New substituted 4-thioxothiazolidin-2-one derivatives: synthesis and structural study

Synthesis and physico-chemical properties of some 3-benzyl- and 3-phenacyl-4-thioxo-5-benzylidenethiazolidin-2-one derivatives are described. Fifteen new compounds were synthesized from thiazolidin-2-one by thionation of the 4-carbonyle, alkylation of the 3-N and aldolisation-crotonisation of 5-CH(2) with aromatic aldehydes. Soon, these new compounds will be tested for their bacteriostatic activity.     

Synthesis and pharmacophore modeling of naphthoquinone derivatives with cytotoxic activity in human promyelocytic leukemia HL-60 cell line

Catalyst/HypoGen pharmacophore modeling approach and three-dimensional quantitative structure-activity relationship (3D-QSAR)/comparative molecular similarity indices analysis (CoMSIA) methods have been successfully applied to explain the cytotoxic activity of a set of 51 natural and synthesized naphthoquinone derivatives tested in human promyelocytic leukemia HL-60 cell line. The computational models have facilitated the identification of structural elements of the ligands that are key for antitumoral properties. The four most salient features of the highly active beta-cycled-pyran-1,2-naphthoquinones [0.1 microM < IC50 < 0.6 microM] are the hydrogen-bond interactions of the carbonyl groups at C-1 (HBA1) and C-2 (HBA2), the hydrogen-bond interaction of the oxygen atom of the pyran ring (HBA3), and the interaction of methyl groups (HYD) at the pyran ring with a hydrophobic area at the receptor. The moderately active 1,4-naphthoquinone derivatives accurately fulfill only three of these features. The results of our study provide a valuable tool in designing new and more potent cytotoxic analogues.     

Synthesis and antimicrobial activity of some new 4-triazolylmethoxy-2H-chromen-2-one derivatives

4-(5-Aryl-4H-[1,2,4]triazol-3-ylmethoxy)-2H-chromen-2-ones have been synthesized by the one pot cyclocondensation reaction of 2-(2-oxo-2H-chromen-4-yloxy)acetohydrazide with aromatic/heterocyclic aldehydes in the presence of ammonium acetate in acetic acid. The structures of all the new compounds have been established on the basis of their analytical and spectral data. These compounds were also evaluated for their antibacterial and antifungal activity against various strains of bacteria and fungi and some are found to possess significant antimicrobial activity when compared with ciprofloxacin and miconazole.     

Synthesis and anticonvulsant activity of some new 4-aryl-4-imidazoline-2-one derivatives.

In this study, some new 4-aryl-4-imidazoline-2-one derivatives have been prepared by the reaction of potassium cyanate with some aminoethanone hydrochlorides. The structure of these compounds have been confirmed by UV, IR, 1H-NMR and elementary analysis. Their anticonvulsant activities were determined by maximal electroshock (MES) and subcutaneous metrazol (ScMet) tests according to the ADD (Antiepileptic Drug Development) programme Phase I. Neurotoxicity of the compounds was evaluated by rotarod test. While 2 of the compounds showed protection against ScMet induced seizures at 30 and 300 mg/kg dose levels, 3 of the compounds showed neurotoxicity.     

Synthesis and biological activity of some derivatives of thiochroman-4-one and tetrahydrothiapyran-4-one.

A small series of pyrazoles and isoxazoles derived from thiochroman-4-one has been synthesized and characterized. The compounds were examined for their in vitro inhibitory activity against Bacillus subtilis and Pseudomonas fluorescens. Among the tested compounds the pyrazole derivative from thiochroman-4-one was found to be the most effective inhibitor of growth of B. subtilis. Extensive H NMR analysis was recorded for all compounds.     

Synthesis and anticancer activity of Indolin-2-one derivatives bearing the 4-thiazolidinone moiety

A novel series of indolin‐2‐one derivatives containing the 4‐thiazolidinone moiety ( 5a—5p ) was synthesized and the cytotoxicity of these derivatives was evaluated in vitro against three human cancer cell lines (HT‐29, H460 and MDA‐MB‐231) by standard MTT assay. Some prepared compounds exhibited significant cytotoxicity against different human cancer cell lines. Several potent compounds were further evaluated against one normal cell line (WI‐38). In particular, the promising compound 5h showed remarkable cytotoxicity and selectivity against the HT‐29 and H460 cancer cell lines (IC₅₀ = 0.016 µmol/L, 0.0037 µmol/L, respectively).     

Substituted 2-thioxothiazolidin-4-one derivatives showed protective effects against diabetic cataract via inhibition of aldose reductase

In an effort to develop a new class of potent aldose reductase inhibitors against diabetic cataracts, a series of novel 2-thioxothiazolidine-4-one derivatives was synthesized in excellent yields via a facile synthetic route. These compounds were tested against aldehyde (ALR1) and aldose reductase (ALR2) enzymes, where they showed considerable inhibitory activity. Among the tested derivatives, compound 6e showed selective and excellent inhibition of ALR2 over ALR1. The experimental diabetes was induced by the intraperitoneal administration of streptozotocin in male Wistar rats. Compound 6e showed positive modulation of body weight, blood glucose, and blood insulin levels in diabetic rats. Compound 6e also showed ALR2 inhibition as evidenced by Western blot analysis in lens homogenates of Wistar rats having cataract. The docking study of 6e was also performed inside the active site of ALR2 to enumerate the key contacts for inhibitory activity.     

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 and pharmacological activity of derivatives of 3-aminomethylenindolin-2-one

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 28, No. 4, pp. 22–26, April, 1994.     

苯氧茚酮类衍生物的合成和乙酰胆碱酯酶抑制活性

目的设计、合成新型的AchE抑制剂。方法在K₂CO₃和乙腈存在下，将2-溴-5,6-二甲氧基-1-茚酮与多种胺烷基苯酚缩合得到一系列苯氧茚酮类衍生物，并采用改进的Ellman方法研究它们的体外AchE和BchE抑制活性。结果合成了16个未见文献报道的化合物8a～p，结构经IR，¹H NMR，MS及元素分析确证。初步体外AchE，BchE抑制活性试验表明，绝大部分化合物都显示出良好的抑制AchE活性，其中8h的IC₅₀为50.0 nmol·L^-1，与石杉碱甲相近(IC₅₀＝53.0 nmol·L^-1)；而所有化合物基本都无BchE抑制活性。结论该类衍生物具有较强的AchE抑制活性，有进一步研究的价值。     

Synthesis,antimicrobial and cytotoxic activity of 2-azetidinone derivatives of pyridyl benzimidazoles

In the present study, a series of novel 6-(1H-benzo[d]imidazol-2-yl)-2-(3-chloro-2-oxo-4-phenylazetidin-1-yl)-4-(aryl)nicotinonitriles 6a–o were efficiently synthesized and evaluated for their in vitro antibacterial activity against Gram-positive (Staphylococcus aureus and Streptococcus pyogenes), Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria and fungal (Candida albicans, Aspergillus niger and Aspergillus clavatus) strains. The results of antimicrobial study revealed that compounds 6b, 6c, 6d, 6h and 6i exhibited substantial antibacterial activity while compounds 6c and 6h emerged as the most potent antifungal agents compared to the standard drugs chloramphenicol and ketoconazole, respectively. From the standpoint of SAR studies, it was observed that the presence of electron-withdrawing groups remarkably enhances the antibacterial activity of newly synthesized compounds. Further, the results of preliminary MTT cytotoxicity studies on HeLa cells suggested that potent antimicrobial activity of 6b, 6c, 6d, 6h and 6i is accompanied by low level of cytotoxic concentrations. All the newly synthesized analogues were characterized by IR, ¹H NMR, ¹³C NMR and mass spectral data.     

Synthesis and cytotoxic activity of genistein derivatives

A series of genistein derivatives was prepared and tested in vitro against leukocythemia (HL-60), colorectal adenocarcinoma (HT-29), and human gastric adenocarcinoma (SGC-7901) cell lines. Among these derivatives, 4′,5-di-n-octoxy-7-gem-difluoromethylenegenistein, 9f, had the strongest activity against HL-60, HT-29, and SGC-7901 cells.      

Synthesis and spasmolytic action of 2-substituted thienopyrimidin-4-one derivatives

In the search for novel compounds to treat disorders of smooth muscle function, efforts have focused on some 2-substituted thieno[2,3-d]pyrimidin-4-one derivatives that show interesting spasmolytic action. Our laboratories have developed a new series of quaternary salts of 2-substituted thieno[2,3-d]pyrimidin-4-one and thieno[3,2-d]pyrimidin-4-one isomers with therapeutic potential. Thesesubstances were prepared starting from simple derivatives of thiophene. Their spasmolytic activity was evaluated on transmurally stimulated guinea-pig ileum. The most active compounds (IC50 1.12-2.71 microM) 7f-7h, 12d and 12f had the terminal piperidino nucleus in the thioalkyl chain and lacked two methyl groups in the thiophene ring. Their relaxant activity on the isolated ileum was potentiated (approx. 20-25%) by phosphodiesterase inhibitors. Compounds 7f-h, 12d and 12f were less effective in inhibiting contractions of the guinea-pig ileum induced by acetylcholine (IC50 26.7-41.4 microM) or histamine (IC50 41.5-63.4 microM) and had a moderate binding activity to muscarinic receptors in membrane homogenates from the rat heart (M2 sites; pKi values between 5.55+/-0.08 and 5.14+/-0.12; n = 3) and submaxillary gland (M3 sites; pKi values between 6.15+/-0.07 and 5.76+/-0.08; n = 3). Action involving soluble guanylyl cyclase or any potential binding to guinea-pig ventricular L-type calcium channels was not considered likely. It is concluded that at least two different mechanisms of action contribute to their spasmolytic activity.