Synthesis and antimicrobial activity of new 4-thiazolidinone derivatives containing 2-amino-6-methoxybenzothiazole

A novel series of Schiff bases 5a–j and 4-thiazolidinones 6a–j have been prepared from the building blocks 2-chloro pyridine-3-carboxylic acid [1] and 2-amino-6-methoxy-benzothiazole [2]. All of the synthesized compounds have been confirmed by elemental analyses, IR, ¹H NMR and ¹³C NMR spectral data. These newly synthesized compounds were screened for their antimicrobial activity. Variable and modest activity was observed against the investigated strains of bacteria and fungi, however, compound 6h revealed significant antibacterial activity against Escherichia coli. Compounds 1, 2, 3, 5c, 5g and 5h, on the other hand, revealed potent antifungal activity against Candida albicans compared to the reference drug greseofulvin.     

Synthesis and evaluation of anticonvulsant and antimicrobial activities of 3-hydroxy-6-methyl-2-substituted 4h-pyran-4-one derivatives

In this study, thirteen 3-hydroxy-6-methyl-2-substituted 4H-pyran-4-one derivatives were synthesized for the evaluation of their potential anticonvulsant activity. Mannich bases were prepared by the reaction of substituted piperazine derivatives with allomaltol and formaline. The structures of the synthesized compounds were confirmed by IR, (1)H-NMR and elemental analysis. Their anticonvulsant activities were determined in vivo by maximal electroshock (MES), sub-cutaneous Metrazol (scMet), and rotorod toxicity tests for neurological deficits. The antimicrobial activities of the synthesized compounds were investigated in vitro against some bacteria and fungi using the microdilution broth method. Ac-cording to the activity studies, 3-hydroxy-6-methyl-2-[4-(2-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-4H-pyran-4-one (3i) was the compound determined to be most active in the scMet test for all doses at four hours and for the 300 mg/kg dose at half an hour. 2-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-3-hydroxy-6-methyl-4H-pyran-4-one (3f) was found to be protective against MES whereas 2-chlorophenyl derivative (3e) was not. Looking at the antifungal activity results, compounds 3b, 3h, and 3i were determined to have activity against all fungi.     

Synthesis and anticancer activity of isatin-based pyrazolines and thiazolidines conjugates

The synthesis and antitumor activity screening of novel isatin based conjugates with thiazolidine and pyrazoline moieties were performed. Reaction of 3,5-diaryl-4,5-dihydropyrazoles with chloroacetyl chloride yielded starting 2-chloro-1-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-ethanones which were utilized in alkylation of isatin and 5-bromoisatin. Thus, corresponding 1-[2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-2-oxoethyl]-1H-indole-2,3-diones (1a-1d) have been obtained. The compounds 1a-1d have been used in Knoevenagel condensation with 4-thiazolidinones for obtaining a series of 5-ylidenederivatives 2a-2f and 3a-3d. The synthesized compounds were tested for their anticancer activity in NCI60 cell lines. Among the tested compounds, 5-bromo-1-{2-[5-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl]-2-oxoethyl}-1H-indole-2,3-dione (1d) was found to be the most active candidate with selective influence on leukemia subpanel tumor cell lines with GI(50) values range of 0.69-3.35 μM.     

Synthesis,characterization and anticancer activity of certain 3-{4-(5-mercapto-1,3,4-oxadiazole-2-yl)phenylimino}indolin-2-one derivatives

A series of 5- or 7-substituted 3-{4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenylimino}-indolin-2-one derivatives were synthesized by treating 5-(4-aminophenyl)-1,3,4-oxadiazole-2-thiol with different isatin derivatives. The newly synthesized compounds were characterized on the basis of spectral (FT-IR, ¹H NMR, MS) analyses. All the synthesized derivatives were screened for anticancer activity against HeLa cancer cell lines using MTT assay. All the synthetic compounds produced a dose dependant inhibition of growth of the cells. The IC₅₀ values of all the synthetic test compounds were found between 10.64 and 33.62 μM. The potency (IC₅₀ values) of anticancer activity of compounds VIb–d was comparable with that of known anticancer agent, Cisplatin. Among the synthesized 2-indolinones, compounds VIb–d with halogen atom (electron withdrawing groups) at C5 position showed the most potent activity. These results indicate that C5 substituted derivatives may be useful leads for anticancer drug development in the future.     

4-吗啉喹唑啉类PI3K抑制剂的合成及活性研究

目的寻找具有新型骨架结构的磷脂酰肌醇3激酶(PI3K)抑制剂。方法基于活性化合物,利用"杂交"设计原理,设计和合成了系列4-吗啉喹唑啉类衍生物。结果目标化合物经1HNMR、质谱确证结构,并评价了其对Rh30细胞的增殖抑制活性。结论大部分化合物具有较好的抑制活性,化合物8b的活性最强,其IC50达0.8μmol.L-1。4-吗啉喹唑啉是一类新型的PI3K抑制剂骨架,值得进一步进行结构修饰研究。     

Synthesis of novel substituted 7-(benzylideneamino)-4-methyl-2H-chromen-2-one derivatives as anti-inflammatory and analgesic agents

A series of novel Schiff' base-containing a 7-amino-4-methylcoumarin moiety have been synthesized III a-l, characterized by spectroscopic data and studied for their anti-inflammatory and analgesic activity. The results of the anti-inflammatory and analgesic activity evaluation of 7-(substituted benzylideneamino)-4-methyl-2H-chromen-2-one derivatives III a-l proved to be comparable or more potent with respect to the reference drugs. In particular, compounds 7-(4-chlorobenzylideneamino)-4-methyl-2H-chromen-2-one III f, 7-(2,4-dichlorobenzylideneamino)-4-methyl-2H-chromen-2-one III g and 7-(4-bromobenzylideneamino)-4-methyl-2H-chromen-2-one III h exhibited potent anti-inflammatory and analgesic activity.     

Synthesis and anticancer activity of new 2-aryl-4h-3,1-benzothiazines

New compounds of 2-aryl-4H-3,1-benzothiazine set were synthesized and tested for their antiproliferative activity as part of our research in the antitumor field. The title compounds were obtained by the reaction of aryl-modified sulfinylbis((2,4-dihydroxyphenyl)methanethione) with 2-aminobenzyl alcohols. The reaction proceeded through thiobenzanilide intermediates, which were converted to the 4H-3,1-benzothiazine fused ring by an endocyclization process. The structures of compounds were identified from elemental, IR, (1) H-NMR, (13) C-NMR, and MS spectra analyses. The cytotoxicity in vitro against four human cancer cell lines was determined. The antiproliferative properties of some compounds were more beneficial than cisplatin studied comparatively.     

Synthesis and pharmacological evaluation of new 1-[3-(4-arylpiperazin-1-yl)-2-hydroxypropyl]-pyrrolidin-2-one derivatives with anti-arrhythmic, hypotensive, and alpha-adrenolytic activity

A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment was synthesized and evaluated for the binding affinity of the alpha(1)- and alpha(2)-adrenoceptors (AR) and for the antiarrhythmic and hypotensive activities of the compounds. The most potent and selective compound 1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one 8 binds with pK(i) = 6.71 for alpha(1)-AR. Derivative 8 was also the most active in the prophylactic antiarrhythmic test in adrenaline-induced arrhythmia in anaesthetized rats. Its ED(50 )value equals 1.9 mg/kg (i.v.). Compounds with substituents such as a fluorine atom 4, a methyl 5, or a hydroxyl 8 group, or two substituents such as fluorine/chlorine atoms and methoxy groups in the phenyl ring, significantly decreased the systolic and diastolic pressure in normotensive anesthetized rats at a dosages of 5-10 mg/kg (i.v.). It was found that the presence of the piperazine ring and a hydroxy group in the second position of the propyl chain are critical structural features in determining the affinity of the compounds tested.     

Structure/activity investigations of 5-substituted 3-methylisoxazole[5, 4-d]1, 2, 3-triazin-4-one derivatives

The series of 5-substituted 3-methylisoxazole[5, 4-d]1, 2, 3-triazin-4-one derivatives was obtained by diazotization of 5-amino-3-methylisoxazol-4-carboxylic acid hydrazide. The immunological activity of these compounds was investigated experimentally in several in vitro and in vivo assays in mice and human models. In the next step, quantum-chemical investigations were performed using density functional theory with the B3LYP hybrid exchange-correlation energy functional and 6-31G(d, p) basis set. The Polarizable Continuum (SCRF/PCM) solvent model was also taken into account in order to show solvent influence on electron density and electrostatic potential around the exemplary molecules. Correlations between molecular structure and biological properties were found using a stepwise selection of scales for the multiple linear regression (MLR).     

Design and synthesis of novel benzopyran-2-one derivatives of expected antimicrobial activity through DNA gyrase-B inhibition

In an attempt to find a new class of antibacterial agents, we have synthesized thirty new coumarin (2H-benzopyran-2-one) analogues. These derivatives include substituted azetidin-2-ones (beta-lactam) 3a-f, pyrrolidin-2-ones 4a-f, 2H-1,3,4-oxadiazoles 5a-f, and thiazolidin-4-ones 6a-f attached to 4-phenyl-2H-benzopyran-2-one through an oxyacetamido or an oxymethyl bridge. The target compounds were synthesized starting from 2-oxo-4-phenyl-2H-benzo[b]pyran-7-yl-oxyacetic acid hydrazides 2a-f. The new compounds were evaluated as DNA gyrase-B inhibitors through molecular modeling and docking techniques using the Molsoft ICM 3.4-8C program. The synthesized compounds were also screened for antibacterial activity against four different species of Gram-positive and Gram-negative bacteria; as well as screening against C. albicans for antifungal activity. The molecular modeling data were in accordance with the antimicrobial screening results.     

咪唑啉-2-酮衍生物的合成及其抗肿瘤活性

目的设计、合成五元环为咪唑啉-2-酮的CA-4的构象限制类似物，以期得到在体内外具有更好活性的化合物。方法取代苯胺与固体光气反应得取代苯异氰酸酯，不经后处理直接与相应的α-氨基苯乙酮盐酸盐在甲苯存在下回流反应得到3,4-二取代苯基-咪唑啉-2-酮-1-甲酰苯胺和3,4-二取代苯基-咪唑啉-2-酮。经MTT法筛选其对PC-3，A549，HO-8910，Hela，HL60，K562和HL60R瘤株的抗肿瘤活性，并对化合物4y进行了初步的作用机制研究。结果按上法制得36个未见文献报道的化合物，其结构经¹H NMR，MS和元素分析确证。结论体外活性测试表明，化合物4y对人白血病具有选择性的抑制作用，其作用机制主要为诱导凋亡。     

Synthesis and anti-measles virus activity of new isoquinolin-4-one derivatives

Despite intense efforts to increase vaccine coverage, measles virus (MV) still causes significant morbidity and mortality in the world sometimes as a results of severe, chronic and lethal diseases. In an effort to develop therapies to supplement immunization strategies a number of 1-oxo-2-[[(1E)-phenylmethylene]amino]-1,2-dihydroisoquinoline-4-carboxylic acid derivatives were synthesized and evaluated for anti-measles activity. The substituents on the aromatic ring were chosen in order to evaluate the influence of electron-withdrawing or electron-donating effects on the electronic density of the aromatic moiety. We also evaluated the introduction of a vinyl chain between the exocyclic nitrogen and phenyl moiety. The biological results allow to outline some preliminary considerations on structure-activity relationship.     

Synthesis, analgesic and anti-inflammatory evaluation of some new 3H-quinazolin-4-one derivatives

In this study, we have synthesized a series of 3H-quinazolin-4-ones in order to obtain new compounds with potential analgesic and anti-inflammatory activity. The structures of the newly synthesized compounds were confirmed by means of infrared, nuclear magnetic resonance and mass spectroscopy. Some compounds were evaluated for their analgesic and anti-inflammatory activities by writhing and carrageenan-induced rat paw edema tests, respectively. In comparison to the standard drug indomethacine, compounds 4, 6c, 12-14, 16, 18, 19, and 22 induced significant reduction in the writhing response while compounds 6c, 12, 14, 16, 18, and 22 produced a good dose-dependent anti-inflammatory activity. The best dual analgesic / anti-inflammatory relative activity was observed with compounds 6c, 14, 16, 18, and 22.     

Synthesis of 2-mercaptobenzimidazole derivatives as potential anti-microbial and cytotoxic agents

A series of novel 2-(1H-benzimidazol-2-ylsulfanyl)-N-(4-oxo-2-phenyl-thiazolidin-3yl)-acetamide 5a-j have been synthesized from various aldehydes and 2-(5-phenyl-[1,3,4]-oxadiazol-2-ylmethylsulfanyl)-1H-benzimidazole 6a-j from various benzoic acids. These compounds were screened for their in-vitro anti-bacterial activity against Staphylococcus aureus and Enterococcus faecalis as Gram positive, Klebsiella pneumoniae and Escherichia coli as Gram negative bacterial strains and for in-vitro anti-fungal activity against Asperigillus fumigatus and Candida albicans. The in vitro cytotoxic properties were studied using brine shrimp bioassay. Results revealed that, compounds 5b, 5d, 5g, 5i, 6b, 6e, 6f, and 6i showed excellent activity against a panel of microorganisms. The cytotoxic activities of 5b, 5g, 5i, 6b, 6f, 6h, and 6i were found to be good. All the newly synthesized compounds were characterized by elemental analysis, IR, (1)H-NMR, (13)C-NMR and MS.     

6-氯-苯并二氢-γ-吡喃酮的合成研究

目的:合成氧杂非甾体雌激素类似物制备的关键中间体6 -氯-苯并二氢-γ-吡喃酮。方法:以对氯苯酚为起始原料经亲核加成、水解和环合反应合成了6 -氯-苯并二氢-γ-吡喃酮。结果:合成产物的结构经熔点、红外光谱、核磁共振氢谱和质谱确证。结论:该合成工艺简单,产品质量好且成本低     

Synthesis and antimycobacterial activity of pyridylmethylsulfanyl and naphthylmethylsulfanyl derivatives of benzazoles, 1, 2, 4-triazole, and pyridine-2-carbothioamide/-2-carbonitrile

A set of four types of benzazoles, 1, 2, 4-triazole, and pyridine-2-carbonitrile/-2-carbothioamide substituted with 1-naphthylmethylsulfanyl or pyridylmethylsulfanyl was prepared to modify the structure of benzylsulfanyl derivatives of the above-mentioned heterocycles. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. avium, and two strains of M. kansasii. The activities were expressed as the minimum inhibitory concentration (MIC). The MIC values fall into a range of 2 to >1000 micromol/L. Introduction of a pyridyl moiety into the molecule mostly decreased the activity. A naphthyl moiety did not influence the activity in comparison with a phenyl. The most active substances were 4-(3-pyridylmethylsulfanyl)pyridine-2-carbothioamide (7b) (MIC = 2 - >62.5 micromol/L) and 4-(1-naphthylmethylsulfanyl)pyridine-2-carbothioamide (7d) (MIC = 2 - >32 micromol/L).     

Synthesis of novel thiazolyl-pyrimidines and their anticancer activity in vitro

A series of novel compounds 7-43 were prepared via the condensation of enaminones 4a-h and the guanidines carbonate 6a-f. The structures of these newly synthesized compounds were confirmed by (1) H-NMR, MS, EA and IR. All the compounds were tested for their cytotoxic activity in vitro against human cancer cell lines including Ishikawa, A549, BEL-7404, SPC-A-01 and SGC-7901. Most of them showed moderate cytotoxic against the tested cell lines. Among them, the most potent compounds 9 and 30 exhibited more efficient activity against Ishikawa, A549.     

Synthesis of 5-substituted 2-methylbenzimidazoles with anticancer activity

A series of compounds comprising the thiocarboximidopyrazolyl 5, the phenylpyrazolyl 6, the dimethylpyrazolyl 7, the nitrophenylpyrazolyl 8, the dimethyloxazolyl 9, the benzoxazepinyl 10, and pyrimidyl 11 a-c derivatives of 3-(2-methyl-1H-benzimidazol-5-ylazo)pentane-2, 4-dione was synthesized. Moreover, 5-amino-2-methylbenzimidazole (3) was reacted with phthalic anhydride or maleic anhydride in acetic acid or in toluene to produce 12-15. Treating 5, 6-diamino-2-methylbenzimidazole (16) with ethyl cyanoacetate or diethyl malonate or acetyl acetone leads to the formation of the benzodiazepine derivatives 17-20. The cytotoxic activity of the compounds 2, 7, 9, 10, and 11 was tested against 60 types of human cancer cell lines. Compounds 7 and 9 were found to be the most potent.     

Synthesis andin vitro antibacterial activity of quaternary ammonium cephalosporin derivatives bearing oxazolidinone moiety

Several oxazolidinones having amine moiety were prepared to form a quaternary ammonium salt with cephalosporin nucleus, and antibacterial activity of the quaternary ammonium cephalosporin derivatives bearing oxazolidinone moiety were examined particularly with expectation of dual activity. However, the cephalosporin-oxazolidinone compounds revealed rather weaker antibacterial activity in vitro than their parent oxazolidinone and cephalosporin without showing any characteristic activity as expected.     

N-甲基-4-苯氧基吡啶-2-甲酰胺衍生物的合成及其抗肿瘤活性研究

目的设计并合成结构新颖的N-甲基-4-苯氧基吡啶-2-甲酰胺衍生物,并对其抗肿瘤活性进行初步评价。方法通过分析索拉菲尼与B-Raf激酶的共结晶模型,在保留其药效团的基础上,设计了16个目标化合物,以吡啶甲酸为原料,经氯代、酯化、取代、还原、氨解及与取代的氨基甲酸苯酯反应制得9个目标化合物;经氯代、氨解、取代及与取代的氨基甲酸苯酯反应得到7个目标化合物;以索拉菲尼为阳性对照,采用MTT法,评价目标化合物对人肺癌细胞株H460、人结肠癌细胞株HT-29和人胃癌细胞株MKN-45增殖的抑制活性。结果与结论部分目标化合物显示出较好的抗肿瘤活性,活性优于或与索拉菲尼相当,其中化合物9b和12f的活性突出。初步构效关系研究表明,末端苯环上取代基的电性效应和取代位置对化合物的活性具有显著影响。