Synthesis and antihypertensive activity of some 2-aminobenzimidazole and indole derivatives.

The synthesis of some 2-aminobenzimidazole and indole amide derivatives containing a 2,6-dichloroaniline moiety is described. The preparation of a theophylline derivative is also reported. All the compounds tested showed no appreciable antihypertensive activity on spontaneously hypertensive rats.     

Synthesis and antiproliferative activity in vitro of 2-aminobenzimidazole derivatives

A novel series of Schiff bases 1-11, the derivatives of 2-aminobenzimidazole and substituted aromatic aldehydes, has been synthesised. Compounds 1-11 reduced by NaBH(4) formed 2-benzylaminobenzimidazoles 12-21. 2-(o-Bromobenzylamino)benzimidazole (15) acylated by cinnamoyl chloride gave 2-(o-bromobenzylamino)-1-cinnamoylbenzimidazole (22). Long heating of 15 and 19 with p-nitrocinnamoyl or cinnamoyl chloride led to the formation of pyrimido[1,2-a]benzimidazol-4-ones 23 and 24. The structures of 1-24 were identified by the results of elemental analysis and their IR, (1)H NMR and MS spectra. Among the compounds 1-24 evaluated for their antiproliferative activity in vitro, 16, 19, 20 and 22 exhibited cytotoxic activity against the cells of human cancer cell lines, namely SW707 (rectal), HCV29T (bladder), A549 (lung) and T47D (breast cancer).     

Synthesis and analgesic and antiinflammatory properties of new benzodiazepine derivatives

Several new N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-carboxamides have been synthesized and characterized with respect to acute toxicity (LD₅₀), analgesic and antiinflammatory properties (formalin-and carrageenan-induced foot edema models), and interaction with morphine-induced antinociception in mice. The new compounds were prepared by acyl coupling of 2-aminobenzophenones with α-(benzotriazol-1-yl)-N-acylglycines followed by displacement of the benzotriazole ring with ammonia and cyclization of the resulting monoacyl aminals. The LD₅₀ of the synthesized compounds exceeds 1000 mg/kg. Three compounds produced significant analgesic action in doses 100–150 μg/kg in the early (painful) phase of the formalin test and potentiated the morphine-induced antinociception in this test. The synthesized drugs neither showed antinociception in the second (inflammatory) phase of the formalin test nor decreased the carrageenan-induced foot edema growth. Thus, the synthesized compounds produce analgesic action but do not possess antiinflammatory properties. The analgesic activity is probably due to the interaction with μ-and δ-opioid receptors. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 12, pp. 21–23, December, 2005.     

Synthesis, antilipidemic and platelet antiaggregatory activity of 2-aminobenzimidazole amide derivatives

The synthesis and preliminary pharmacological evaluation of 2-aminobenzimidazole amide derivatives are reported. None of these compounds showed antilipidemic or platelet antiaggregatory activity comparable to that of drugs used in therapy.     

Synthesis and antiinflammatory activity of coumarin derivatives

The synthesis of several coumarin Mannich bases is described. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity was determined experimentally by RPTLC method. All compounds were evaluated for their antiinflammatory and antioxidant activity and for their ability to inhibit in vitro lipoxygenase. The derivatives were found to present antioxidant and antiinflammatory activities. The tested derivatives inhibited carraggeenin-induced hind paw edema. They also significantly suppressed the arthritis induced by Freund's adjuvant. Compound 10, the most active in vivo, was found to possess protective properties against adjuvant-induced arthritis in rats. The biological in vitro activities were concentration dependent. Hydrophilicity, the presence of a free 7-OH, and steric requirements for the substituent at position 8 are the most important factors in terms of SAR. An attempt was made to correlate several physicochemical properties of the molecules with their in vivo/in vitro activity.     

一氧化氮供体型氟罗布芬衍生物的合成及抗炎活性

目的获得抗炎活性强、胃肠道不良反应小的新型非甾体抗炎药(NSAIDs).方法将具有不同释放机制的一氧化氮(NO)供体,包括NO合酶(NOS)底物类似物、硝酸酯和呋咱氮氧化物通过酯键与正在Ⅲ期临床研究的NSAID氟罗布芬(1)相偶联,测定偶联物的抗炎活性,考察其胃肠道毒副作用,研究其释放NO的作用.结果合成19个未见文献报道的新化合物,结构经MS、IR、1H-NMR和元素分析确证.初步药理筛选结果表明:10个目标物(Ⅰ1、Ⅰ3～5、Ⅰ8、Ⅰ12、Ⅱ2,3、Ⅱ6,7)显示了较高的抗炎活性,其中5个(Ⅰ1、Ⅰ3,4、Ⅱ3、Ⅱ6)活性与氟罗布芬相当(P＞0.05);所有活性化合物均表现出较小的胃肠道不良反应,其中Ⅰ1、Ⅰ3、Ⅰ5、Ⅱ7的不良反应显著小于氟罗布芬(P＜0.05).结论Ⅰ1和Ⅰ3的综合指标优于氟罗布芬,值得深入研究.     

Synthesis of carboxyalkylthio-triazoles and bicyclic derivatives with antiinflammatory and analgesic activity.

3-Carboxyalkylthio derivatives of 5-alkoxyphenyl-1,2,4-triazole were prepared, performing some substitutions both on carboxyalkyl chain, by lengthening it or introducing substituents with increasing molecular weight in alpha- at the carboxy group, and on N-4 atom in the triazole ring, by introducing an amino or methyl group, so that to vary steric conformation along with the lipophilicity of molecules. The corresponding bicyclic thiazolo-triazolone and triazolo-thiazinone derivatives, which represent the rigid models of carboxymethylthio- and carboxyethylthio- open structures, were also obtained. All the compounds show "in vivo" antiinflammatory activity, while only carboxyalkylthio derivatives of 4-amino- and 4-methyltriazole display an appreciable analgesic one. From the relief of some data on substituent present in the synthesized compounds, a structure-activity relationship is also suggested.     

Immunotropic properties of 2-aminobenzimidazole derivatives in cultures of human peripheral blood cells, Part 5

The reaction of 2-aminobenzimidazole with selected 4-methoxy-,2,4-dimethoxy-, 4-chloro-, 4-nitro-, and 2-nitrocinnamic acid under different conditions has been described. Two series of derivatives were obtained: 4-aryl-1,2,3,4-tetrahydropyrimido[1,2-a]-benzimidazol-2-ones (1-3) or substituted amides 4, 5, 7. The following compounds: 4-(p-methoxyphenyl)- (1), 4-(2,4-dimethoxyphenyl)- (2), 4-(p-chlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazo l-2-one (3), amides: 2-(p-nitrocinnamoylamino)- (4), 2-(p-methoxycinnamoylamino)-benzimidazole (5), and 3-methyl-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-2-one (6), recently synthesized, have been selected for further studies. Among the studied compounds, 3 and 4 strongly inhibited PHA-induced proliferation of human lymphocytes and weaker, but significantly, MLC-induced lymphocyte proliferation. 3 and 4 inhibited also LPS- or MLC-induced TNF-alpha production. In addition, TNF-alpha production, induced by LPS, was inhibited by compounds 1 and 2. Higher activity of 3 and 4 could be associated with the presence in their structures of -Cl and -NO2 substituents as compared with compounds possessing -OCH3 groups. Compounds 3 and 4 were not toxic when administered orally to mice which predisposes them for further investigations with a chance of clinical application.     

Synthesis and antiinflammatory activity of various 1,4-benzothiazine derivatives

A new series of dihydro-4H-1,4-benzothiazine derivatives was prepared. These compounds were obtained by reductive N-alkylation reaction with sodium borohydride in acetic acid of the corresponding 4H-1,4-benzothiazine. Some of the latter compounds were synthesized by a new synthetic method employing 2-aminobenzenethiol and alkynes as starting material. Preliminary pharmacological data on the antiinflammatory activity of these compounds by using carrageenin paw edema assay are reported.     

Synthesis and antiinflammatory properties of N-substituted 4,5-dioxopyrrolidine-3-carboxanilides.

The synthesis and physical properties of a series of N-methyl- and N-phenyl-4,5-dioxopyrrolidine-3-carboxanilides are described. Unlike previously reported carboxanilides derived from 1,3(2H,4H)-dioxoisoquinoline and 2-oxobenzofuran, the currently described agents exist solely as the enol tautomers and, as a result, do not display comparable acidic properties. None of the newly reported compounds exhibited activity equal to that of aspirin in the carrageenin-induced rat foot edema assay.     

Synthesis and evaluation of antiinflammatory activity of substituted chalcone derivatives

In an effort to develop potent antiinflammatory agents, a series of substituted chalcone derivatives was synthesized and evaluated for antiinflammatory activity through monitoring of their ability to inhibit xylene-induced ear edema in mice. Some of the tested compounds exhibited significant activity, and compounds 3f [(E)-1-(2,4-dihydroxyphenyl)-3-(4-dimethylamino)phenyl)prop-2-en-1-one] and 3h [(E)-3-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one] showed the highest antiinflammatory activity (62 and 68% inhibition, respectively, 2 h before administration), comparable with or even slightly more potent than the reference drug ibuprofen (53%). Furthermore, the structure–activity relationship of these substituted chalcone derivatives was demonstrated.