ABSTRACT
A number of new 3-(1-R-3(5)-methyl-4-nitroso-1H-5(3)-pyrazolyl)-5-methylisoxazoles 6a-g (7b-f) were synthesized and tested for antibacterial and antifungal activity. Some of these compounds displayed antifungal activity at non-cytotoxic concentrations. Derivative 6c was 9 times more potent in vitro than miconazole and 20 times more selective against C. neoformans. 6c was also 8- and 125-fold more potent than amphotericin B and fluconazole, respectively. None of the compounds was active against bacteria. Preliminary structure-activity relationship (SAR) studies showed that the NO group at position 4 of the pyrazole ring is essential for the activity. Lipophilicity of the pyrazole moiety, N-alkyl chain length and planarity of the two heterocyclic rings appear to play a decisive role in modulating cytotoxicity and antifungal activity.
Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Anti-Bacterial Agents , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antifungal Agents/chemistry , Cryptococcus neoformans/drug effects , Fungi/drug effects , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , HIV-1/drug effects , Humans , Isoxazoles/chemistry , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
The new of 1-(2-hydroxyethoxy)methylindole derivatives 3a-i were prepared in good yields. None of them showed any significant anti-HIV activity and therefore the benzocondensation between the 2 and 3 positions of the pyrrole ring definitely reduced the weak activity found in the analogues 1a-c.
Subject(s)
Anti-HIV Agents/chemistry , Indoles/chemistry , Pyrroles/chemistry , Animals , Anti-HIV Agents/pharmacology , Cell Line , Chlorocebus aethiops , Cytopathogenic Effect, Viral/drug effects , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , HIV-1/drug effects , HIV-1/pathogenicity , Humans , Microbial Sensitivity Tests , Pyrroles/pharmacology , Vero Cells , Virus Replication/drug effectsABSTRACT
Acyclic glycosidopyrroles of type 1, synthesized in good overall yields, were evaluated for anti-viral activity. Compound 10i was found to inhibit the HIV-1 replication at concentrations that were very close to those cytotoxic for MT-4 cells. Compounds 10a,f,i inhibited both strains HSV-1 and HSV-2 at concentrations slightly below those cytotoxic for Vero cells. However for this series of glycosidopyrroles some relationship between calculated log P values and the observed cytotoxicity was found.
Subject(s)
Antiviral Agents/chemical synthesis , Pyrroles/chemical synthesis , Animals , Antiviral Agents/pharmacology , Chlorocebus aethiops , Pyrroles/pharmacology , Vero CellsABSTRACT
Acyclic glycosidopyrroles of type 3 were synthetized in good overall yields, according to the Scheme. When evaluated for antiviral activity against DNA and RNA viruses, only compound in which R1 = R2 = Ph, R3 = NH2 was found to inhibit the HIV-1 replication at concentrations that were not cytotoxic for MT-4 cells.
Subject(s)
Antiviral Agents/chemical synthesis , Ganciclovir/analogs & derivatives , Antiviral Agents/pharmacologyABSTRACT
The series of 1-(1,3-dihydroxy-2-propoxy)methylpyrroles 2a-o were prepared in good overall yields according to Scheme I. When evaluated for antiviral activity against HIV-1, only compounds of the triphenyl series (R3 = NH2, N3, Br) were found to inhibit the HIV-1 replication at concentrations that were very not cytotoxic for MT-4 cells, with selectivity index 1.5-9.3. None of these compounds showed antibacterial or antifungal activity.
Subject(s)
Anti-HIV Agents/pharmacology , Pyrroles/pharmacology , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Chlorocebus aethiops , HIV-1/drug effects , HIV-1/physiology , Humans , Pyrroles/chemical synthesis , Pyrroles/chemistry , Vero Cells , Virus Replication/drug effectsABSTRACT
3-Diazopyrroles, a class of compounds particularly interesting from a chemical and biological point of view, were assayed for their ability to induce gene mutations employing back mutation (his+ reversion) test in the philamentous bacterium Streptomyces coelicolor at various time during life cycle. Our results suggest that in evaluating the mutagenicity and toxicity of chemicals in Streptomyces system it is important to consider factors such as growth phase. Furthermore in this series of diazopyrroles a relationship between toxicity, mutagenicity and chemical structure was found. The observed mutagenic activity can be the molecular basis for the appearance of antitumor activity.
Subject(s)
Azo Compounds/chemical synthesis , Mutagens/chemical synthesis , Pyrroles/chemical synthesis , Streptomyces/genetics , Azo Compounds/pharmacology , Mutagenicity Tests , Mutagens/pharmacology , Pyrroles/pharmacology , Streptomyces/drug effects , Streptomyces/growth & development , Structure-Activity RelationshipABSTRACT
Indolo[3,2-c]cinnolines of type 5, variously substituted either in the indole and in the cinnoline moieties, were prepared in good overall yields, by intramolecular cyclization of indolo derivatives 4. Compounds 5a-d showed a good cytotoxic activity against FLC and K562 leukemic cell lines, both sensitive and multi-drug resistant.
Subject(s)
Antineoplastic Agents/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Leukemia/drug therapy , Antineoplastic Agents/pharmacology , Humans , Tumor Cells, CulturedABSTRACT
Pyrrolo-, pyrazolo- and triazolo-phenanthridines were synthetized by using a Pschorrtype cyclization reaction or an intramolecular cyclization of arylnitrenium ions. By using these synthetic methods several azolo-phenanthridines, variously functionalized either in the azolo ring and in the phenanthridine moiety, were prepared. The title compounds, tested against murine leukemia cell lines, sensible and multidrug resistant, showed moderate activity with IC50 in the range 5-50 microM.
