New isothiazole derivatives: synthesis, reactivity, physicochemical properties and pharmacological activity

The synthesis and biological investigation of the series of amide and ester derivatives 10-20 of 5-(4-chlorobenzoyl)amino-3-methyl-4-isothiazolecarboxylic acid 5 are presented. Because the amide series of 5-benzoylamino-3-methyl-4-isothiazolecarboxylic acid 2 has been studied extensively and from this series denotivir (vratizolin) 4 became the antiviral drug. The influence of exchanging the N-benzoyl for a N-(4-chlorobenzoyl) group at position 5 of the isothiazole ring on the pharmacological activity of 5-benzoylamino-3-methyl-4-isothiazolecarboxylic acid 2 derivatives is dealt with here. The effect of structure modifications in the carboxylic group of the 5-(4-chlorobenzoyl)amino-3-methyl-4-isothiazolecarboxylic acid 5 series of derivatives on their biological activity is discussed. Some of the tested 5-(4-chlorobenzoyl)amino-3-methyl-4-isothiazolecarboxylamides revealed significant anti-inflammatory activity in carrageenan induced edema and air-pouch inflammation tests. Physicochemical properties of 6-(4-chlorophenyl)-3-methylisothiazolo[5,4-d]-4H-1,3-oxazin-4-one 6 are described. Its use in the synthesis of isothiazole derivatives and its reactivity are also presented.     

New amides of 5-acylamino-3-methyl-4-isothiazolecarboxylic acid and their immunotropic activity

Several new amides 4 of 5-substituted 3-methyl-4-isothiazolecarboxylic acid were obtained. These compounds have acetylamino or benzoylamino groups in position 5 of the isothiazole ring. In position 4, the carboxylic group was transformed in the amides using amino-acid esters. Activities of the obtained derivatives were checked in the humoral immune response and delayed type hypersensitivity reaction to sheep red blood cells (SRBCs) in vivo.     

2-Amino-3-cyano-4-(5-arylisoxazol-3-yl)-4H-chromenes: synthesis and in vitro cytotoxic activity

A new series of 4-aryl-4H-chromenes bearing a 5-arylisoxazol-3-yl moiety at the C-4 position were prepared as potential anticancer agents. The in vitro cytotoxic activity of the synthesized compounds was investigated against a panel of tumor cell lines including MCF-7 (breast cancer), KB (nasopharyngeal epidermoid carcinoma), Hep-G2 (liver carcinoma), MDA-MB-231 (breast cancer), and SKNMC (human neuroblastoma) using the MTT colorimetric assay. Doxorubicin, a well-known anticancer drug, was used as positive standard drug. Among the synthesized compounds, the 5-(3-methylphenyl)isoxazol-3-yl analog (7j) showed the most potent cytotoxic activity against all five human tumor cell lines.     

Efficient regioselective three-component domino synthesis of 3-(1,2,4-Triazol-5-yl)-1,3-thiazolidin-4-ones as potent antifungal and antituberculosis agents

In research for promising antibacterial and antifungal compounds, a series of 2‐aryl 3‐[1,2,4]triazol‐5‐yl 4‐thiazolidinones 1 were synthesized by a domino reaction of 5‐amino‐1H‐[1,2,4]triazoles 3 , aromatic aldehydes, and α‐mercaptoacids in boiling toluene in the presence of molecular sieves 4 Å. Of the twenty novel 3‐[1,2,4]triazol‐5‐yl 4‐thiazolidinone derivatives, four compounds 2‐benzo[d][1,3]dioxol‐6‐yl‐3‐[(3‐morpholin‐4‐yl)‐1H‐1,2,4‐triazol‐5‐yl)]‐1,3‐thiazolidin‐4‐one ( 1i ), 2‐(4‐chlorophenyl)‐5‐methyl‐3‐[3‐(4‐methylpiperazin‐1‐yl)‐1H‐1,2,4‐triazol‐5‐yl]‐1,3‐thiazolidin‐4‐one ( 1p ), 2‐benzo[d][1,3]dioxol‐6‐yl‐3‐[3‐(4‐methylpiperazin‐1‐yl)‐1H‐1,2,4‐triazol‐5‐yl]‐1,3‐thiazolidin‐4‐one ( 1s ), 2‐benzo[d][1,3]dioxol‐6‐yl‐5‐methyl‐3‐[3‐(4‐methylpiperazin‐1‐yl)‐1H‐1,2,4‐triazol‐5‐yl]‐1,3‐thiazolidin‐4‐one ( 1t ) exhibited MICs of 4 µg/mL or less versus Mycobacterium tuberculosis. Moreover, these compounds were screened against Candida albicans. Compounds 1p , 1s gave MICs of 1 µg/mL or less, and were fungicidal. Finally, compound 1s was evaluated against an expanded fungal panel and showed good activity against Cryptococcus neoformans. In addition, compound 1s also appeared to be fungicidal against Aspergillus arrhizus, with MIC <1 µg/mL.     

Modification of the structure of 4, 6-disubstituted 2-(4-alkyl-1-piperazinyl)pyridines: synthesis and their 5-HT2A receptor activity

Structure-activity relationship studies of a series of novel 4, 6-disubstituted 2-(1-piperazinyl)pyridines were conducted to revise our model of serotonin 5-HT(2A) receptor antagonist. Target compounds were synthesized using the benzotriazole-assisted Katritzky method. The majority of those compounds were found to be selective 5-HT(2A)/5-HT(1A) receptor ligands, though less potent than their previously described pyrimidine counterparts. In particular, the three compounds 6-8 showed the highest 5-HT(2A) receptor affinity (K(i) = 34-78 nM) and were classified as 5-HT(2A) antagonists in in vivo experiments. The influence of the structural modifications on the in vitro results was discussed; however, the elucidation of the role of the central core system requires further studies.     

Synthesis and antibacterial activity of 4-benzoyl-1-(4-carboxy-phenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid and derivatives

A new 1H-pyrazole-3-carboxylic acid 2, along with hydrazono-pyridazinone 3, a by-product, and its derivatives 4–7 were synthesized and the structures confirmed by infrared (IR) and ¹H and ¹³C nuclear magnetic resonance (NMR) data. These new compounds were evaluated for their antibacterial activities against Gram-positive and Gram-negative bacteria using the tube dilution method. The minimal inhibitory concentrations (MICs) experiments revealed that most compounds exerted inhibitor effects against Klebsiella pneumonia, Escherichia coli, Bacillus subtilus, and Xanthomonas compestris test microorganisms. Moreover, the results showed that the pyrazolo[3,4-d]pyridazine compounds were the best compounds of the series, exhibiting antibacterial activity against both Gram-positive and Gram-negative bacteria.     

Fungicide Activity of 5‐(4‐Chlorobenzylidene)‐(Z)‐2‐dimethylamino‐1,3‐thiazol‐4‐one against Cryptococcus Neoformans

The present work describes the synthesis and antifungal evaluation of new 5‐arylidene‐(Z)‐2‐dimethylamino‐1,3‐thiazol‐4‐ones 4a – f , obtained by the reaction of aromatic aldehydes 1 and rhodanine 2 followed by treatment with DMF. All compounds were tested against a panel of yeasts, hialohyphomycetes, and dermatophytes using the microbroth dilution method. Compounds 4a and 4c showed antifungal activity, with compound 4a being the most active one. Compound 4a demonstrated to be fungicidal rather than fungistatic and selective activity against Cryptococcus neoformans and dermatophytes. MIC₁₀₀, MIC₈₀, and MIC₅₀ of 4a were determined against a panel of clinical isolates of C. neoformans showing ranges of MICs between 2 and 16 μg/mL.     

Synthesis, physicochemical and anticonvulsant properties of new N-4-arylpiperazin-1-yl amides of (2-aza-1,3-dioxospiro[4.4]non-2-yl)- and [4.5]dec-2-yl)-propionic acid

In continuation of the search of new anticonvulsants, a series of N-4-arylpiperazin-1-yl 2-aza-1,3-dioxospiro[4.4]non-2-yl- (5-8) and [4.5]dec-2-yl- (9-15) propionamides, structurally related to the previously described N-4-arylpiperazin-1-yl amides of 2-aza-1,3-dioxospiro[4.5]dec-2-yl-acetic acid, were synthesized. The designed compounds 5-15 were prepared by condensation of the formerly obtained (2-aza-1,3-dioxospiro[4.5]dec-2-yl)- (3) and (2-aza-1,3-dioxo[4.4]non-2-yl)-(4) propionic acids with the appropriately substituted 4-arylpiperazines, in the presence of the N,N-carbonyldiimidazole (CDIM) reagent. All the compounds were tested for their anticonvulsant activity in the maximum electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Several compounds 7-10, 13 and 14 revealed protection in the MES screening.     

Synthesis and pharmacological activity of 2-(substituted)-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-ones

Loperamide is a well-known peripherally acting opiate used for the treatment of diarrhoea. To gain more knowledge on the structure-activity relationships of antidiarrhoeal drugs and to develop new active molecules, a series of aryl-cyano-piperidinoalkyl-thiazolidinones related to Loperamide was synthesized and screened for antidiarrhoeal activity in mice by castor oil test. To characterize the potency and toxicity of the synthesized compounds ED50 and LD50 values were also determined. The thiazolidinones 2-6 displayed antidiarrhoeal activity at doses ranging between 15 and 82 mg/kg. Although the results show that the synthesized compounds are 15- to 80-fold less active respect to the reference compound, Loperamide, they are much less toxic (> or = 1000 mg/kg and 108.9 mg/kg, respectively). Besides, to evaluate the involvement of opioid receptors in antidiarrhoeal activity, Naloxone was administered prior to test the 2-phenyl-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-one (2), the more active compound of this series. The results obtained by this study, suggest that the antidiarrhoeal activity of this series of thiazolidinone derivatives could involve the opioid receptors.     

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).     

New 4-thiazolidinones of nicotinic acid with 2-Amino-6-methylbenzothiazole and their biological activity

The title compounds 6aaj, 2-[(6-methyl-1,3-benzothiazol-2-yl)amino]-N-[2-(substituted phenyl/furan-2-yl)-4-oxo-1,3-thiazolidin-3-yl]nicotinamides, were prepared from 2-chloropyridine-3-carboxylic acid (1) and 2-amino-6-methyl-benzothiazole (2) by known methods. All the compounds have been established by IR, (1)H NMR, (13)C NMR and elemental analyses. The in vitro antimicrobial screening of the compounds were carried out against two Gram positive (S. aureus, S. pyogenes), two Gram negative (E. coli, P. aeruginosa) bacteria and three fungal species (C. albicans, A. niger, A. clavatus) using the broth microdilution method. Some of the compounds are comparable with standard drugs.     

4-[1-烷基-5-氧代-1H-1,2,4-三唑-4(5H)-基]-苯甲酸的合成

目的制备用于全合成卡泊芬净类环六脂肽抗真菌剂的关键脂肪酸侧链4-[1-烷基5-氧代-1H-1,2,4-三唑4（5H）-基]-苯甲酸（5）。方法以对氨基苯甲酸（1）为起始原料,经氨基苯氧羰酰化、肼解、甲脒环合及N-烃化4步反应制备目标化合物。结果以42．9％～46．2％的总收率成功合成了目标化合物5a～5n,其结构经电喷雾质谱（ESI—MS）和氢谱（^1HNMR）确证;所有目标化合物均为首次报道。结论该合成路线具有操作简便及收率高等优点,适合工业化生产。     

Synthesis of non-nucleosides: 7- and 1,3-substituents of new pyrrolo[2,3-d]pyrimidin-4-ones on antiviral activity

A series of non-nucleosides 9-47 were synthesized. Compounds 1-4 were reacted with formic acid (85%) to afford compounds 5-8. Then, the latter compounds were reacted with alkyl halides a-f (2-bromopropane, 2-bromobutane, benzyl bromide, benzyl chloromethyl ether, chloromethyl ethyl ether, phenacyl bromide) in the presence of NaH in dry DMF to give the desired compounds 9-47, which were evaluated for activity against herpes simplex virus type-II (HSV-II).     

New lanthanum (III) complex--synthesis, characterization, and cytotoxic activity

The complex of lanthanum (III) was synthesized reacting the respective inorganic salt with 5-aminoorotic acid in amounts equal to the metal:ligand molar ratio of 1:3. The complex was prepared by adding an aqueous solution of lanthanum (III) nitrate to an aqueous solution of the ligand, subsequently raising the pH of the mixture gradually to approx. 5.0 through addition of a dilute solution of sodium hydroxide. The structure of the final complex was determined by means of spectral data (IR, Raman,( 1)H-NMR) and elemental analysis. Significant differences in the IR spectrum of the complex were observed as compared to the spectrum of the ligand. A comparative analysis of the Raman spectrum of the complex with that of the free 5-aminoorotic acid allowed a straightforward assignment of the vibrations of the ligand groups involved in coordination. The ligand and the complex were tested for the cytotoxic activities on the chronic myeloid leukemia derived K-562, overexpressing the BCR-ABL fusion protein and the non-Hodgkin lymphoma derived DOHH-2, characterized by a re-expression of the anti-apoptotic protein bcl-2 cell lines. The results obtained indicate that the tested compounds exerted a considerable cytotoxic activity upon the evaluated cell lines in a concentration-dependent matter, which enabled the construction of dose-response curves and the calculation of the corresponding IC(50 )values. The inorganic salt exerted a very weak cytotoxic effect on these cells, which is in contrast to the lanthanum (III) complex.     

3-methyl-2-(4-substituted phenyl)-4,5-dihydronaphtho[1,2-c]-pyrazoles: synthesis and in-vitro biological evaluation as antitumour agents

The synthetic strategies and characterization of some novel derivatives of 3-methyl-2-(4-substituted phenyl)-4,5-dihydronaphtho[1,2-c]pyrazoles carrying different pharmacophores and heterocyclic rings that are relevant to potential antitumour and cytotoxic activities are described. The antitumour activities of the newly synthesized compounds were evaluated according to the protocol of the National Cancer Institute (NCI) in-vitro disease-oriented human cells screening panel assay. The results revealed that six compounds, namely 6, 8, 11, 15, 17 and 18; displayed promising in-vitro antitumour activity in the 60-cell lines assay. The sulfonylthioureido group emerged as the most favourable pharmacophore. Incorporating such thioureido counterpart into the 6-membered 1,3-thiazinan-5-one resulted in better antitumour activities than those displayed by the 5-membered thiazoles and the 6-membered 1,3-thiazinan-4-one ring systems. Further ring expansion led to a total loss of the antitumour activity. The analog 18, 3-benzyl-2-[4-(3-methyl-4,5-dihydronaphtho-[1,2-c]pyrazol-2-yl)-benzenesulfonylimino]-1,3-thiazinan-5-one, proved to be the most active member identified in this series of compounds (GI(50), TGI, and LC(50) MG-MID values of 34.7, 85.1 and 97.7 microM, respectively). The differential cytotoxicity of the six active compounds to cancer and normal cells was studied utilizing the standard MTT cell viability assay. Compounds 17 and 18 were totally selective for the breast cancer cell line MCF7 (IC(50 )8.5 and 4.7 microM), without exerting any inhibitory effect on the normal breast cell line MCF-10A at the concentration level used (25 microM).     

咪苯嗪酮对花生四烯酸诱导的大鼠脑血栓形成的影响

花生四烯酸(AA)0.25～1 mg·kg~(-1)经颈内动脉注射能诱发大鼠同侧大脑半球脑内血栓形成,明显增加伊文思蓝通过血脑屏障渗入脑实质的量,峰值为205±s 50 mg·kg~1脑组织,相应对照组为10±s 5mg·kg~1,咪苯嗪酮0.25～0.5mg·kg~1 iv能对抗AA引起的大鼠脑血栓形成,显著降低脑实质内伊文思蓝的含量,作用呈剂量依赖性,且强于哒唑氧苯     

Asymmetric synthesis of L‐[4‐13C]glutamic acid and glutamine

L ‐[4‐^l3C]Glutamic acid ( 1 ) and L ‐[4‐¹³C]glutamine ( 2 ) were synthesized from sodium [2‐¹³C]acetate ( 5 ) and Dellaria's oxazinone 3 as a chiral glycine equivalent. Sodium [2‐¹³C]acetate ( 5 ) was converted to [2‐¹³C]acrylate 4 . Diastereoselective Michael addition of the enolate of 3 to the acrylate 4 proceeded with high diastereoselectivity to give the adduct 12 . Reductive cleavage of the C–S bond, ethanolysis, hydrogenolysis and hydrolysis gave L ‐[4‐¹³C]glutamic acid ( 1 ). L ‐[4‐¹³C]Glutamine ( 2 ) was synthesized from 1 in 4 steps. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of three isotopically labeled versions and a metabolite of Aurora A kinase inhibitor

Sodium ring‐[¹⁴C]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoate (1A, MLN8054), an Aurora A kinase inhibitor, was synthesized from [¹⁴C]‐cyanamide in two steps in an overall radiochemical yield of 7%. The intermediate, [¹⁴C]‐4‐guanidinobenzoic acid, was prepared by coupling [¹⁴C]‐cyanamide with 4‐aminobenzoic acid. Sodium carboxyl‐[¹⁴C]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoate (1B) was synthesized from carboxyl‐[¹⁴C]‐4‐guanidinobenzoic acid in one step in a radiochemical yield of 35%. [D₄,¹⁵N]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid (1C) was synthesized from [¹⁵N₂]‐cyanamide and [D₄]‐4‐aminobenzoic acid in two steps in an overall yield of 37%. The major metabolite, β‐acyl glucuronide of 4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid (14), was synthesized from D‐glucuronic acid in three steps in an overall yield of 1%. The key intermediate for synthesis of glucuronide was prepared by HATU catalyzed coupling of 4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid with allyl glucuronate. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of 13C and 15N multilabeled 5‐aminolevulinic acid

5‐[4‐¹³C,¹⁵N]‐ and 5‐[5‐¹³C,¹⁵N]Aminolevulinic acid (ALA) were simply synthesized in four steps by the condensation of [1‐¹³C,¹⁵N]‐ or [2‐¹³C,¹⁵N]glycine, respectively, with phthalic anhydride, followed by conversion to the chloride, coupling reaction with a three‐carbon unit and hydrolysis. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis and biological activity of 5-hydroxy-4-quinolones and 5-methoxy-4-quinolones as truncated acridones

A series of 5-hydroxy-4-quinolone (3) and 5-methoxy-4-quinolone (4) derivatives were synthesized as truncated acridone analogues and evaluated for antitumor, antiherpes and antituberculosis activities. Among them 5-hydroxy-8-methoxy-quinolone showed potent antitumor activity (IC₅₀=17.7 μM for HL60) which was greater than that of acronycine. However, these compounds didn't show any significant antiherpes or antituberculosis activity.