acid, respectively, were synthesized and tested for antiinflammatory, analgesic, lipid peroxidation, ulcerogenic and antibacterial actions. A fair number of compounds were found to have good antiinflammatory activity in carrageenan-induced rat paw edema test, while a few compounds showed significant antibacterial activity. The newly synthesized compounds showed very low ulcerogenic action.     

Design,Synthesis, and Biological Evaluation of Indole Biphenylcarboxylic Acids as PPARγ Antagonists

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Synthesis and antitumor evaluation of acyclic 1-[ω-(N′-2-chloroethyl-N′-nitrosoureido)alkyl]thymidine nucleoside analogues

In the preparation of acyclic thymidine nucleoside analogues, K₂CO₃ (or NaH) treated thymine in DMSO was alkylated with ω-chloroalkyl nitrite (Cl-(CH₂)_n-CN; n=1, 2, 3, 4) to provide an isomeric mixture of 1-(ω-cyanoalkyl)thymine (2a-d) and 1,3-bis(ω-cyanoalkyl)thymine in approximately 5∶1 ratios. Reduction of the cyano function2a-d with NaBH₄/CoCl₂·6H₂O gave the corresponding 1-(ω-aminoalkyl)thymine (3a-d). The newly formed primary amino function in3a-d was directly reacted with 2-chloroethylisocyanate to afford the 1-[ω-(N′2-chloroethy-lureido) alkyl]thymine (4a-d) in good yields. Nitrosation of 1-[5-(N′-2-chloroethylureido)pentyl] thymine (4d) with glacial acetic acid and dry NaNO₂ powder in anhydrous CH₂Cl₂ gave two types of regioisomeric nitrosoureas, 1-[5-(N′-2-chloroethyl-N′-nitrosoureido)pentyl]thymine (5d) and 1-[5-(N′-2-chloroethyl-N-nitrosoureido)pentyl]thymine in approximately 5∶1 ratios. The in vitro cytotoxicity of the synthesized compounds (2a-d, 3a-d, 4a-d and5a-d) against three cell lines (K-562, P-388 and FM-3A) are measured as IC₅₀ values. Compounds3d and4c showed moderate activities against all three cell lines, and all other compounds were found to be not active.     

Synthesis and Biological Activities of Some Mannich Bases of 5-(4-Hydroxyphenyl)-1,3,4-Oxadiazole-2-Thione

以对羟基苯甲酸乙酯为原料，经肼解、环化合成５（４羟基苯基）１，３，４二唑２硫酮，继而经Ｍａｎｎｉｃｈ反应合成了四种新曼尼希碱，其结构经红外光谱、核磁共振和元素分析证实。初步抑菌活性试验表明，显示弱的抑菌活性。     

Synthesis, characterization, and antimicrobial activity of copper(II) complexes with N,N′-propanediyl-bis-benzenesulfonamide and N,N′-ethanediyl-bis-2-methylbenzenesulfonamide

Copper(II) complexes of new aryldisulfonamides (L ₁  = N,N′-bis[(2-methylphenyl)sulfonyl]ethylenediamine) and L ₂  = N,N′-propanediyl-bis-benzenesulfonamide with 1,10-phenanthroline have been synthesized and characterized by using elemental analyses, FT-IR, LCMS, conductivity, and magnetic susceptibility techniques. The structures of [Cu(phen)₂]L₁ (1) and [CuL₂(phen)₂] (2) compounds have been determined. Complex (1) has also been characterized by single crystal X-ray diffraction. The complex (1) crystallizes in the triclinic system, space group P1, with cell constants a = 12.9353(8) Å, b = 13.8543(9) Å, c = 14.4513(10) Å, α = 103.593(5)°, β = 113.713(5)°, γ = 106.104(5)°, and Z = 1. The antibacterial activities of synthesized compounds were studied against Gram-positive bacteria: Staphylococcus aureus, Bacillus subtilis, and B. cereus and Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa, and Yersinia enterocolitica by microdilution (as MICs in μg/mL) and disk diffusion (as diameter zone in mm) method. The biological activity screening showed that (1) has more activity than (2) against the tested bacteria.     

Synthesis and Evaluation of Novel Erlotinib–NSAID Conjugates as More Comprehensive Anticancer Agents

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Synthesis and antibacterial activity of 4,4′-(aryl or alkyl methylene)-bis(1H-pyrazol-5-ol) derivatives

A rapid, improved, and environmentally benign synthesis of 4,4′-aryl or alkyl methylene-bis(1H-pyrazol-5-ols) has been accomplished by tandem Knoevenagel–Michael reaction of 1-aryl-3-alkyl-1H-pyrazol-5-ol with various aldehydes catalyzed by ammonium acetate. All the synthesized compounds 3a–v were evaluated in vitro for their antibacterial activity against Pseudomonas aeruginosa, Xanthomonas protophormiae, Bacillus licheniformis, and Staphylococcus aureus. Among the tested compounds, compounds with trifluromethyl group show excellent antibacterial activity.     

Synthesis and antifungal activity of sulfides,sulfoxides, and sulfones based on (1S)-(-)-β-pinene

Attachment of 2-mercaptoethanol and thioglycolic acid methyl ester to the double bond of (1S)-(-)-β-pinene yielded pinane sulfides with the cis configuration. Oxidation of sulfides with m-chloroperbenzoic acid yielded the corresponding sulfoxides and sulfones. The resulting compounds were screened for antimycotic activity and the dynamics of changes in antifungal properties in sulfides-sulfoxide-sulfone series were studied.     

Hydrolysis of Carbonates,Thiocarbonates, Carbamates,and Carboxylic Esters of α-Naphthol, β-Naphthol,and p-Nitrophenol by Human,Rat, and Mouse Liver Carboxylesterases

Thirty carbonates, thiocarbonates, carbamates, and carboxylic esters of -naphthol, -naphthol, and p-nitrophenol were synthesized and tested as substrates for liver carboxylesterases from the crude microsomal fractions of human and mouse, and purified isozymes, hydrolases A and B, from rat liver microsomes. The carbonates, thiocarbonates, and carboxylic esters of -naphthol were cleaved more rapidly than the corresponding -naphthol isomers by the mammalian liver esterases. -Naphthyl esters of acetic, propionic, and butyric acids were among the best substrates tested for these enzymes. The majority of the substrates was consistently hydrolyzed at higher rates by hydrolase B compared with hydrolase A, although the Michaelis–Menten constant (K _m) values of selected substrates differed widely with these two isozymes. Malathion was a 15-fold better substrate for hydrolase B than for hydrolase A. Compared with the corresponding carboxylates, the carbonate moiety of - and -naphthol and p-nitrophenol lowered the specific activities of the enzymes by about fivefold but improved stability under basic conditions. The optimum pH of mouse liver esterase with the acetate, methylcarbonate, and ethylthiocarbonate of -naphthol was between pH 7.0 and pH 7.6. Human and mouse liver microsomal esterase activities were about five orders of magnitude lower than the esterase activities of purified rat liver hydrolase B. A relationship between the catalytic activity of the enzymes and the lipophilicity of the naphthyl substrates indicated that (i) in the - and -naphthyl carbonate series, an inverse relationship between enzyme activity and lipophilicity of the substrates was observed, whereas (ii) in the -naphthyl carboxylate series, an increase in enzyme activity with increasing lipophilicity of the substrates up to a log P value of about 4.0 was observed, after which the enzyme activity decreased.     

Synthesis,Characterization, and Evaluation of the Local Irritant Action of an Ibuprofen - β-Cyclodextrin Inclusion Complex

Pharmaceutical Chemistry Journal -     

Synthesis of New 6-{[ω-(Dialkylamino(heterocyclyl)alkyl]thio}-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones and Evaluation of their Anticancer and Antimicrobial Activities

Several novel 6-thio-3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-based compounds containing an ω-(dialkylamino(heterocyclyl)]alkyl fragment were synthesized to examine their anticancer activity. Some of the 6-{[ω-(hetero-cyclyl)alkyl]thio}-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (3.1-3.10) were obtained by the nucleophilic substitution of 6-[ω-halogenalkyl]thio-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (2.1-2.8) with azaheterocycles. Alternatively, compounds 3.1-3.22 were synthesized by alkylation of 3-R-6-thio-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones potassium salts (1.1-1.4) with (2-chloroethyl)-N,N-dialkylamine hydrochlorides or 1-(2-chloroethyl)heterocycle hydrochlorides. The structures of compounds were elucidated by (1)H, (13)C NMR, LC-MS and EI-MS analysis. Then anticancer and antibacterial, bioluminescence inhibition of Photobacterium leiognathi Sh1 activities of the substances were tested in vitro. It was found that compound 3.18 possessed a wide range of anticancer activity against 27 cell lines of cancer: non-small cell lung, colon, CNS, ovarian, renal, prostate, breast, melanoma and leukemia (log GI(50) < -5.65). The "structure-activity" relationship was discussed. COMPARE analysis for synthesized anticancer active compounds was performed.     

Total Syntheses and Biological Evaluation of (±)-Botryosphaeridione, (±)-Pleodendione, 4-epi-Periconianone B,and Analogues

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Evaluation of the anti-inflammatory activity of N,N′-bis(3-dimethylamino-1-phenyl-propylidene)hydrazine dihydrochloride

This study investigated the anti-inflammatory effect of N, N′-bis(3-dimethylamino-1-phenyl-propylidene)hydrazine dihydrochloride, D1, on carrageenan-induced edema. In addition, its effect on hyaluronidase-induced vascular permeability was also tested. D1 was synthesized, and anti-inflammatory activity was determined by carrageenan-induced hind paw edema in rats (n?=?30) at 50, 100, and 200?mg kg^?1 doses of D1 and also a 25?mg kg^?1 dose of indomethacin. The effects of D1 and indomethacin on hyaluronidase-induced capillary permeability were investigated in rabbits (n?=?18) at a 100?mg kg^?1 dose of D1 and 25?mg kg^?1 dose of indomethacin. D1 inhibited carrageenan-induced inflammation by 40, 20, and 10% at 50, 100, and 200?mg kg^?1 doses after 1?h. The inhibitions were 22.5, 32.7, 28.6% and 15.6, 33.4, 8.9% at 2?h and 3?h, respectively. The inhibitions due to indomethacin (25?mg kg^?1 dose) were 67.5, 87.8, and 91.1%, at 1?h, 2?h, and 3?h, respectively. The subcutaneous spreading areas of Trypan blue at 1, 5, 30, and 60?min after subcutaneous injection of hyaluronidase were 172.6?±?41.6, 210.2?±?39.7, 363?±?50, and 400.2?±?46.7?mm² in the D1 (100?mg kg^?1) treated group. The spreading areas at these time periods were 38.8?±?3.7, 48.2?±?4.5, 100.6?±?6.9, and 119.8?±?22.5?mm² in the indomethacin treated group. Our results showed that D1 inhibits carrageenan-induced inflammation in rats. A tendency to decrease the capillary permeability suggested that the mechanism of action of the anti-inflammatory effect of D1 may partly depend on inhibition of the hyaluronidase enzyme.