2,4,5-三芳基-1H-吡唑-3(2H)-酮类化合物的合成与生物活性评价

目的 设计合成2,4,5-三芳基-1H-吡唑-3(2H)-酮类化合物,并研究其对ALK5信号通路、COX-1和COX-2信号通路的抑制活性,以期发现新型的ALK5或COX抑制剂。方法 关键中间体3-氧代-2,3-芳基丙酸甲酯（6）可以由两种方法制备：一是由芳基醛（1）与芳基乙酸甲酯（2）Aldol缩合后经Swern氧化的方法得到;二是通过芳基酰氯（5）与芳基乙酸甲酯的钠盐（4）直接缩合得到。化合物6与4-腈基苯肼（7）缩合得到4-（3,4-二芳基-5-氧代吡唑啉-1-基]）苯腈（8）,将化合物8的腈基水解为酰氨得到化合物（9）。应用基于细胞的TGF-Smad2检测评价化合物的ALK5抑制活性; 采用化学发光法测试化合物对COX1和COX2的抑制活性;采用MTT法检测化合物的细胞毒性。结果与结论 本文所合成的化合物和中间体均为新化合物,所有目标化合物和大部分中间体的结构经过了核磁与质谱的确证,其中目标化合物18个。多个化合物显示具有很好的对ALK5信号通路、COX信号通路的抑制活性,并且细胞毒性较小。     

Design,Synthesis, and Biological Evaluation of 1,5‐Diaryl‐1,2,4‐triazole Derivatives as Selective Cyclooxygenase‐2 Inhibitors

A series of 1,5‐diaryl‐1,2,4‐triazole derivatives were synthesized and evaluated as cyclooxygenase‐2 (COX‐2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b , 6b , 6c , 7c , 8b , 8d , 9c , and 9d have potent anti‐inflammatory activity (P < 0.01), while compounds 6b , 6c , and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro, compound 6c was identified as a potent and selective inhibitor of COX‐2 (COX‐2 IC₅₀ = 0.37 µM; SI = 0.018), being equipotent to celecoxib (COX‐2 IC₅₀ = 0.26 µM; SI = 0.015). In a rat carrageenan‐induced paw edema assay, 6c exhibited moderate anti‐inflammatory activity (35% inhibition of inflammation) at 2 h after administration of 15 mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX‐2 in a similar mode to that of the known selective COX‐2 inhibitor SC‐558.     

Synthesis and hypoglycemic activity of some new flavone derivatives. 3rd communication: 3'-flavonyl-2,4-thiazolidinediones

A new series of 3'-flavonyl-2,4-thiazolidinedione, 2,4-imidazolidinedione and 2-thiohydantoin derivatives (1-10) were synthesized and their chemical structures have been elucidated by various spectral data. The prepared compounds were tested for their insulinotropic effects in INS-1 cells. Inhibitory effects were observed for compounds 1 and 2. In contrast compounds 4, 7 and 8 were able to increase insulin release compared with glibenclamide.     

Novel analgesic/anti-inflammatory agents: diarylpyrrole acetic esters endowed with nitric oxide releasing properties

The design of compounds that are able to inhibit cyclooxygenase (COX) and to release nitric oxide (NO) should give rise to drugs endowed with an overall safer profile for the gastrointestinal and cardiovascular systems. Herein we report a new class of pyrrole-derived nitrooxy esters (11a-j), cyclooxygenase-2 (COX-2) selective inhibitors endowed with NO releasing properties, with the goal of generating new molecules able to both strongly inhibit this isoform and reduce the related adverse side effects. Taking into account the metabolic conversion of nitrooxy esters into corresponding alcohols, we also studied derivatives 12a-j. All compounds proved to be very potent and selective COX-2 inhibitors; nitrooxy derivatives displayed interesting ex vivo NO-dependent vasorelaxing properties. Compounds 11c, 11d, 12c, and 12d were selected for further in vivo studies that highlited good anti-inflammatory and antinociceptive activities. Finally, two selected compounds (11c and 12c) tested in human whole blood (HWB) assay proved to be preferential inhibitors of COX-2.     

R-1579类似物的合成及其二肽基肽酶IV(DPP-IV)抑制活

目的 设计合成R-1579的类似物,并对其体外DPP-IV抑制活性进行评价。方法 以取代苯甲醛和丙二腈为原料经缩合、与脒环合、氧化及催化氢化等反应制得目标化合物;选择其中部分化合物测试其DPP-IV抑制活性。结果与结论 共制得18个目标化合物,经过1H-NMR、MS确证结构,其中化合物8h、10c及10d的活性优于阳性对照R-1579。     

Search for new pharmacophore as antimalarial agent: synthesis and antimalarial activity of some 2(3H)-furanones bearing quinoline moiety

A series of substituted 3-[(substituted-2-chloroquinolin-3-yl)methylene]-5-(substituted-phenyl)-furan-2(3H)-ones (4a-p) have been synthesized and evaluated for their in vitro antimalarial activity against P. falciparum. The title compounds were synthesized by condensing 3-(substituted-benzoyl)propionic acids (3a-d) with substituted 2-chloroquinoline-3-carbaldehydes (2a-d) following modified Perkin's reaction. Compounds 3-[2-chloro-6-methylquinolin-3-yl)methylene]-5-(2,4-dimethyl-phenyl)-furan-2(3H)-one (4n) and 3-[2-chloro-6-methoxyquinolin-3-yl)methylene]-5-(2,4-dimethyl-phenyl)-furan-2(3H)-one (4p) showed promising antimalarial activity with MIC of 10 microg/mL.     

Synthesis and Biological Evaluation of 4‐Arylphthalazones Bearing Benzenesulfonamide as Anti‐Inflammatory and Anti‐Cancer Agents

Nine 4‐arylphthalazones bearing benzenesulfonamide (2a – i ) were synthesized by the condensation of the appropriate 2‐aroylbenzoic acid ( 1a – i ) and 4‐hydrazinobenzenesulfonamide in ethanol. The structures of these compounds were elucidated by elemental analysis, IR, ¹H NMR, ¹³C NMR, and MS spectroscopy. Two compounds, 2b and 2i , showed significant anti‐inflammatory activity comparable to that of the standard drug celecoxib in the carrageenan‐induced rat paw edema model. These compounds ( 2b and 2i ) had selective inhibitory activity towards the COX‐2 enzyme. Compound 2b had a better selectivity ratio (COX‐1/COX‐2) compared to that of celecoxib and can be used as a novel template for the design of selective COX‐2 inhibitors. Compounds 2d and 2i were screened for their antiproliferative activity toward 60 human cancer cell lines by the National Cancer Institute (USA). The compounds 2d and 2i displayed mild activity toward the renal cancer cell line UO‐31.     

Synthesis and prostaglandin synthase inhibitory activity of new aromatic O-alkyloxime ethers substituted with methylsulfonamido or methylsulfonyl groups on their aliphatic portion

Some aromatic O-alkyloxime ethers substituted with methylsulfonamido (7) or methylsulfonyl (8) groups on their aliphatic portions were prepared as analogues of structurally related cyclooxygenase (COX) inhibitors (6) bearing a carboxylic group typical of the classic non-steroidal anti-inflammatory drugs (NSAIDs) in the place of the sulfurated moiety. In addition, also analogues of compounds 8 in which the aliphatic chain is further lengthened by 1 (9), 2 (10), or 3 (11) carbon atoms were synthesized. All compounds (7-11) were tested in vitro towards COX2, and compounds 7-9 towards COX1, by measuring prostaglandin E2 (PGE(2)) production in activated J774.2 macrophages and U937 cell lines, respectively. While all new compounds were found to possess little or no activity on the COX2 isoenzyme, some of these (7a-7d, 8a, 8d, 9e and 9f) appeared to possess an appreciable activity on COX1, with % inhibition values at a concentration of 1 microM ranging from 30% of 8a to 76% of 9e. The COX1 selectivity of the new compounds was tentatively explained by means of a docking study of one of the more active compounds tested on both COX isoenzymes (7d), which indicated a different number of hydrogen bonding interactions with the Arg120 of the active sites of the two enzymes, and therefore, an energetically favored interaction (3.5 kcal/mol) with COX1, compared with COX2.     

Synthesis and analgesic profile of novel N-containing heterocycle derivatives: arylidene 3-phenyl-1,2,4-oxadiazole-5-carbohydrazide

This paper describes recent results of a research program aimed at the synthesis and pharmacological evaluation of new heterocyclic N-acylhydrazone (NAH) compounds, belonging to the arylidene (3-phenyl)-1,2,4-oxadiazolyl-5-carboxyhydrazide (8a-p) series. These compounds were structurally planned by applying the molecular hybridization strategy on previously described arylidene 1-phenylpyrazole-4-carbohydrazide (5) derivatives, considered as lead-compounds, which present potent analgesic properties. The analgesic profile of the title compounds 8a-p, evaluated in the model of abdominal constrictions induced by acetic acid, showed that the 4-methoxybenzylidene derivatives 8c and 8k were the most active ones, exhibiting a relative analgesic activity comparable with that of dipyrone 1 used as standard.     

Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase inhibitors and antitumor agents: synthesis and biological activities of 2,4-diamino-5-methyl-6-[(monosubstituted anilino)methyl] pyrido[2,3-d]pyrimidines.

Thirteen 2,4-diamino-5-methyl-6-[(monosubstituted anilino)methyl]pyrido[2,3-d]pyrimidines 5-17 were synthesized as potential Pneumocystis carinii (pc) and Toxoplasma gondii (tg) dihydrofolate reductase (DHFR) inhibitors and as antitumor agents. Compounds 5-17 were designed to investigate the structure-activity relationship of monomethoxy and monohalide substitution in the phenyl ring and N10-methylation of the C9-N10 bridge. The synthetic route to compounds 5-12 involved the reductive amination of a common intermediate, 2,4-diamino-5-methylpyrido[2, 3-d]pyrimidine-6-carbonitrile (18), with the appropriate anilines. N10-Methylation was achieved by reductive methylation. In contrast to previous reports of trimethoprim, the removal of methoxy and chloro groups from the phenyl ring in the 2, 4-diamino-5-methyl-6-[(substituted anilino)methyl]pyrido[2, 3-d]pyrimidine series generally did not decrease DHFR inhibitory activity. The monosubstituted phenyl analogues 5-12 were as potent against pcDHFR and tgDHFR as the previously reported disubstituted phenyl analogues. N10-Methylation generally resulted in a marginal increase in potency against both pcDHFR and tgDHFR. Compounds 5, 7, and 9 were evaluated and shown to inhibit the growth of T. gondii cells in culture at nanomolar concentrations. Compounds 6-8, 9, 11, and 16 were selected by the National Cancer Institute for evaluation in an in vitro preclinical antitumor screening program. All six compounds showed GI50 values in the 10(-7)-10(-9) M range in more than 20 cell lines.     

Xanthone aus Chromon-Derivaten

Xanthones from Chromone Derivatives The 3-acyl-2-(methylthio)chromones 2a - 2c and the 6-acetyl-7-(methylthio)furochromone 10 react with the CH-acidic compounds 5a-5f, 11 and potassium tert.-butylate to yield the 3-acylchromones 4a - 4d and 9 , the xanthones 1 und 6a - 6d and the furoxanthones 13a-13c and 20 . With ammonium acetate, 4b and 4c gave the benzopyranopyridinones (azaxanthones) 8a - 8b .     

Synthesis and hypoglycemic activity of some new flavone derivatives. 2nd communication: 4'-flavonyl-2,4-thiazolidinediones

A new series of 4'-flavonyl-2,4-thiazolidinedione, 2,4-imidazolidinedione and 2-thiohydantoin derivatives (1-10) were synthesized. Their chemical structures have been elucidated by IR, 1H-NMR, mass spectra and elementary analysis. The synthesized compounds were tested for their insulinotropic effects in INS-1 cells. Inhibitory effects were observed for compounds 1, 2, 6 and 7.     

Amide derivatives of [5-chloro-6-(2-chloro/fluorobenzoyl)-2-benzoxazolinone-3-yl]acetic acids as potential analgesic and anti-inflammatory compounds

In this study, we have explored the prevention of gastric side effects such as gastric lesions and bleeding while maintaining the high analgesic and anti-inflammatory activities by the derivatization of the carboxylate moiety into amides in [5-chloro-6-(2-chloro/fluorobenzoyl)-2-benzoxazolinone-3-yl]acetic acids. We have tested the analgesic and anti-inflammatory activities of the synthesized compounds in vivo by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. Compounds 3a, 3d, 3e, 3j and 3k potent analgesic and anti-inflammatory activities without gastric lesions in the tested animals. Therefore, conversion of the carboxylate moiety into certain amide derivatives generated potent analgesic and anti-inflammatory compounds while eliminating the gastrointestinal side effects. Cyclooxygenase (COX)-selectivity of the active compounds was also investigated by using in vitro human whole blood assay. Compounds 3a, 3e, 3h and 3k selective inhibition of COX-2 to some extent although the inhibitory activity was not very potent.     

New indole and triazino[5,4-b]indol-4-one derivatives: synthesis and studies as inotropics and inhibitors of blood platelet aggregation.

New triazino[5,4-b]indol-4-one derivatives carrying amino groups in position 3 were synthetized and tested as inotropic agents and inhibitors of platelet aggregation. 2h, 2p, 5p, and 6g are the most active as inotropic agents. Compounds were tested as inhibitors of platelet aggregation induced by adenosine 5'-diphosphate (ADP) and arachidonic acid (AA) (guinea pig whole blood). 2k, 2p, 5o, 6d, 6m, and 6o are the most active as inhibitors of the platelet aggregation induced by AA. 6d, 6h, and 6o are most active compounds also in the aggregation induced by ADP. Radioimmunoassay studies, following AA induced aggregation, measuring thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) were carried out on compounds 2b, 2d, 2f, 2g, 2h, 2i, 2k, 2m, 2o, 2p, 2r, 5i, 5j, 5k, 5r, and 5f, which inhibit platelet aggregation induced by AA. None of the compounds tested turned out to be selective inhibitors. Compounds 2h and 2p showed both inotropic and platelet aggregation inhibiting activity.     

Synthesis of 1-acyl-2-alkylthio-1,2,4-triazolobenzimidazoles with antifungal, anti-inflammatory and analgesic effects

Some new derivatives of 1,2,4-triazolo[2,3-a]benzimidazoles were synthesized through the reaction of 1,2-diaminobenzimidazole with carbon disulfide. The resulting 1,2,4-triazolo[2,3-a]benzimidazole-2-thione intermediate reacted with one equivalent of the alkyl halide to give the corresponding 2-alkylthio derivative 3a-g. The latters were acylated to afford the 1-acyl-2-alkylthio-1,2,4-triazolo[2,3-a]-benzimidazole derivatives 4-10 in good yields. Structures of the new compounds were verified on the basis of spectral and elemental methods of analyses. Fourteen of the prepared compounds were tested for their possible antifungal activities. Most of the tested compounds showed activity against Candida albicans and Fusarium oxysporum comparable to that of fluconazole as a reference drug. Compounds 8a, 9a, and 10d are the most active ones against most of the fungi used. Compounds 3e, 4d, 5d, 6d, 7d, 8c, 8d, 9d, and 10d were tested for their anti-inflammatory and analgesic effects; most of these compounds showed potent and significant results compared to indomethacin. Moreover, ulcerogenicity and the median lethal dose (LD(50)) of the most active compound 8d were determined in mice; LD(50) was found to be 275 mg kg(-1) (i.p.).     

Synthesis and biological evaluation of N-pyrazolyl-N'-alkyl/benzyl/phenylureas: a new class of potent inhibitors of interleukin 8-induced neutrophil chemotaxis

Neutrophils chemotaxis is a complex multistep process that, if upregulated, causes acute inflammation and a number of autoimmune diseases. We report here the synthesis of a new N-(4-substituted)pyrazolyl-N'-alkyl/benzyl/phenylureas that are potent inhibitors of interleukin-8 (IL8)-induced neutrophil chemotaxis. The first series of compounds, obtained by functionalization with a urea moiety of the 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 3, blocked the IL8-induced neutrophil chemotaxis, while they did not block N-formylmethionylleucylphenylalanine-mediated chemotaxis. The most active compounds, 3-benzyl- (4d), 3-(4-benzylpiperazinyl)- (4i), 3-phenyl- (4k) and 3-isopropylureido (4a) derivatives, showed an IC50 of 10, 14, 45, and 55 nM, respectively. Several different molecules were then synthesized to obtain more information for SAR study. Compounds 4a, 4d, and 4k were inactive in the binding assays on CXCR1 and CXCR2 (IL8 receptors), whereas they inhibited the phosphorylation of PTKs (protein tyrosine kinases) in the 50-70 kDa region. Moreover, in the presence of the same derivatives, we observed a complete block of F-actin rise and pseudopod formation.     

Synthesis,Molecular Docking,and Biological Evaluation of Some Novel Hydrazones and Pyrazole Derivatives as Anti‐inflammatory Agents

2‐Hydrazinyl‐N‐(4‐sulfamoylphenyl)acetamide 3 was the key intermediate for the synthesis of novel hydrazones 4–10 and pyrazole derivatives 11–17 . All compounds were tested for their in vivo anti‐inflammatory activity and their ability to inhibit the production of PGE₂ in serum samples of rats. IC₅₀ values for the most active compounds for inhibition of COX‐1 and COX‐2 enzymes were determined in vitro, and they were also tested for their ulcerogenic effect. Molecular docking was performed on the active site of COX‐2 to predict their mode of binding to the amino acids. Most of the synthesized compounds showed good anti‐inflammatory activity especially compounds 3, 4, 8, 9, 15, and 17 which showed better activity than diclofenac as the reference drug. Compounds 3, 8, 9, 13, and 15–17 were less ulcerogenic than indomethacine as the reference drug. Most of the synthesized compounds interacted with Tyr 385 and Ser 530 in molecular docking study with additional hydrogen bond for compound 17 . Compound 17 showed good selectivity index value of 11.1 for COX‐1/COX‐2 inhibition in vitro.     

环氧酶选择性抑制剂筛选模型的建立

目的　建立COX1和COX2活性检测模型,为COX2选择性抑制剂的筛选及抗炎作用机制研究提供可靠方法。方法　COX1抑制剂筛选模型用新生小公牛主动脉内皮细胞为酶源,6-keto-PGF_1α的含量变化评价化合物对COX1的抑制作用。COX2抑制剂筛选模型用激活的小鼠腹腔巨噬细胞,PGE₂含量变化评价化合物对COX2的抑制作用。结果　Indomethacin可显著地抑制COX1的活性, Meloxicam可显著地抑制COX2的活性, 其对COX2的选择性抑制作用高于前者。结论　COX1和COX2抑制剂筛选模型可用于COX2选择性抑制剂的筛选和机制研究。     

Convenient synthesis and antimicrobial activity of new 3-substituted 5-(benzofuran-2-yl)-pyrazole derivatives

The reaction of ethyl 4-(benzofuran-2-yl)-2,4-dioxobutanoate 2 with two moles of hydrazine hydrate afforded 5-(benzofuran-2-yl)-1H-pyrazole-3-carbohydrazide 4a, while its reaction with equimolar amount of phenylhydrazine gave ester 3b which then converted to 5-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-carbohydrazide 4b. Various new compounds such as imides 5 and 6, acyl hydrazones 7 and 8, bi-pyrazoles 9-12, and 1,3-thiazole derivatives 14 and 15 were prepared from carbohydrazide derivatives 4a, b. The new compounds are tested for their antimicrobial activity. Compounds 2, 5, 7, and 8 showed antifungal activities against C. albicans. Also, compounds 2, 6, 8, and 15 showed antibacterial activities.     

Aromatase inhibitors. Synthesis and evaluation of mammary tumor inhibiting activity of 3-alkylated 3-(4-aminophenyl)piperidine-2,6-diones

The synthesis and biological evaluation of 3-alkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones as inhibitors of estrogen biosynthesis are described [H (1), methyl (2), ethyl (3), n-propyl (4), isopropyl (5), n-butyl (6), isobutyl (7), sec-butyl (8), n-pentyl (9), isopentyl (10), 2-methylbutyl (11), sec-pentyl (12), n-hexyl (13), n-heptyl (14)]. In vitro compounds 4-14 showed a stronger inhibition of human placental aromatase compared to aminoglutethimide (AG, compound 3), which recently has become used for the treatment of hormone-dependent breast cancer. The most active derivative, compound 10, showed a 93-fold stronger inhibition than AG. With the exception of 5, 7, and 8, all other compounds exhibited similar or decreased inhibition of bovine adrenal desmolase compared to AG. Compounds 4 and 6-12 showed a stronger inhibition of the plasma estradiol concentration of pregnant mare serum gonadotropin (PMSG) primed Sprague-Dawley (SD) rats compared to the parent compound. Compounds 4, 6-8, 10, and 12 inhibited the testosterone-stimulated tumor growth of ovariectomized 9,10-dimethyl-1,2-benzanthracene (DMBA) tumor-bearing SD rats more strongly than AG. Being stronger and more selective inhibitors of the estrogen biosynthesis than AG, some of the newly developed derivatives of AG might be better candidates for the treatment of the hormone-dependent human breast cancer.