Synthesis and antimicrobial activity of 3-(1,3,4-Oxadiazol-2-yl)quinazolin-4(3H)-ones

In attempt to find new pharmacologically active molecules, we report here the synthesis and in vitro antimicrobial activity of various 3-(1,3,4-oxadiazol-2-yl)-quinazolin-4(3H)-ones. The antimicrobial activity of title compounds were examined against two gram positive bacteria (S. aureus, S. pyogenes), two gram negative bacteria (E. coli, P. aeruginosa) and three fungi (C. albicans, A. niger, A. clavatus) using the broth microdilution method. Some derivatives bearing a bromo or iodo group exhibited very good antimicrobial activity.     

Synthesis and antileukemic activity of new 3-(5-methylisoxazol-3-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones

3-(3-Methylisoxazol-5-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones 8a-l and 9a,c-e,h-l were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 6 and 8 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 8a-l and 9a,c-e,h-l were tested in vitro for their antileukemic activity against L-1210 (murine leukemia), K-562 (human chronic myelogenous leukemia) and HL-60 (human leukemia) cell lines showing in some cases good activity.     

Synthesis and Antimicrobial Activity of Some New 2-(3-(4-Aryl)-1-phenyl-1H-pyrazol-4-yl) Chroman-4-ones

Seven new 2-(3-(4-aryl)-1-phenyl-1H-pyrazol-4-yl) chroman-4-ones (4a-4g) have been synthesized by cyclization of 2-hydroxychalcone analogues of pyrazole 3a-3g using conc. HCl in acetic acid. The structures of the compounds 4a-4g were established by the combined use of (1)HNMR, IR and mass spectra. All the seven compounds were tested in vitro for their antibacterial activity against two Gram positive bacteria namely Staphylococcus aureus and Bacillus subtilis and two Gram negative bacteria Escherichia coli and Pseudomonas aeruginosa. The compounds 4b, 4c, 4e, 4f, 4g have displayed good antibacterial activity when compared with commercially available antibiotic, ciprofloxacin. These compounds also were screened for their antifungal activity against two ear pathogenic fungi, namely Aspergillus Niger and A. flavus. The compounds 4a, 4c, 4d, 4g exhibited good antifungal activity when compared with commercially available antifungal, fluconazole.     

Synthesis and antiproliferative activity of 3-aryl-2-[1H(2H)-benzotriazol-1(2)-yl]acrylonitriles variously substituted: Part 4

A new series of variously substituted 3-aryl-2-[1H(2H)-benzotriazol-1(2)-yl]acrylonitriles was synthesized and tested for antiproliferative and antitubercular activity as part of our continuing research program in the antimicrobial and antitumor fields. The most cytotoxic derivatives (5a,g,i,j,l and 7b) (CC50 < 3.0 microM against MT-4 cells) were evaluated against a panel of human cell lines derived from hematological and solid tumors, using 6-mercaptopurine (6-MP) and etoposide as reference drugs. In particular, E-2-(5,6-dimethyl-1H-benzotriazol-1-yl)-3-(3-nitrophenyl)acrylonitrile (5g) resulted more potent than 6-MP on all cell lines, even if 2-14-fold less potent than etoposide. In the antitubercular screening, the derivatives 5i,j and 7e showed moderate activity against some resistant strains of Mycobacterium tested.     

Synthesis and antimycobacterial activity of 3-aryl-, 3-cyclohexyl- and 3-heteroaryl- substituted-2-(1H(2H)-benzotriazol-1(2)-yl)prop-2-enenitriles, prop-2-enamides and propenoic acids. II

A series of 32 3-aryl-, 3-cyclohexyl-, and 3-heteroaryl-substituted-2-(1H(2H)-benzotriazol-1(2)-yl)-prop-2-enenitriles, prop-2-enamides and propenoic acids, was synthesized as a part of our research in the antitubercular field, according to an international program with the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF). This work reports the preparation and analytical and spectroscopic characterization (MS, UV, IR, 1H NMR) of all compounds synthesized. Among these only a few compounds (E-4b,c, E-5a, E-7e and E-8d) were found to be endowed with modest growth inhibition of Mycobacterium tuberculosis. However, the obtained results allowed to acquire interesting structure-activity relationships.     

2-(3-Methoxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (HKL-1) induces G2/M arrest and mitotic catastrophe in human leukemia HL-60 cells

2-(3-Methoxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (HKL-1), a 2-phenyl-1,8-naphthyridin-4-one (2-PN) derivative, was synthesized and evaluated as an effective antimitotic agent in our laboratory. However, the molecular mechanisms are uncertain. In this study, HKL-1 was demonstrated to induce multipolar spindles, sustain mitotic arrest and generate multinucleated cells, all of which indicate mitotic catastrophe, in human leukemia HL-60 cells. Western blotting showed that HKL-1 induces mitotic catastrophe in HL-60 cells through regulating mitotic phase-specific kinases (down-regulating CDK1, cyclin B1, CENP-E, and aurora B) and regulating the expression of Bcl-2 family proteins (down-regulating Bcl-2 and up-regulating Bax and Bak), followed by caspase-9/-3 cleavage. These findings suggest that HKL-1 appears to exert its cytotoxicity toward HL-60 cells in culture by inducing mitotic catastrophe.     

通过碳碳双键连接的吲哚-2-酮与喹唑啉-4（3H）-酮杂合物的合成与抗肿瘤活性评价

通过2-甲基4-氧代喹唑啉-6-甲醛与不同的吲哚-2-酮的缩合反应,制备了一系列吲哚-2-酮与喹唑啉-4（3H）-酮的杂合物5a-j。MTT法测试结果表明,只有化合物5e对人肿瘤细胞A549、MCF-7、HeLa、HT-29和HCT-116表现出一定的细胞毒活性,50μM浓度下的抑制率为32．0％-62．3％。     

Synthesis and antileukemic activity of new 3-(1-phenyl-3-methylpyrazol-5-yl)-2-styrylquinazolin-4(3H)-ones

3-(1-Phenyl-3-methylpyrazol-5-yl)-2-styrylquinazolin-4(3H)-ones 14a-q and 15a-q were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 12 and 13 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 14a-q and 15a-q were tested in vitro for their antileukemic activity against L1210 (murine leukemia), K562 (human chronic myelogenous leukemia) and HL60 (human leukemia) cell lines showing in some cases good activity.     

Synthesis,Characterization and In Vitro Antimicrobial Evaluation of Novel Pyrazolothiazol-4(5H)-one Derivatives

Antimicrobial screening of several novel pyrazolothiazol-4(5H)-one derivatives (3a-3j) has been performed. Reaction of aromatic aldehydes with aromatic ketones yielded starting chalcones (1a-1j) which have been subsequently reacted with thiosemicarbazide for obtaining N-thiocarbamoylpyrazole derivatives (2a-2j). These were further cyclized to pyrazolothiazol-4(5H)-one derivatives (3a-3j) in the presence of ethylbromoacetate. The structures of newly synthesized compounds were confirmed by FTIR and ¹H NMR and/or MS. The in vitro antimicrobial activity of these compounds was evaluated against Gram positive bacteria, Gram negative bacteria and fungi. Their minimum inhibitory concentration was determined by tube dilution method. The results showed that most of the compounds have promising antimicrobial activity as compared to standard drugs. Among the test compounds, 2-[5(4-chlorophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl]-thiazol-4(5H)-one (3e) was found to show the most potent antimicrobial activity.     

KF26777 (2-(4-bromophenyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one dihydrochloride), a new potent and selective adenosine A3 receptor antagonist

We investigated the biochemical and pharmacological properties of a new adenosine A(3) receptor antagonist, KF26777 (2-(4-bromophenyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one dihydrochloride). This compound was characterized using N(6)-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide ([125I]AB-MECA) or [35S]guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) binding to membranes from human embryonic kidney 293 (HEK293) cells expressing human adenosine A(3) receptors. KF26777 showed a K(i) value of 0.20+/-0.038 nM for human adenosine A(3) receptors labeled with [125I]AB-MECA and possessed 9000-, 2350- and 3100-fold selectivity vs. human adenosine A(1), A(2A) and A(2B) receptors, respectively. The inhibitory mode of binding was competitive. KF26777 inhibited the binding of [35S]GTPgammaS stimulated by 1 microM 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA). The IC(50) value was 270+/-85 nM; the compound had no effect on basal activity. Dexamethasone treatment for HL-60 cells, human promyelocytic leukemia, up-regulated functional adenosine A(3) receptors expression, and resulted in the enhanced elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)) via the adenosine A(3) receptor. KF26777 antagonized this [Ca(2+)](i) mobilization induced by Cl-IB-MECA, with a K(B) value of 0.42+/-0.14 nM. These results indicate that KF26777 is a highly potent and selective antagonist of the human adenosine A(3) receptor.     

Synthesis,Structural Elucidation,and In Vitro Antitumor Activities of Some Pyrazolopyrimidines and Schiff Bases Derived from 5-Amino-3-(arylamino)-1H-pyrazole-4-carboxamides

The reaction of 5-amino-3-(arylamino)-1H-pyrazole-4-carboxamides 1a,b with acetylacetone 2 and arylidenemalononitriles 5a–c yielded the pyrazolo[1,5-a]-pyrimidine derivatives 4a,b and 7a–f respectively. On the other hand, Schiff bases 9a,b and 12a–j were obtained upon treatment of carboxamides 1a,b with isatin 8 and some selected aldehydes 11a–e. The newly synthesized compounds were characterized by analytical and spectroscopic data. Representative examples of the synthesized products 4a,b, 7e, 7f, 9b, 12b–f, 12h, and 12j were screened for their in vitro antitumor activities against different human cancer cell lines and the structure-activity relationship (SAR) was discussed.     

Search for Compounds with Hypoglycemic Activity in the Series of 1-[2-(1H-Tetrazol-5-yl)-R1-phenyl]-3-R2-phenyl(ethyl)ureas and R1-Tetrazolo[1,5-c]quinazolin-5(6H)-ones

Methods of 1-[2-(1H-tetrazol-5-yl)-R¹-phenyl]-3-R²-phenyl(ethyl)ureas and R¹-tetrazolo[1,5-c]quinazolin-5(6H)-ones synthesis were designed. IR, LC-MS, ¹H NMR, and elemental analysis data evaluated the structure and purity of the obtained compounds. Different products, depending on the reaction conditions, were distinguished and discussed. The preliminary hypoglycemic activity of 36 synthesized compounds was revealed. Docking studies to 11β-hydroxysteroid dehydrogenase 1, γ-peroxisome proliferator-activated receptor, and dipeptidyl peptidase-4 were conducted. Eight of these substances were further tested on glucocorticoid-induced insulin resistance models, namely glucose tolerance, oral rapid insulin, and adrenalin tests. One of the most active compounds turned out to be tetrazolo[1,5-c]quinazolin-5(6H)-one 3.1, exceeding the reference drugs Metformin (50 and 200 mg/kg) and Gliclazide (50 mg/kg).     

Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure

Phosphodiesterase-5 (PDE5) inhibitors have been approved for the treatment of erectile dysfunction and pulmonary hypertension, but enthusiasm on discovery of PDE5 inhibitors continues for their potential new applications. Reported here is discovery of a series of new PDE5 inhibitors by structure-based design, molecular docking, chemical synthesis, and enzymatic characterization. The best compound, 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (57), has an IC₅₀ of 17 nM against the PDE5 catalytic domain and good selectivity over other PDE families. The crystal structure of the PDE5 catalytic domain in complex with 57 was determined at 2 Å resolution and showed that 57 occupies the same pocket as other PDE5 inhibitors, but has a different binding pattern in detail. On the basis of the binding pattern of 57, a novel scaffold can be proposed as a candidate of PDE inhibitors.     

S-3(-三氟甲基)-6，7-双[4(-三氟甲基)苯基]-3，4-二氢喹啉-2(1H)-酮下调STAT3信号通路抑制人结直肠癌细胞生长的作用研究

目的 基于信号转导和转录活化因子3（STAT3）信号通路探讨三氟甲基化二氢喹喔啉酮类化合物S-3-（三氟甲基）-6,7-双［4-（三氟甲基）苯基］-3,4-二氢喹啉-2（1H）-酮（2o）对人结直肠癌细胞生长的抑制作用。方法 采用 MTT法检测三氟甲基化二氢喹喔啉酮类化合物 2b、2e、2f、2g、2k、2l、2m、2o、2q（20 μmo·L^-1）作 用 48 h 对 人 结 直 肠 癌 细 胞DLD-1 存活率的影响,检测化合物2o（0.5、1.0、2.0、5.0、7.5、10.0、12.5、15.0、17.5 μmo·L^-1）作用48 h对人结直肠癌细胞HCT116、RKO和DLD-1存活率的影响;克隆形成实验检测化合物2o（2.5、5.0、10.0 μmo·L^-1）对RKO、DLD-1、HCT116细胞增殖的影响;流式细胞术和 Hoechst染色检测化合物 2o 对细胞凋亡的影响;细胞划痕实验检测化合物 2o 对 DLD-1 和RKO 细胞迁移率的影响;Western blotting 法检测化合物 2o 对 RKO 细胞 p-STAT3、STAT3、骨髓白血病细胞分化蛋白（MCL）-1、生存素（Survivin）、B淋巴细胞瘤-2（Bcl-2）、Bcl-2相关X蛋白（Bax）蛋白表达水平的影响,检测化合物2o对白细胞介素-6（IL-6）刺激下p-STAT3、STAT3蛋白表达水平的影响。结果 化合物2o对DLD-1细胞的杀伤能力较其他化 合 物 强 ; 化 合 物 2o 对 HCT116、 RKO 和 DLD-1 细 胞 的 半 数 抑 制 浓 度 （IC₅₀） 分 别 为 （3.573±0.172）、（8.056±0.458）、（6.226±0.458）μmo·L^-1。与对照组比较,化合物2o明显降低了HCT116、RKO和DLD-1细胞的集落形成能力;显著降低DLD-1和RKO细胞迁移率（P＜0.01、0.001）;明显增加RKO、DLD-1细胞凋亡率;明显增加HCT116和RKO细胞核亮染比例;明显降低p-STAT3、MCL-1、Survivin、Bcl-2蛋白表达,明显升高Bax蛋白表达,对STAT3蛋白表达无明显影响。与对照组比较,IL-6刺激的模型组p-STAT3蛋白表达明显升高,STAT3蛋白表达无明显变化;与模型组比较,随着化合物2o浓度的升高,p-STAT3蛋白表达明显降低,STAT3蛋白表达无明显变化。结论 化合物2o可能通过下调STAT3信号通路发挥抗人结直肠癌作用。     

3-取代苯甲酰基-4H-色烯-4-酮的合成及其抗快速增殖分枝杆菌活性研究

目的 设计合成3-苯甲酰基-4H-色烯-4-酮类化合物,并测定其体外抗快速增殖分枝杆菌活性。 方法 以焦性没食子酸和取代苯甲酸为原料,经Friedel-Crafts酰基化、Baker-Venkataraman重排等反应合成目标化合物,初步测定了目标化合物的抗快速增殖分枝杆菌活性。结果 共合成8个3-苯甲酰基-4H-色烯-4-酮类化合物,其结构经核磁共振氢谱和质谱确证。化合物2a、2e呈现边缘抗快速增殖分枝杆菌活性。结论 在具有抗快速增殖分枝杆菌活性的天然产物(S)-3-(4-甲氧苄基)-7,8-亚甲二氧基二氢高异黄酮的2,3-位引入双键、7,8-位更换为甲氧基以及9位以羰基替代亚甲基均会导致抗快速增殖分枝杆菌活性的大幅降低。     

Synthesis and Antimicrobial Activity of Some New Quinazolin-4(3H)-one Derivatives

A new series of 6-iodo-2-phenylquinazolin-4(3H)-one derivatives was prepared and screened for antimicrobial activity. The thioureide derivatives 4–6, the carbohydrazide derivatives 19–21 and 24 displayed excellent broad-spectrum antimicrobial activity. Some compounds showed moderate activity against Candida albicans and Pseudomonas aeruginosa. None of the tested compounds was as active as the reference standard drugs ampicillin and clotrimazole. The detailed synthesis, antimicrobial activity, and the minimum inhibitory concentrations (MIC) are reported.     

Enhancements of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism and carcinogenic risk via NNK/arsenic interaction

Epidemiological studies indicated an enhancement of cigarette smoke-induced carcinogenicity, including hepatocellular carcinoma, by arsenic. We believe that arsenic will enhance the expression of hepatic CYP2A enzyme and NNK metabolism (a cigarette smoke component), thus its metabolites, and carcinogenic DNA adducts. Male ICR mice were exposed to NNK (0.5 mg/mouse) and sodium arsenite (0, 10, or 20 mg/kg) daily via gavaging for 10 days and their urine was collected at day 10 for NNK metabolite analysis. Liver samples were also obtained for CYP2A enzyme and DNA adducts evaluations. Both the cyp2a4/5 mRNA levels and the CYP2A enzyme activity were significantly elevated in arsenic-treated mice liver. Furthermore, urinary NNK metabolites in NNK/arsenic co-treated mice also increased compared to those treated with NNK alone. Concomitantly, DNA adducts (N(7)-methylguanine and O(6)-methylguanine) were significantly elevated in the livers of mice co-treated with NNK and arsenic. Our findings provide clear evidence that arsenic increased NNK metabolism by up-regulation of CYP2A expression and activity leading to an increased NNK metabolism and DNA adducts (N(7)-methylguanine and O(6)-methylguanine). These findings suggest that in the presence of arsenic, NNK could induce greater DNA adducts formation in hepatic tissues resulting in higher carcinogenic potential.     

2-(4-氯-3-甲基苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮的合成

对硝基邻甲苯胺经重氮化、氯代、还原、闭环、水解、脱羧6步反应得到2-（4-氯-3-甲基苯基）-1,2,4-三嗪-3,5（2H,4H）-二酮,总收率约40%。     

Hypolipidemic Activity of 3-Amino-1-(2,3,4-mononitro-, mono-, or dihalophenyl)propan-1-ones in Rodents

A series of 3-amino-1-(2,3,4-mononitro-, mono-, or dihalophenyl)propan-1-ones were synthesized and shown to be effective in lowering both serum cholesterol and triglyceride levels significantly in CF₁ mice and Sprague-Dawley rats. All analogs showed better activity than the standard drugs, lovastatin and clofibrate, in reducing the serum cholesterol and triglyceride levels in mice at 8 mg/kg/day intraperitoneally. The best active analogs, 3-morpholino-1-(3-nitrophenyl)propan-1-one ( 4 ) and 3-piperidino-1-(3-nitrophenyl)propan-1-one ( 5 ), exhibited 58% and 67% reduction of serum cholesterol levels, respectively, and 42% and 46% reduction of serum triglyceride levels, respectively, after 16 days of administration at 8 mg/kg/day intraperitoneally in CF₁ mice. In Sprague-Dawley rats at 8 mg/kg/day oral administration, both compounds ( 4 and 5 ) significantly decreased the serum cholesterol and triglyceride levels. Rat tissue lipid levels were reduced significantly by compound 4, while less effects resulted from compound 5. The cholesterol and triglyceride levels in chylomicrons, VLDL, and LDL fractions were reduced by both analogs while the HDL cholesterol levels were significantly increased. Compound 5 was also effective in lowering serum cholesterol and triglyceride levels in hyperlipidemic mice, at 8 mg/kg/day intraperitoneally, but not effective in hyperlipidemic rats at 8 mg/kg/day intraperitoneally, but not effective in hyperlipidemic rats at 8 mg/kg/day orally. Cholesterol and triglyceride lowering effects of the agents were correlated with inhibition of the activities of liver acetyl CoA synthetase, HMG CoA reductase, phosphatidylate phosphohydrolase, and lipoprotein lipase, and with elevation of the activity of cholesterol ester hydrolase.     

3-氯代亚甲基色满-4-酮类化合物的设计、合成及体外抗真菌活性研究

本文以取代苯酚为原料,经微波条件下的取代反应和多聚磷酸中进行的环合反应制备了取代色满酮,取代色满酮与甲酸乙酯的缩合产物经氯化反应制备了3-氯代亚甲基色满-4-酮类化合物,共合成了10种未见文献报道的新化合物。化合物结构经质谱和核磁共振氢谱进行了确证,并且采用二倍稀释法对目标化合物的体外抗真菌活性进行了测试,结果表明它们具有很好的体外抗真菌活性,其中化合物4c、4e、4g和4h对石膏样小孢子菌的MIC值为1μg.mL1,高于对照药氟康唑和两性霉素B,具有进一步研究价值。