The synthesis and antifungal activities of new 1,5-diarylpyrrole derivatives are reported. Antimicrobial data in comparison with pyrrolnitrin show that only carboxamide derivatives exhibit satisfactory antifungal activity. By contrast all tested compounds show very poor antibacterial activity. The displacement of NO2 group from para to meta or ortho position of the aryl at C5 of the pyrrole ring affects the antimicrobial activity.
The synthesis of a new class of potential angiotensin converting enzyme (ACE) inhibitors, analogs of enalapril, is reported. In these molecules the C-terminal amino acidic sequence Ala-Pro of enalapril was replaced by the sequence Pro-Pro. The compounds were tested both in vitro and in vivo. They showed no in vivo activity but only a week in vitro inhibitory activity.
The synthesis of title compounds (VI) by 1,4-cycloaddition of phenylchloroketene to N,N-disubstituted (E)-2-aminomethylene-3,4-dihydro-(6-methoxy)-1(2H)naphthalenones, followed by dehydrochlorination with DBN and dehydrogenation with Pd/C of the resulting cycloadducts, is described. Some compounds (VI) showed antiarrhythmic activity in rats higher or like that of quinidine and platelet antiaggregating activity in vitro like that of acetylsalycilic acid, as well as moderate infiltration anesthesia in mice and weak hypotensive, bradicardic and antiinflammatory activities in rats.
Several S ‐aryl(tetramethyl)isothiouronium salts were synthesized. In vitro some of the compounds revealed interesting antibacterial activities.
Teicoplanin is a complex formed by five closely related glycopeptides and by a small amount of a hydrolysis product. Minor quantities of related substances are also present. Two of them (named RS-1 and RS-2) were isolated and purified starting from the tailing fractions of a teicoplanin batch. Preparative reversed-phase liquid chromatography on large low-pressure and medium high-pressure scales, concentration, desalting, and freeze-drying steps were applied. 300 mg of RS-1 and 900 mg of RS-2 were obtained in a purity grade (about 90%) sufficient for structural investigation. Starting from considerations on the HPLC retentivity and on biosynthesis, the structures were assigned on the basis of 1H-N.M.R. spectra and homonuclear CO-SY 2D experiments, FAB-MS spectrometry, and GC-MS of the esters of the fatty acids obtained by hydrolysis. RS-1 and RS-2 are teicoplanins having 10-methyl-undecanoic acid and n-dodecanoic acid, respectively as fatty acid chains. No major difference in the in vitro activity of these teicoplanins emerged in comparison with teicoplanin complex.
A series of 3-aryl-6-alkoxy- and some 3-aryl-6-thioalkyl-, 3-aryl-6-alkylsulphinyl-, and 3-aryl-6-alkylsulphonyl-1,2,4-triazolo[3,4-a]phthalazines were synthesised and tested for inhibition of the in vitro binding of 3H-Diazepam to benzodiazepine receptors in membranes isolated from rat brain synaptosomes. 6-Alkoxy-3-(4'-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazines were more active than or as active as diazepam in the binding assay (Ki nM) but unlike diazepam their binding to the benzodiazepine receptors was not enhanced by 4-aminobutyric acid. These compounds did not antagonize pentylenetetrazole induced convulsions and were inactive in modifying the conditioned behaviour of rats. Compound (II a) counteracted the muscle relaxant effects of diazepam (traction test). These results suggest that (II a) may be a benzodiazepine receptor antagonist.
Amidinosemicarbazido derivatives of pyrazole having various substituents on pyrazole ring were prepared and their effect on platelet function and blood coagulation was determined in vitro. Platelet aggregation and serotonin release induced by ADP, collagen, arachidonic acid and thrombin were markedly inhibited by pyrazole derivatives at mM concentrations. Compounds with a hydrophobic nucleus at position 1 of the pyrazole ring showed the most potent antiplatelet activity. On the contrary, their effect on blood coagulation was faintly inhibitory.
New 5-aryl-6-methyl-4,5-dihydropyridazin-3(2H)ones (III) and related 5-aryl-6-methyl-pyridazin-3(2H)ones (IV) were synthesized in order to evaluate their pharmacological profile in comparison with that of the known class of antihypertensive and platelet aggregation inhibitors 5-methyl-6-aryl-4,5-dihydropyridazin 3(2H)ones (I). Though none of the tested derivatives was found to possess the antihypertensive potency of the reference compounds, some of them displayed significant antithrombotic and antiulcer properties. In particular, 5(p. acetylaminophenyl)-6-methyl-pyridazin-3-one (IV c) was found highly effective (ED50 = 1.2 mg/kg) in inhibiting indomethacin-induced ulcers.
This report describes the effects of a fungal polysaccharide mixture on the Experimental Allergic Encephalitis (EAE) in guinea pigs. The clinical, histopathological and IgG intrathecal synthesis related studies in the EAE sensitized group was compared with that observed in EAE sensitized groups treated with fungal polysaccharides. The results indicate that the fungal polysaccharide mixture is capable of inducing a more localized and milder inflammatory reaction in the guinea pig with EAE. We hypothesize that the fungal polysaccharides can activate complement by the alternative pathway, subtracting it to the specific immune response to EAE.
The synthesis, structure and biological activities of a series of derivatives of normorphine, noracetylmethadol (IV a), 6-amino-4,4-diphenyl-3-heptanol acetate (V a), and norpropoxyphene (VI a), in which the corresponding nitrogen supports an alkylating group (chloroethyl or fumaroyl) are reported. Structural identification was achieved spectroscopically. 13C Nuclear Magnetic Resonance proved the most useful tool in this task. N-Chloroethylnoracetylmethadol (IV c), acted as a potent long-lasting analgesic. Although some compounds (IV c), (V c) and (V d) showed substantial cytostatic activity, no antineoplastic activity in mice with P388 leukaemia was detected in the series.
Sixteen 2-(4'R')phenyl-5R-benzimidazoles and two 2-(4'-pyridinyl)-5R-benzimidazoles were prepared and tested, together with 2-phenylbenzimidazole, for their activity on the acquisition of a conditioned avoidance response in rats and for analgesic activity in mice, and compared with chlorpromazine and acetylsalicylic acid. Several compounds inhibit strongly the acquisition of a C.A.R., with 2-(4'-alkoxy)phenylbenzimidazoles (XVI) and (XVII) clearly exceeding chlorpromazine. Analgesic activity is also generally present in the examined compounds; those bearing in the position 5 a trifluoromethyl or an acetyl group exhibit an activity higher than that of acetylsalicylic acid. Deconditioning and analgesic activities are not correlated with each other.
A series of 6-aryl-3,8-disubstituted-1,2,4-triazolo[3,4-a]phthalazines was synthesised starting from suitable o-benzoylbenzoic acids. The compounds were tested in vitro for inhibition of the specific binding of 3H-Diazepam to benzodiazepine receptors in preparations of membranes from rat brain synaptosomes. None of the compounds was notably active in this test.
The synthesis of a few derivatives of the angiotensin converting enzyme inhibitor enalapril is described. In these molecules the chelating carbethoxy group is substituted with an imidazolyl one. The compounds were tested both in vitro and in vivo. None of them showed in vivo activity but only a marginal in vitro inhibitory activity.
Some N-acylderivatives of 4-aroylanilines were prepared and tested for phytoiatric antimycotic activity. The substances, most unknown, were subjected to in vitro and in vivo tests (in preventive phase). The compounds studied proved to have interesting activity.
The cytostatic activity of several triterpenequinone methides isolated from Rzedowskia tolantonguensis and Maytenus horrida (Celastraceae) was evaluated against HeLa cell cultures. Their ID50 were determined and compared with those of other related compounds. A preliminary study of the antibacterial activity of the above triterpenequinone methides was also carried out.
Twelve new fluoroquinolones, structurally related to norfloxacin, have been synthesized in order to investigate the effect of substituents at the secondary nitrogen of the piperazine ring on antimicrobial activity. The new substances (carbamates, isoureas, guanidines, ureas and cyanamides) tested on a variety of gram-positive and gram-negative organisms showed lower activity than the model compound.
The central effects of carboxyethyl-gamma-aminobutyric acid (CEGABA) have been studied both in rabbits and in the guinea pig myoclonus model. This drug caused EEG synchronization and behavioural sedation both after intravenous (i.v.) and intracerebroventricular (i.c.v.) administration in a dose-dependent manner, in rabbits. CEGABA showed a protective action against myoclonus induced by means of L-5-HTP in young guinea pigs. These data substantiate the hypothesis that CEGABA is a drug active on the central nervous system and probably exerts its action by strengthening cortical inhibition and/or directly acting on lower brainstem.
Khellin, a naturally occurring furochromone, used in the past as a coronary vasodilator, has recently been used in the photochemotherapeutic treatment of vitiligo and psoriasis. With the aim of elucidating its mechanism of action, the interactions both in ground and excited states between the drug and DNA were studied in vitro. Khellin forms in the dark a molecular complex with DNA. By subsequent irradiation (365 nm) the drug photoconjugates covalently with the macromolecule, although the rate of photobinding is rather low. The in vivo photobinding of khellin to the DNA of Ehrlich ascites tumor cells is also low. In photoaddition with the macromolecule the drug forms inter-strand cross-links, although again in small amounts. The furan side monoadduct between khellin and thymine, formed in the photoreaction between the drug and DNA, was isolated and characterized, and shows a cis-syn configuration.
Esters and amides of N-(3,3-dimethyl-1-triazeno)benzoylamino acids have been synthesized as inhibitors of cell surface neutral proteases. Preliminary data on activity against P-388 lymphocytic leukemia are also reported.
