Synthesis and anticonvulsant activity of new acylthiosemicarbazides and thiazolidones

A number of 1-(3-phenyl-4(3H)-quinazolinone-2-ylmercaptoacetyl)-4-substituted thiosemicarbazide and 2-(3-phenyl-4(3H)-quinazolinone-2-ylmercaptoacetylhydrazono)-3-sub stituted 4-thiazolidone derivatives were synthesized and evaluated for anticonvulsant activity. Some of the tested compounds showed significant activity against MES and ScMet induced seizures.     

Synthesis and anticonvulsant activity of a new class of 2-[(arylalky)amino]alkanamide derivatives

Although most epilepsies are adequately treated by conventional antiepileptic therapy, there remains an unfulfilled need for safer and more effective anticonvulsant agents. Starting from milacemide, a weak anticonvulsant, and trying to elucidate its mechanism of action, we discovered a structurally novel class of potent and preclinically safe anticonvulsants. Here we report the structure-activity relationship (SAR) study within this series of compounds. Different parts of the structural lead 2-[[4-(3-chlorobenzoxy)benzyl]amino]acetamide (6) were thus varied (Figure 1), and many potent anticonvulsants were found. As an outcome of this study, 57 ((S)-2-[[4-(3-fluorobenzoxy)benzyl]amino]propanamide methanesulfonate, PNU-151774E) emerged as a promising candidate for further development for its potent anticonvulsant activity and outstanding therapeutic indexes (TIs) in different animal tests.     

Synthesis of N-aryl-N'-heteroaryl-substituted urea and thiourea derivatives and evaluation of their anticonvulsant activity

Starting from amino(di)azines and 2-chloro-6-methyliso(thio)cyanate a series of aryl-substituted urea and thiourea derivatives was prepared and screened as potential antiepileptics. Among the new derivatives tested, only 2b and 3c exhibited adequate anticonvulsant effects, whereas 3d and 4d were found to be convulsants per se.     

Synthesis and anticonvulsant effects of some aminoalkanolic derivatives of xanthone

Synthesis and physicochemical properties of alkanolamine derivatives of xanthone are described. Alkanolamines were synthesized by of the reaction of an appropriate aminoalcohol with corresponding 2-bromomethylxanthones. The obtained compounds 1-13 were evaluated for anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure threshold (scMet) assays and for neurotoxicity (TOX). Several alkanolamines were found to be active in both the anticonvulsant tests. Most interesting were the 2-amino-1-propanol-, 1-amino-2-propanol- or 1-amino-2-butanol derivatives of 6-methoxy- or 6-chloroxanthone, which displayed anti MES activity with a protective index (TD50/ED50) in the range 2.21-5.84 corresponding with that for phenytoin, carbamazepine and valproate.     

Synthesis of some indane derivatives of central muscle relaxant and anticonvulsant profiles

A series of 2,2-bis(hydroxymethyl)indane derivatives 1a-f, 2a-e and 3a-f were synthesized to investigate their central muscle relaxant and anticonvulsant activities. The synthesized compounds 1a-f, 2a-e and 3a-f were found to be devoid of central muscle relaxant activity using meprobamate (100 mg/kg) as a reference standard. However, they showed remarkable anticonvulsant properties in a dose of 80 mg/kg (s.c.) compared with diphenylhydantoin sodium (80 mg/kg) as a reference standard.     

Synthesis and anti-inflammatory activity of chalcone derivatives

This is a report on the surgical intervention in 79 patients with acute pancreatitis, who were operated in the Department of Surgery of the University Clinic RWTH Aachen in the period from 1986 to 1993. The main objective was the stratification of pancreatitis according to the Ranson-Score, the analysis of the surgical treatment and the timing of operation depending on the clinical condition. The average Ranson-score was 3.3 (median 3). 56 patients had necroses, which were removed because of the deteriorating clinical condition. In these cases the average Ranson-score was 4.2 (median 4). Seven patients (8.9% of the total number and 12.5% of the patients with necroses of the pancreas) died. This small number is the result of a severity-adapted management in a modern intensive care-unit and the good cooperation with the Department of Internal Medicine.     

Synthesis of new alpha-hydrazinoarylacetic acids and derivatives

The synthesis of some alpha-hydrazinoarylacetic acids (I) by reaction of alpha-bromoarylacetic acids with hydrazine, alkylhydrazines and carbobenzyloxyhydrazines is described. Reduction of the hydrazones of 2- and 3-thienylglyoxylic acids provided a general and effective route to the thienylic series. In view of the use of compounds (I) for the preparation of new penicillins, the experimental conditions for their conversion into cyclohexylamides (XI) via the corresponding carbobenzyloxyderivatives (III) were also investigated.     

Synthesis and antimicrobial activity of new tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives

A series of 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thiones was synthesized and evaluated for antibacterial and antifungal activity. All of the tested compounds were found active against Staphylococcus aureus and Staphylococcus epidermidis. The compounds were also active against yeast-like fungi and molds where the anticandidal activity of 3a against Candida albicans was superior to the standards miconazole and clotrimazole.     

Synthesis and antitumor activity of novel benzophenone derivatives

Novel benzophenone derivatives were synthesized and screened for cytotoxic and antitumor activity. Friedel-Crafts condensation was employed to construct the benzophenone skeleton. Among the compounds synthesized, morpholino and thiomorpholino benzophenones 3a-d exhibited potent cytotoxic activity against P388 murine leukemia and PC-6 human lung carcinoma cells in vitro, and compounds 3a, 3c, and 3j, when administered intraperitoneally, showed significant antitumor activity against the malignant ascites caused by intraperitoneal inoculation of P388 cells in mice.     

Synthesis and antiestrogenic activity of diaryl thioether derivatives

The reaction of 1,2-diarylethanol and mercapto side chain catalyzed by ZnI2 was used as a key step in the short (three to five steps) and efficient synthesis of 17 diaryl thioether derivatives. Several of these compounds contain a methyl butyl amide chain and an hydroxyaryl moiety, respectively, for antiestrogenic activity and binding affinity on estrogen receptor. No binding affinity for crude cytosolic preparation of the estrogen receptor was observed for compounds without phenolic group, while a low affinity (0.01-0.05%) was measured for mono- or diphenol derivatives. Like the pure steroidal antiestrogen EM-139, these novel nonsteroidal compounds did not exert any stimulatory effect on cell proliferation of (ER+) ZR-75-1 human breast cancer cells and partially reversed the amplitude of the stimulatory effect induced by estradiol on this (ER+) cell line. No proliferative or antiproliferative effect on (ER-) MDA-MB-231 human breast cancer cells was also observed for three of these compounds (39-41). Among the newly synthesized nonsteroidal compounds, the thioether derivative 41 (N-butyl-N-methyl-13,14-bis(4'-hydroxyphenyl)-12-thiatetradecanamide+ ++), with a long methylbutylalkanamide side chain and a diphenolic nucleus, was selected as the best antiestrogenic compound. However, this compound was 100-fold less antiestrogenic in (ER+) ZR-75-1 cells than the steroidal antiestrogen EM-139.     

Synthesis and anti-inflammatory evaluation of new sulfamoylheterocarboxylic derivatives

A series of new sulfamoylthiophene and sulfamoylpyrazole carboxylic acid derivatives was synthesized. Some of these compounds show interesting analgesic properties and significant nonsteroidal anti-inflammatory activities in several models of inflammation.     

Synthesis and antitumour activity of new derivatives of flavone-8-acetic acid (FAA). Part 2: Ring-substituted derivatives

A range of 18 derivatives of flavone-8-acetic acid (FAA) with substituents on the 2-phenyl group have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. There was no clear-cut relationship between in vitro and in vivo activity but the activity in each situation was found to be very sensitive to the precise substitution pattern with closely related isomers giving widely different activities. Some of the compounds, notably 10b,c,j, and r, were active in vivo and these require further studies in order to evaluate their potential for development.     

Synthesis and in vitro anthelmintic activity against Nippostrongylus brasiliensis of new 2-amino-4-hydroxy-delta-valerolactam derivatives

The synthesis of a series of 2-amino-4-hydroxy-delta-valerolactam derivatives is described (compounds 4 to 10). These compounds showed a high anthelmintic in vitro activity against the Nippostrongylus brasiliensis model.     

Synthesis and antituberculosis activity of thiocarboxamide derivatives of Schiff bases

Synthesis of some N-(4-thiocarboxamidobenzylidene)arylamines and N-(substituted benzylidene)-p-thiocarboxamidoanilines from various arylaldehydes and arylamines is described. Fourteen representative compounds were tested in vitro on the ground H37RV.     

Synthesis and aldose reductase inhibitory activity of benzoyl-amino acid derivatives

Discoid lupus erythematosus (DLE) is an uncommon disease in childhood. We present two patients initially diagnosed as impetigo and photosensitive eczema with impetigo, respectively, who failed to respond to topical and systemic antistaphylococcal agents and in whom a diagnosis of discoid lupus erythematosus subsequently became apparent.     

Synthesis and analgesic properties of new 5-thioaryl pyrazole derivatives

A new series 5-thio aryl pyrazole derivatives were proposed aiming analgesic activity. In this work, 8 new compounds of this class were synthesized using usual synthetic methodology, having as key intermediate the 3-methyl-4-nitro-5-chloropyrazole-1-phenyl derivative and subsequent reaction with several nucleophiles sulfides. Pharmacological evaluation of this series showed analgesic activity in the some extent in especially for 5-(4-bromophenyl)-thio-3-methyl-4-nitro-1-phenylpyrazole which was the most potent in this series, presenting an analgesic action comparable to that show by dipyrone.     

Synthesis and antioxidant activity of novel amphipathic derivatives of tea polyphenol

Hydrophobic derivatives of a tea polyphenol have been synthesized. 6, 8-Bis(octylthiomethyl)-epigallocatechin 3-O-gallate, 6, 8-bis(octylthiomethyl)-4 beta-(2-hydroxyethylthio)epigallocatechin 3-O-gallate and epigallocatechin 3-O-[4-O-(N-octadecylcarbamoyl)gallate] showed strong inhibition activity against lipid peroxidation of liposome caused by both lipid-soluble and water-soluble radical generators.