Antibacterial effect of substituted 4-quinazolylhydrazines 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 modifed 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 forE. fœcalis, 250 mg/L forS. aureus, 200 mg/L forP. aeruginosa and 350 mg/L forE. 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. Dedicated to Professor Vladimír Betina, DSc. on the occasion of his 65th birthday     

Antimicrobial effects of the macrocyclic Cu(II)-tetraanhydroaminobenzaldehyde complex

The Cu(II)-tetraaza macrocyclic complex exhibited antimicrobial effects on bacteria, yeasts and filamentous fungi. The highest antibacterial activity was found withB. subtilis andS. aureus, the respective IC₅₀ values being 18 and 80 μg/L and the MIC values 50 and 1000 μg/L. A concentration of 1 mg/L exerted a bacteriocide effect onS. aureus. The MIC value forB. subtilis was 250 times lower and forP. aeruginosa 10 times lower than the corresponding values for ampicillin. The Cu-complex was inactive against all tested yeasts. The strongest antifungal effect was manifested forR. nigricans, with an IC₅₀ value under 0.1 mg/L, whereas inA. alternata the IC₅₀ was 13.5 mg/L.     

Inhibition of yeast-mycelium transformation by 2-alkylthio-6-amino-and 2-alkylthio-6-formamidobenzothiazoles and theirin vitro antifungal activity

The antifungal effect of 2-alkylthio-6-amino-and 2-alkylthio-6-formamidobenzothiazoles (22 derivatives in all) onAspergillus niger and variousCandida yeasts was tested. No significant effect was observed withA. niger. With the pathogenic yeast speciesC. albicans andC. guilliermondii, the most efficient derivatives (6-formamido-2-propylthio-, 6-formamido-2-butylthio-, 6-formamido-2-pentylthio-and 6-formamido-2-isopentylthiobenzothiazole) exhibited ED₅₀ values in the range from 2.2 to 21 mg/L and were thus 3–35 times more efficient than 2-mercaptobenzothiazole (Dermacid) that is normally used. 6-Amino-2-pentylthiobenzothiazole was found to be an efficient specific inhibitor of the transformation of the yeast form ofC. albicans to its mycelial one, IC_95(M) being 10 mg/L, which was a concentration 25 times lower than MIC_Y+M.     

Antibacterial and mutagenic activities of new isothiocyanate derivatives

Nine newly synthetized isothiocyanate derivatives were demonstrated to posses antibacterial and genotoxic activitiesin vitro. 4-Hydroxybutyl isothiocyanate exhibited a broad antibacterial effect, with MIC values of 762 μmol/L forStaphylococcus aureus andEscherichia coli. Ethyl 4-methylsulfoxidobutanoate had the highest antibacterial activity in Gram-positive bacteria, the MIC value being 425 μmol/L forS. aureus. The highest tested concentrations of ethyl 4-isothiocyanatobutanoate and 4-hydroxybutyl isothiocyanate produced a bacteriocidal effect in Gram-positive bacteria. The compounds showed no mutagenic effects onSalmonella typhimurium tester strains TA 98 and TA 100, either in the absence or in the presence of a metabolically active microsomal S9 fraction from rat liver using standard Ames test.     

Synthesis,Anti-Oomycete and Anti-fungal Activities of Novel Cinchona Alkaloid Derivatives Containing Sulfonate Moiety

Using cinchona alkaloid as the lead compound, twenty-four cinchona alkaloid sulfonate derivatives ( 1 a – l , 2 a – c , 3 a – c , 4 a – c , and 5 a – c ) were designed and prepared by modifying their C9 position, and structurally confirmed by ¹H-NMR, ¹³C-NMR, HR-MS and melting points. Moreover, the stereochemical configurations of compounds 1 f and 1 l were unambiguously confirmed by single-crystal X-ray diffraction. Furthermore, we determined the anti-oomycete and anti-fungal activities of these target compounds against Phytophthora capsici and Fusarium graminearum in vitro. The results showed that two compounds 4 b and 4 c exhibited prominent anti-oomycete activity, and the median effective concentration (EC₅₀) values of 4 b and 4 c against P. capsici were 22.55 and 16.32 mg/L, respectively. This study suggested that when the C9 position of cinchona alkaloid sulfonate derivatives is in the S configuration and the 6′-position methoxy group is not present, the anti-oomycete activity is superior. In addition, five compounds 1 e , 1 f , 1 k , 3 c and 4 c displayed significant anti-fungal activity, with EC₅₀ values of 43.64, 45.07, 80.18, 48.58 and 41.88 mg/L against F. graminearum, respectively. This result indicates that only when a specific substituent is introduced into the structural framework of the target compound, the corresponding compound exhibits significant inhibitory activity against fungi.     

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.     

Synthesis and Anti-Oomycete Activity of 1-Sulfonyloxy/Acyloxydihydroeugenol Derivatives

Endeavor to discover biorational natural products-based fungicides, two series (26) of novel 1-sulfonyloxy/acyloxydihydroeugenol derivatives ( 3a – p and 5a – j ) were prepared and assessed for their fungicidal activity against P. capsici Leonian, in vitro. Results of fungicidal activity revealed that, among all compounds, especially compounds 3a , 5c , and 5e displayed the most potent anti-oomycete activity against P. capsici with EC₅₀ values of 69.33, 68.81, and 67.77 mg/L, respectively. Overall, the anti-oomycete activities of 1-acyloxydihydroeugenol derivatives ( 5a – j ) were higher than that of 1-sulfonyloxydihydroeugenol derivatives ( 3a – p ). It is proved that the introduction of the acyl group at hydroxy position of dihydroeugenol is more beneficial to improve its anti-oomycete activity than that of the sulfonyl group. These preliminary results will pave the way for further modification of dihydroeugenol in the development of potential new fungicides.     

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

Eigh 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 hightest antibacterial effect (MIC of 1 mg/L forE. coli andP. mirabilis and <1 mg/L forS. aureus andB. subtilis). The most effective derivatives have the carbon aromatic ring substituted with chlorine and the pyrimidine ring with morpholine or with secondary amine group.     

Antiproliferative and antibacterial activity of some glutarimide derivatives

Antiproliferative and antibacterial activities of nine glutarimide derivatives (1–9) were reported. Cytotoxicity of compounds was tested toward three human cancer cell lines, HeLa, K562 and MDA-MB-453 by MTT assay. Compound 7 (2-benzyl-2-azaspiro[5.11]heptadecane-1,3,7-trione), containing 12-membered ketone ring, was found to be the most potent toward all tested cell lines (IC₅₀?=?9–27?μM). Preliminary screening of antibacterial activity by a disk diffusion method showed that Gram-positive bacteria were more susceptible to the tested compounds than Gram-negative bacteria. Minimum inhibitory concentration (MIC) determined by a broth microdilution method confirmed that compounds 1, 2, 4, 6–8 and 9 inhibited the growth of all tested Gram-positive and some of the Gram-negative bacteria. The best antibacterial potential was achieved with compound 9 (ethyl 4-(1-benzyl-2,6-dioxopiperidin-3-yl)butanoate) against Bacillus cereus (MIC 0.625?mg/mL; 1.97?×?10^?3?mol/L). Distinction between more and less active/inactive compounds was assessed from the pharmacophoric patterns obtained by molecular interaction fields.     

Effect of structure on antibiotic action of new 9-(ethylthio)acridines

Six new 9-(ethylthio)acridine derivatives were examined for antibacterial and antifungal activities with 10 bacterial and 8 yeast strains. The only active compounds were 2-and 3-amino derivatives. The observed MICs (mg/L) for 2-amino-9-(ethylthio)acridine (possessing the highest biological activity) were 12 (P. mirabilis), 30 (B. subtillis), 60 (C. freundii), 90 (E. coli), 128 (E. vulneris) and 500 (S. marcescens andS. aureus). Both amino derivatives have also lowest half-wave potential (E _1/2) and field Swain-Lupton constants (describing oxidoreduction behavior) what supports the importance of acridine ion formation in the mechanism of antimicrobial action.     

Synthesis and antileishmanial activity of novel pyridinium-hydrazone derivatives

A series of substituted phenylethylidenehydrazinylpyridinium derivatives bearing methyl, ethyl, propyl, and propylphenyl groups on the pyridinium nitrogen were synthesized and evaluated for in vitro antileishmanial activity against Leishmania tropica by using the microdilution method. Among the tested compounds, 3d, 5c, 3b, and 3c were found to be the most active derivatives against the promastigotes of L. tropica (IC₅₀ values are 6.90, 9.92, 11.69 and 12.03 µM, respectively) and to be more active than reference drug meglumine antimonaite (glucantime) (IC₅₀ value: 20.49 µM). The derivatives investigated in this study may have the potential to be lead compound against leishmanial infection.     

Naphthalene Derivatives and Quinones from Ventilago denticulata and Their Nitric Oxide Radical Scavenging,Antioxidant, Cytotoxic,Antibacterial, and Phosphodiesterase Inhibitory Activities

New naphthalene derivatives ( 1 and 2 ) and a new isomer ( 3 ) of ventilagolin, together with known anthraquinones, chrysophanol ( 4 ), physcion or emodin 3‐methyl ether ( 5 ), and emodin ( 6 ), were isolated from vines of Ventilago denticulata. The isolated compounds exhibited cytotoxic activity with IC₅₀ values of 1.15 – 40.54 μg/ml. Compounds 1 – 3 selectively exhibited weak antibacterial activity (MIC values of 200.0 – 400.0 μg/ml), while emodin ( 6 ) displayed moderate antibacterial activity with MIC value of 25.0 μg/ml. The isolated compounds showed nitric oxide and DPPH radical scavenging activities. Compounds 1 – 3 and 6 exhibited weak xanthine oxidase inhibitory activity, while emodin ( 6 ) acted as an aromatase inhibitor with the IC₅₀ value of 10.1 μm . Compounds 1 and 2 exhibited phosphodiesterase 5 inhibitory activity with IC₅₀ values of 8.28 μm and 6.48 μm , respectively.     

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.     

Benzimidazole derivatives endowed with potent antileishmanial activity

Two sets of benzimidazole derivatives were synthesised and tested in vitro for activity against promastigotes of Leishmania tropica and L. infantum. Most of the tested compounds resulted active against both Leishmania species, with IC₅₀ values in the low micromolar/sub-micromolar range. Among the set of 2-(long chain)alkyl benzimidazoles, whose heterocyclic head was quaternised, compound 8 resulted about 100-/200-fold more potent than miltefosine, even if the selectivity index (SI) versus HMEC-1 cells was only moderately improved. In the set of 2-benzyl and 2-phenyl benzimidazoles, bearing a basic side chain in position 1, compound 28 (2-(4-chlorobenzyl)-1-lupinyl-5-trifluoromethylbenzimidazole) was 12-/7-fold more potent than miltefosine, but exhibited a further improved SI. Therefore, compounds 8 and 28 represent interesting hit compounds, susceptible of structural modification to improve their safety profiles.     

Efficacy of methylchloro/methylisothiazolone biocide againstLegionella pneumophila in cooling tower water

Summary Methylchloro/methylisothiazolone biocide was tested for efficacy in cooling tower water againstLegionella pneumophila (strains Flint 1 and 2) andL. gormanii. These analyses are the first reports on the efficacy of isothiazolones againstLegionella in actual cooling tower water; the results of data reported previously obtained from more arbitrary laboratory tests are discussed and compared. The biocide was effective in cooling tower water at the two pH levels tested (pH 8.0 and 6.7). The concentration of biocide required to eliminate theL. pneumophila depended on contact time and pH: 99% of the bacteria were killed after 6 and 3 h of contact by 1.07 and 3.13 ppm active ingredient, respectively, when the pH was 8.0: 99% of the bacteria were killed after 6 and 3 h of contact by 2.23 and 9.43 ppm active ingredient, respectively, when the pH was 6.7. 24 h of contact with 0.35 ppm active ingredient methylchloro/methylisothiazolone biocide reduced the concentration of viable bacterial cells by more than four orders of magnitude (>99.99%), regardless of pH.     

Anticonvulsant evaluation of aminoalkanol derivatives of 2- and 4-methylxanthone

A series of 17 new aminoalkanol derivatives of 6-methoxy- or 7-chloro-2-methylxanthone as well as 6-methoxy-4-methylxanthone was synthesized and evaluated for anticonvulsant activity. All compounds were verified in mice after intraperitoneal (ip) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scMet) induced seizures as well as neurotoxicity assessment. Eleven of the tested substances showed protection against electrically evoked seizures in the majority of the tested mice at the dose of 100 mg/kg. Additionally, one was effective at the dose of 30 mg/kg. Five substances were active at the dose of 300 mg/kg or at the dose of 100 mg/kg in the minority of the tested mice. The most promising compound revealed ED₅₀ value of 47.57 mg/kg in MES (mice, ip, 1 h after administration) and at the same time its TD₅₀ was evaluated as above 400 mg/kg. Those values gave PI (calculated as TD₅₀/ED₅₀) of more than 8.41. Three other synthesized xanthone derivatives also proved to act as anticonvulsants and showed ED₅₀ values in MES test (mice, ip) ranged 80–110 mg/kg. Results were quite encouraging and suggested that in the group of xanthone derivatives new potential anticonvulsants might be found.     

Design,Synthesis, and Antimycobacterial Evaluation of Novel Tetrahydroisoquinoline Hydrazide Analogs

A series of novel 2-substituted-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carbohydrazide were designed, synthesized and structures were confirmed by analytical methods, viz., ¹H-NMR, ¹³C-NMR and Mass spectrometry. Synthesized derivatives were evaluated for their anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Ra. Among all the evaluated compounds, 10A25 containing biphenyl moiety exhibited significant inhibition with IC₅₀ 4.7 μM. 10A19 , with an electron-withdrawing Iodo group in the ortho position of the phenyl exhibited significant anti-tubercular activity with IC₅₀ 8.8 μM. IC₅₀ values of the remaining compounds ranged from 9.2 to 73.6 μM. Molecular docking study of the significantly active compound 10A25 was performed to determine the putative binding position of the test ligand at the active site of the selected target proteins Mycobacterium tuberculosis enoyl reductase (InhA) PDB – 4TZK and peptide deformylase PDB – 3E3U. A suitable single crystal for one of the active compounds, 10A12 , was generated and analysed to further confirm the structure of the compounds.     

Synthesis and biological evaluation of 3-(azolylmethyl)-1H-indoles and 3-(α-azolylbenzyl)-1H-indoles as selective aromatase inhibitors

This present study identifies a number of azolyl-substituted indoles as potent inhibitors of aromatase. In the sub-series of 3-(azolylmethyl)-1H-indoles, four imidazole derivatives and their triazole analogues were tested. Imidazole derivatives 11 and 14 in which the benzyl moiety was substituted by 2-chloro and 4-cyano groups, respectively, were the most active, with IC₅₀ values ranging between 0.054 and 0.050 μM. In the other sub-series, eight 3-(α-azolylbenzyl)-1H-indoles were prepared and tested. Compound 30, the N-ethyl imidazole derivative, proved to be an aromatase inhibitor, showing an IC₅₀ value of 0.052 μM. All target compounds were further evaluated against 17α-hydroxylase/C17,20-lyase to determine their selectivity profile.     

Tolerance of a ruminant ciliate <Emphasis Type="Italic">Entodinium caudatum</Emphasis> against mercury,copper and chromium

The effects of three heavy metal cations, mercury (II), copper (II), and chromium (VI), on the growth of the rumen ciliate Entodinium caudatum in vitro culture was studied. The E. caudatum culture was challenged by HgCl₂, CuCl₂, and K₂Cr₂O₇ for a period of 4 days. The tested concentrations of mercury (II) and copper (II) were 1, 5, 10, 20, 50 mg/L and 2, 10, 20, 40 mg/L for chromium (VI) at single dose with either untreated or inhibited bacterial co-culture population. Effective metal concentrations required to reduce ciliate growth by 50% (EC₅₀) for mercury (II), copper (II), and chromium (VI) either with untreated or inhibited bacterial co-culture population after 24 h of metal application were 24, 20, and 21 or 15, 20, and 19 mg/L, respectively. After 4 days of metal application, corresponding EC₅₀ values for mercury (II), copper (II), and chromium (VI) were 16, 20, and 17 (with untreated bacterial population) or not determinable, 20, and 15 mg/L, respectively (with inhibited bacterial population). Increased sensitivity of E. caudatum to tested heavy metals with inhibited bacterial co-culture population indicate that the ciliate resistance to the heavy metal tested depends on detoxification abilities of rumen bacterial population.     

一株深海热液口嗜热芽孢杆菌SY27F代谢产物活性的研究

【目的】对一株来源于深海热液口嗜热芽孢杆菌的次生代谢产物进行抑菌活性和抗肿瘤活性的初步研究。【方法】采用纸片法和微量肉汤稀释法检测嗜热芽孢杆菌SY27F次生代谢产物的抑菌活性,采用CCK-8法测定其次生代谢产物的抗肿瘤活性。【结果】抑菌实验表明,嗜热芽孢杆菌代谢产物对大肠杆菌、金黄色葡萄球菌均有抑菌作用,其最低抑菌浓度分别为1.56 mg/mL和3.13 mg/mL;细胞实验表明,其代谢产物对肿瘤细胞A549、HepG2、HeLa、MCF-7均有一定的抑制作用,其半致死浓度分别为0.390、0.451、0.704、1.105 mg/mL;与人肝肿瘤细胞(HepG2)相比,其对人正常肝细胞(L02)表现出良好的生物相容性。【结论】嗜热芽孢杆菌SY27F次生代谢产物具有一定的抑菌和抗肿瘤活性,可为寻找新型抑菌抗肿瘤活性物质提供优质资源。