Antimicrobial activity of some substituted triazoloquinazolines.

Fifteen substituted 1,2,4-triazolo[4,3-c]quinazolines were tested for antibacterial and antifungal effects. The most effective derivatives had the triazoloquinazoline skeleton substituted with the pharmacologically active chromophores--morpholine, chlorine and nitro group. The broadest antimicrobial activity was found with 5-morpholin-4-yl-3-(5-nitrothien-2-yl)[1,2,4]triazolo[4,3-c]quinazoline in concentration of 10 mg/L for B. subtilis, 50 mg/L for S. aureus and 100 mg/L for C. tropicalis. The highest tested concentration of derivative caused 83% growth inhibition of R. nigricans.

Biological activity of some 4-anilinoquinazolines: cytotoxic, genotoxic and antiprotease effects, induction of necrosis and changes of actin cytoskeleton.

Fourteen substituted 4-anilinoquinazolines have been tested for cytotoxic effect and structure activity relationships. The most active derivatives were substituted by chlorine or bromine group in the aromatic ring, in the pyrimidine ring by morpholine group and in the aniline skeleton by nitro group in position 4 or 2. Derivatives 6-bromo-2-(morpholin-1-yl)-4-(4'-nitroanilino)quinazoline, 6-bromo-2-morpholin-1-yl)-4-anilinoquinazoline, 2-(morpholin-1-yl)-4-(4'-bromoanilino)-quinazoline and 6-chloro-2-(morpholin-1-yl)-4-(4'-nitroanilino)quinazoline inhibited growth of tumor cell lines HeLa, B16 and L1210. Mutagenic data provided by Ames test showed, that the compounds 6-bromo-2-morpholin-1-yl)-4-anilinoquinazoline and 2-(morpholin-1-yl)- 4-(4'-bromoanilino)quinazoline did not exhibit the mutagenic effect, whereas the compounds 6-bromo-2-(morpholin-1-yl)-4-(4'-nitroanilino)quinazoline and 6-chloro-2-(morpholin-1-yl)-4-(4'-nitroanilino) quinazoline increased slightly the number of revertants of the strain TA 98 without metabolic activation. Concentration 26 micromol/L of 6-bromo-2-(morpholin-1-yl)-4-anilinoquinazoline induced necrosis of tumor cells B16. Concentration 5.2 micromol/l induced a significant increase of filamentous actin in the transformed HepG2 cells. Derivatives 6-bromo-2-(morpholin-1-yl)-4-(4'-nitroanilino)quinazoline, 6-bromo-2-morpholin-1-yl)-4-anilinoquinazoline, 2-(morpholin-1-yl)-4-(4'-bromoanilino)quinazoline and 6-chloro-2-(morpholin-1-yl)-4-(4'-nitroanilino)quinazoline exhibited antiprotease effect on plasmine. This results could be relevant for the anticancer properties of these compounds.

[Antibacterial and antineoplastic activity of 2,4-disubstituted 6H-5,1,3-benzothiadiazocines]. / Antibakteriálna a protinádorová aktivita 2,4-disubstituovaných 6H-5,1,3-benzotiadiazocínov.

Nine 2,4-disubstituted 6H-5,1,3-benzothiadiazocines have been tested for antibacterial and cytotoxic efficacy. None of the tested compounds showed any significant antibacterial activity in comparison with ampicillin. The most cytotoxic effect was manifested by those derivatives which have morpholine or phenyl in position 2 and benzimidazole, imidazole or 1,2,4-triazole in position 4. The highest concentrations of derivatives I, VII, IX induced an acute cytotoxic effect which was manifested by cell lysis after 24 h of culturing. Derivative VII, concentration 30.5 mumol/L, and derivative IX, concentration 13.3 mumol/L, exhibited a delayed cytotoxic effect on L1210 cells. While during the first 24 and 48 h a certain part of cell population proliferated, during further 24 h a total inhibition of cell division was found. The cytotoxic concentration of derivative IX induced damage to the integrity of the cytoplasmic membrane. Benzothiadiazocines I, VII and IX induced a two-phase unbalanced growth. Based on these results, benzothiodiazocines I, VII and IX could be considered new potential anticancer drugs which are appropriate for further research.

Antibacterial effects of trisubstituted quinazoline derivatives.

Five trisubstituted quinazolones and eight trisubstituted quinazoline-4-thiones have been tested for antibacterial effects by a microdilution method. Four derivatives exerted a significant effect on E. coli, P. aeruginosa, S. aureus and B. subtilis (IC50 < 100 mg/L). In the bacterium P. aeruginosa six quinazolines showed a higher antibacterial effect than ampicillin. The most sensitive to the effects of the quinazolines was S. aureus; a concentration of 100 mg/L of six derivatives induced a bacteriostatic effect on S. aureus. The quinazoline-4-thiones were generally more active than the quinazolones. All the tested concentrations of the four most effective quinazolines influenced the specific growth rate.

Antibacterial effect of some substituted tricyclic quinazolines and their synthetic precursors.

Eleven substituted tricyclic quinazolines and their synthetic precursors were tested for antibacterial effects. 3-Chloromethylcarbonyl-2-methylquinazolin-4-thione and 5-phenyl-2,3-dihydro-1,2,4-triazolo[4,3-c]quinazolin-3-one had the highest antibacterial effect against Bacillus subtilis, the MIC values being 50 mg/L. Two tested derivatives were more active against Pseudomonas aeruginosa than ampicillin, the IC50 values being 80 and 100 mg/L. The most effective derivatives contained in the structure generally pharmacologically active chromophores--methyl group in position 2 and a chloromethyl configuration on the carbonyl group in position 3.

Relationships between the structure, cytotoxicity and hydrophobicity of quinazoline derivatives by quantitative structure-activity relationship.

Cytotoxicities of 93 quinazoline derivatives against HeLa cells have been determined as the isoeffective concentrations inhibiting, after a single dose, the protein synthesis to 50% of the control amount after 48 h incubation. The dependence of cytotoxicity on hydrophobicity of the studied derivatives has been described using a previously published model-based approach. The studied derivatives are classified into nine classes each forming a smooth hydrophobicity-cytotoxicity curve. Owing to the acceptable agreement between the model and the data it can be inferred that: (1) the compounds except two derivatives bind to the receptors with approximately the same affinity; (2) the criterion for the classification is the different rate of metabolism. The results represent a basis for a rational development of more potent quinazoline derivatives.

Antiproliferation activity and the mechanism of action of 9-bromo-5-morpholino-tetrazolo[1,5-c]quinazoline--potential anticancer drug.

9-Bromo-5-morpholino-tetrazolo[1,5-c]quinazoline (BMTQ) at the two highest tested concentrations (74.6; 29.8 mumol@l) induced retarded cytotoxic effect. After 24 hours of culturing 23.1-98.8% of the cell population proliferated but after 48 and 72 hours 6.4-80.4% of the cell population degenerated. Other concentrations induced toxicity that was concentration-and time-dependent. The cytolytic concentrations of BMTQ induced integrity damage of cytoplasmatic membrane. The inhibition of cell cycle and the elevated content of proteins in the cell exposed to the cytotoxic concentrations of BMTQ suggest that the cells synthesize protein without entering into mitosis and that dying cells are in the S-phase before death. BMTQ induced 1.75-3.01 times increase of the level of ssDNA in comparison with the control.

Antibacterial effect of substituted 4-quinazolyl-hydrazines and their arylhydrazones determined by a modified microdilution method.

Eight 4-quinazolylhydrazines and eleven their arylhydrazones have been tested for antibacterial effects and for structure-activity relationships by a modified microdilution method. The derivative 6-chloro-2-morpholino-4-quinazolyl-5'-nitro-2'-furylhydrazone++ + had the highest antibacterial effect, the MIC values being 100 mg/L for E. faecalis, 250 mg/L for S. aureus, 200 mg/L for P. aeruginosa and 350 mg/L for E. coli. The most effective derivatives were those with the benzene ring substituted with chlorine or methyl group in position 6 or 8 and with pyrimidine ring substituted with a secondary amine in position 2. The modified microdilution method did not give rise to any statistically significant deviations in the MIC values for ampicillin in comparison with reported reference collection values.

Antimicrobial effects of new 1-(1,2,4-triazol-1-yl)-acetanilides.

Fourteen synthetically prepared 1-(1,2,4-triazol-1-yl)acetanilides were tested for antimicrobial effect. None of the prepared derivatives influenced the B. subtilis, P. fluorescens nor the tested yeasts. Only the derivatives with substituents in positions para or ortho and para were biologically effective. The widest antimicrobial spectrum was manifested by the pentachloro derivative, which was effective with G+ and G- bacteria and with filamentous fungi.

Structure-activity relationships of some 4-quinazolylthiosemicarbazides and their triazolo derivatives.

Eight 4-quinazolylthiosemicarbazides and nine of their structural analogues have been tested for antibacterial effects and for structure activity relationships. 9-Chloro-5-morpholino-1,2,4-triazolo[4,3-c]quinazoline-3-thione has demonstrated the highest antibacterial effect (MIC of 1 mg/L for E. coli and P. mirabilis and < 1 mg/L for S. aureus and B. subtilis). The most effective derivatives have the carbon aromatic ring substituted with chlorine and the pyrimidine ring with morpholine or with secondary amine group.