Synthesis and antimicrobial activities of halogenated bis(hydroxyphenyl)methanes

A series of halophenols was prepared by the reaction of bis(hydroxyphenyl)methanes with effective halogenating agents such as bromine and sulfuryl chloride. One of these compounds, a biologically active halophenol—2,2′,3,3′-tetrabromo-4,4′,5,5′-tetrahydroxydiphenylmethane (1)—frequently isolated from red algae, was synthesized for the first time. Other halophenols included several novel compounds, together with known derivatives that were synthesized from the phenolic intermediates, bis(3,4-dihydroxyphenyl)methane (5) and bis(2-hydroxyphenyl)methane (14). All of the synthesized compounds were tested for antimicrobial activity against Gram-positive, Gram-negative bacteria and fungi. The preliminary structure–activity relationship was investigated in order to determine the essential structural requirements for their antimicrobial activity. Of all these halophenols, 2,2′,3,3′,6-pentabromo-4,4′,5,5′-tetrahydroxydiphenylmethane (8) was found to be the most active against Candida albicans, Aspergillus fumigatus, Trichophyton rubrum, and Trichophyton mentagrophytes while 3,3′,5,5′-tetrachloro-2,2′-dihydroxydiphenylmethane (18) exerted a powerful antibacterial effect against Staphylococcus aureus, Bacillus subtilis, Micrococcus luteus, Proteus vulgaris, and Salmonella typhimurium.     

Syntheses of benzophenone-xanthone hybrid polyketides and their antibacterial activities

Muchimangins are benzophenone-xanthone hybrid polyketides produced by Securidaca longepedunculata. However, their biological activities have not been fully investigated, since they are minor constituents in this plant. To evaluate the possibility of muchimangins as antibacterial agent candidates, five muchimangin analogs were synthesized from 2,4,5-trimethoxydiphenyl methanol and the corresponding xanthones, by utilizing p-toluenesulfonic acid monohydrate for the Brønsted acid-catalysis. The antibacterial assays against Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, and Gram-negative bacteria, Klebsiella pneumoniae and Escherichia coli, revealed that the muchimangin analogs (±)-1,3,6,8-tetrahydroxy-4-(phenyl-(2′,4′,5′-trimethoxyphenyl)methyl)-xanthone (1), (±)-1,3,6-trihydroxy-4-(phenyl-(2′,4′,5′-trimethoxyphenyl)methyl)-xanthone (2), and (±)-1,3-dihydroxy-4-(phenyl-(2′,4′,5′-trimethoxyphenyl)methyl)-xanthone (3) showed significant activities against S. aureus, with MIC values of 10.0, 10.0, and 25.0 μM, respectively. Analogs (±)-1 and (±)-2 also exhibited antibacterial activities against B. subtilis, with MIC values of 50.0 and 12.5 μM, respectively. Furthermore, (+)-3 enhanced the antibacterial activity against S. aureus, with a MIC value of 10 μM.     

Synthesis and on-target antibacterial activity of novel 3-elongated arylalkoxybenzamide derivatives as inhibitors of the bacterial cell division protein FtsZ

Novel 3-elongated arylalkoxybenzamide derivatives were designed, synthesized and evaluated for their cell division inhibitory activity and antibacterial activity. Among them, the subseries of 3-alkyloxybenzamide derivatives exhibited greatly improved on-target activity against Bacillus subtilis and Staphylococcus aureus, and remarkably increased antibacterial activity against B. subtilis ATCC9372, penicillin-susceptible S. aureus ATCC25923, methicillin-resistant S. aureus ATCC29213 (MRSA) and penicillin-resistant S. aureus PR compared with 3-methoxybenzamide. In contrast, the subseries of 3-phenoxyaklyloxybenzamide, 3-heteroarylalkyloxybenzamide and 3-heteroarylthioalkyloxybenzamide derivatives only showed a significant improvement in on-target activity and antibacterial activity against B. subtilis ATCC9372.     

Synthesis and characterization of zinc oxide nanoparticles by using polyol chemistry for their antimicrobial and antibiofilm activity

The present investigation deals with facile polyol mediated synthesis and characterization of ZnO nanoparticles and their antimicrobial activities against pathogenic microorganisms. The synthesis process was carried out by refluxing zinc acetate precursor in diethylene glycol(DEG) and triethylene glycol(TEG) in the presence and in the absence of sodium acetate for 2 h and 3 h. All synthesized ZnO nanoparticles were characterized by X-ray diffraction (XRD), UV visible spectroscopy (UV), thermogravimetric analysis (TGA), fourier transform infrared spectroscopy (FTIR), field emission scanning electron microscopy(FESEM), transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDX) technique. All nanoparticles showed different degree of antibacterial and antibiofilm activity against Gram-positive Staphylococcus aureus (NCIM 2654)and Gram-negative Proteus vulgaris (NCIM 2613). The antibacterial and antibiofilm activity was inversely proportional to the size of the synthesized ZnO nanoparticles. Among all prepared particles, ZnO nanoparticles with least size (~ 15 nm) prepared by refluxing zinc acetate dihydrate in diethylene glycol for 3 h exhibited remarkable antibacterial and antibiofilm activity which may serve as potential alternatives in biomedical application.     

A new triterpenic diester from the aerial parts of Chrysanthemum macrocarpum

A new triterpenic diester, 3,21-dipalmitoyloxy-16β,21α-dihydroxy-β-amyrine (1), along with two natural cyclitols, conduritol C (2) and viburnitol (3), four known triterpenes (4–7), and seven known flavonoids (8–14) were isolated from the aerial parts of Chrysanthemum macrocarpum. Their structures were established on the basis of extensive 1D and 2D NMR (¹H, ¹³C, COSY, HMBC, HSQC, and ROESY) and ESIMS studies. The chloroform fraction, taraxasterol (4) and β-sitosterol (7) were investigated for their antibacterial activity against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. The chloroform fraction and taraxasterol (4) showed a weak antibacterial activity and were evaluated for their cytotoxic activity against human colon cancer HT-29 cells and human prostate carcinoma PC3 cells. The results indicated that both the chloroform fraction and taraxasterol (4) inhibited cell proliferation of both PC3 and HT-29 cells.     

Prenylated flavonoids from Desmodium caudatum and evaluation of their anti-MRSA activity

Seven prenylated flavonoids and a prenylated chromanochroman derivative, together with eight known flavonoids, were isolated from roots of Desmodium caudatum. The 15 structures were elucidated by extensive spectroscopic analyses. The antibacterial activity of many of other compounds was evaluated against methicillin-resistant Staphylococcus aureus (MRSA: COL and 5) by a disc diffusion method, and the minimum inhibitory concentrations (MICs) to MRSA were determined.     

Identification of 3′,4′,5′-trimethoxychalcone analogues as potent inhibitors of Helicobacter pylori-induced inflammation in human gastric epithelial cells

Efforts to identify potent small molecule inhibitors of Helicobacter pylori led to the evaluation of 23 3′,4′,5′-trimethoxychalcone analogues. Some of the compounds displayed potent antibacterial activity against H. pylori. Three most active and selective compounds 1, 7, and 13 also showed the bactericide activity against the reference as well as multidrug-resistant strains of H. pylori. Additionally, the aforementioned three compounds potentially inhibited the H. pylori adhesion and invasion to human gastric epithelial (AGS) cells. Furthermore, these selective compounds inhibited the H. pylori-induced gastric inflammation by reduced inflammatory mediator’s nuclear factor kappa B activation, and the secretion of interleukin-8.     

Synthesis and evaluation of a class of new coumarin triazole derivatives as potential antimicrobial agents

A series of new coumarin-based 1,2,4-triazole derivatives were designed, synthesized and evaluated for their antimicrobial activities in vitro against four Gram-positive bacteria (Staphylococcus aureus, MRSA, Bacillus subtilis and Micrococcus luteus), four Gram-negative bacteria (Escherichia coli, Proteus vulgaris, Salmonella typhi and Shigella dysenteriae) as well as three fungi (Candida albicans, Saccharomyces cerevisiae and Aspergillus fumigatus) by two-fold serial dilution technique. The bioactive assay showed that some synthesized coumarin triazoles displayed comparable or even better antibacterial and antifungal efficacy in comparison with reference drugs Enoxacin, Chloromycin and Fluconazole. Coumarin bis-triazole compounds exhibited stronger antibacterial and antifungal efficiency than their corresponding mono-triazole derivatives.     

Tetraoxygenated xanthones and biflavanoids from the twigs of Garcinia merguensis

One new tetraoxygenated xanthone, merguensinone (1), along with one known xanthone, 1,5,6-trihydroxy-2-prenyl-6′,6′-dimethyl-2H-pyrano(2′,3′:3,4)xanthone (2) and five known biflavanoids, (?)-GB-1a (3), (?)-GB-2a (4), (+)-morelloflavone (5), (+)-volkensiflavone (6), and amentoflavone (7) were isolated from the methanol extract from the twigs of Garcinia merguensis. Their antibacterial activity against the standard Staphylococcus aureus ATCC 25923 and methicillin-resistant S. aureus and antioxidation activity with DPPH assay were examined.     

Synthesis,molecular docking and biological evaluation of metronidazole derivatives containing piperazine skeleton as potential antibacterial agents

Metronidazole has a broad-spectrum antibacterial activity. Hereby a series of novel metronidazole derivatives were designed and synthesized based on nitroimidazole scaffold in order to find some more potent antibacterial drugs. For these compounds which were reported for the first time, their antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus were tested. These compounds showed good antibacterial activities against Gram-positive strains. Compound 4m represented the most potent antibacterial activity against S. aureus ATCC 25923 with MIC of 0.003 μg/mL and it showed the most potent activity against S. aureus TyrRS with IC₅₀ of 0.0024 μM. Molecular docking of 4m into S. aureus tyrosyl-tRNA synthetase active site were also performed to determine the probable binding mode.     

Synthesis and biological evaluation of novel isoxazolo[4,3-e]indoles as antibacterial agents

The synthesis of a new series of 8-bromo-6-alkyl-1-aryl-6H-isoxazolo[4,3-e]indole derivatives is described. All the newly synthesized compounds were screened for their antibacterial activity against Escherichia coli HB101, Staphylococcus aureus pathogens (methicillin resistant S. aureus and methicillin susceptible S. aureus), Pseudomonas aeruginosa, and Bacillus subtilis; also MIC values of these compounds were determined.     

Design,synthesis and molecular modeling studies of new series of s-triazine derivatives as antimicrobial agents against multi-drug resistant clinical isolates

Three novel series of s-triazine derivatives, including thirty-five new compounds 2a-d, 3a-3p, 4b-d, 5b-d, 6d-6d, and 7a-7f were synthesized comprising a diversity of substituents based on the structure of Astrazeneca arylaminotriazine DNA gyrase B inhibitor. The antimicrobial activity was determined for all compounds against Staphylococcus aureus, Escherichia coli and Candida albicans using the two-fold serial dilution technique and against reference standards Ampicillin for the antibacterial screening and Clotrimazole regarding the antifungal evaluation. The tested compounds showed strong to moderate antibacterial inhibitory action and weak antifungal activity. Compounds 3j and 6b were the most potent antibacterial agents against the tested strains and multi-drug resistant (MDR) clinical isolates of Klebsiella pneumoniae and methicillin resistant Staphylococcus aureus (MRSA1) with minimal toxicity in comparison to the reference drugs. In silico molecular properties calculations and molecular docking study for 3j and 6b revealed that both compounds could be considered as promising antibacterial DNA gyrase B inhibitors.     

Antibacterial activities of viriditoxin congeners and synthetic analogues against fish pathogens

Viriditoxin is a fungal secondary metabolite of the fungus Paecilomyces variotii derived from the inner tissues of the giant jellyfish Nemopilema nomurai. Viriditoxin exhibits antibacterial activity against Streptococcus iniae and Streptococcus parauberis, which are major pathogens of aqua cultured fish. Viriditoxin induced abnormal cell morphologies in the fish pathogens S. iniae and S. parauberis, presumably by inhibiting FtsZ polymerization as was previously observed in Escherichia coli. Synthetic analogues of viriditoxin, designed based on docking simulation results to FtsZ of Staphylococcus aureus, were prepared and compared with viriditoxin for antibacterial activity. Reconstitution of free hydroxyl or carboxyl groups of the methoxyl or methyl ester groups of viriditoxin led to significant reduction of antibacterial activity, implying that the natural molecule is optimized for antibacterial activity to deter bacteria potentially harmful to Paecilomyces.     

Examination of pineal indoles and 6-methoxy-2-benzoxazolinone for antioxidant and antimicrobial effects

Oxidative modification of low density lipoprotein (LDL) induced by free radicals is implicated in the development of atherosclerosis. The aim of the present study was to examine the ability of various pineal indoles in inhibiting LDL oxidation which is accompanied by an increase in mobility in agarose gel electrophoresis and by an augmented generation of thiobarbituric acid-reactive substance induced by Cu²⁺. It was found that the order of potencies in inhibiting malondialdehyde formation was 5-hydroxytryptamine (serotonin)>5-hydroxytryptophol and 5-hydroxyindole-3-acetic acid when tested at 4 mM. 5-Methoxytryptamine was as effective as 5-hydroxytryptophol and 5-hydroxyindole-3-acetic acid when tested at 4 mM but was inactive at 1 mM. 5-Methoxytryptophol was marginally active at 4 mM. Melatonin, 5-methoxyindole-3-acetic acid and 6-methoxy-2-benzoxazolinone were inactive even at 4 mM. The ranking of antioxidative potencies as reflected in the shift of mobility in agar gel electrophoresis was 5-hydroxytryptamine>5-methoxytryptamine>5-hydroxyindole-3-acetic acid and 5-methoxytryptophol>5-hydroxytryptophol and melatonin. Another aim of this investigation was to ascertain the action of the aforementioned pineal indoles on the enhanced lipid peroxidation brought about in the mouse kidney and liver by intraperitoneal administrations of carbon tetrachloride. It was found that all pineal indoles tested demonstrated an inhibitory effect in the kidney but not in the liver. 6-Methox-2-benzoxazolinone and 5-methoxyindole-3-acetic acid exerted antifungal activity against Mycosphaerella arachidicola, Botrytis cinerea and Physalospora piricola. 6-Methoxy-2-benzoxazolinone exhibited antibacterial activity against Proteus vulgaris and 5-methoxytryptamine against Staphylocccus aureus and Bacillus subtilis. Other pineal indoles did not possess antifungal or antibacterial action.     

Synthesis of new 3-phenylquinazolin-4(3H)-one derivatives as potent antibacterial agents effective against methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA)

Occurrence of infections due to the drug resistant Staphylococcus aureus is on rise necessitating the need for rapid development of new antibacterial agents. In our present work, a series of new 3-phenylquinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP (E. coli, S. aureus, K. pneumoniae, A. baumannii, P. aeroginosa) pathogen panel and pathogenic mycobacterial strains. The study revealed that compounds 4a, 4c, 4e, 4f, 4g, 4i, 4o and 4p exhibited selective and potent inhibitory activity against Staphylococcus aureus with MIC values in the range of 0.125–8 µg/mL. Further, the compounds 4c, 4e and 4g were found to be non toxic to Vero cells (CC₅₀ = >10–>100 µg/mL) and exhibited favourable selectivity index (SI = 40–>200). The compounds 4c, 4e and 4g also showed potent inhibitory activity against various MDR-S. aureus including VRSA. The promising results obtained indicated the potential use of the above series of compounds as promising antibacterial agents for the treatment of multidrug resistant Staphylococcus aureus infections.     

New fluorescent rosamine chelator showing promising antibacterial activity against Gram-positive bacteria

The restricted number of antibiotics to treat infections caused by common multidrug resistant bacterial pathogens in the clinical setting demands a continuous search for new molecules with antibacterial properties. Bacterial iron deprivation represents a promising alternative, being iron chelators an attractive class for drug design in which particular compounds seem to have antibacterial effect.In this work, we report the synthesis and characterization of a new fluorescent 3-hydroxy-4-pyridinone (3,4-HPO) iron chelator functionalized with a carboxyrosamine fluorophore (MRB20). The antibacterial activity of MRB20 was assessed against representative strains from clinically relevant Gram-positive and Gram-negative bacterial species and further compared with the inhibitory effect of a set of structurally related iron chelators including Deferiprone (1,2-dimethyl-3-hydroxy-4-pyridinone). Compounds exhibiting a promising minimal inhibitory concentration (MIC < 10 mg/L) were further tested against a wider range of bacterial genera and species (Staphylococcus spp. Enterococcus spp. Listeria monocytogenes, Bacillus spp.), including multidrug resistant bacteria.With the exception of the novel compound (MRB20), all chelators inhibited the strains assayed at very high concentrations [minimum inhibitory concentrations (MIC) ranging from 70 mg/L to >180 mg/L]. MRB20 revealed a good antibacterial activity (6.7–13.2 mg/L) against Gram-positive strains from different genera and species, including clinically relevant species (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium, Enterococcus faecalis), which might be eventually compatible with a therapeutic application or as adjuvant.     

Extraction and bioautographic-guided separation of antibacterial compounds from Ulva lactuca

This study aimed to optimize an extraction and separation procedure to obtain a concentrated fraction with antibacterial activity from the macroalga Ulva lactuca. Antibacterial compounds were extracted using eight solvents, and consistent activity against Staphylococcus aureus, Bacillus subtilis and methicillin-resistant (MR) S. aureus was observed from a dilute (1:100, w/v) ethyl acetate extract. Seasonal analysis revealed that antibacterial activity was the lowest in spring/summer and the highest in autumn/winter. Bioautography was found to be a more appropriate assay compared to disc diffusion when screening crude extracts, as it separates the masking compounds from the antibacterial compounds and a direct assessment of the bands responsible for the antibacterial effect could be made. The antibacterial compounds were first separated from the crude extract using preparative thin-layer chromatography, followed by column chromatography to obtain a semi-pure sub-fraction. Using this approach, the antibacterial compounds were successfully concentrated from a crude extract (300 μg) to semi-pure fractions (6 μg) in which antibacterial activities were greatly enhanced. This study also revealed that prolonged storage (9 months) under a nitrogen atmosphere at ?20°C resulted in a considerable increase in antibacterial activity. This is the first report of seasonal assessment of antibacterial compounds from seaweeds collected in Ireland. In addition, an antibacterial fraction was successfully isolated from U. lactuca which exhibited potent anti-MR S. aureus activity.     

Flavonoids of Gardenia cramerii and G. fosbergii bud exudates

From the bud exudates of Gardenia cramerii and G. fosbergii, two species endemic to Sri Lanka, a new flavonoid with an unusual B-ring oxidation pattern, 5,5′-dihydroxy-6,7,2′,3′-tetramethoxyflavone, was characterized. Two other rare flavonoids, 5,3′,5′-trihydroxy-3,6,7,4′-tetramethoxyflavone and 5-hydroxy-6,7,3′,4′,5′-pentamethoxyflavone were also isolated from both Gardenia species.     

Design and synthesis of biaryloxazolidinone derivatives containing amide or acrylamide moiety as novel antibacterial agents against Gram-positive bacteria

A series of novel biaryloxazolidinone derivatives containing amide and acrylamide structure were designed, synthesized and evaluated for their antibacterial activity. Most compounds generally exhibited potent antibacterial activity with MIC values of 1 μg/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as positive controls. Compound 17 exhibited good antibacterial activity with MIC values of 0.5 μg/mL against S. aureus, MRSA, MSSA and VRE and 0.25 μg/mL against LREF. The results indicated that compound 17 might serve as a potential hit-compound for further investigation.     

Phaseollin formation and metabolism in Phaseolus vulgaris

Following fungal-inoculation, P. vulgaris was found to produce small amounts of 7,4′-dihydroxyisoflavone (daidzein), 7,2′,4′-trihydroxyisoflavone, 7,2′,4′-trihydroxyisoflavanone, (6aR, 11aR)-3,9-dihydroxypterocarpan, and (3R)-7,2′,4′-trihydroxyisoflavan. The structures of the latter four compounds were confirmed by synthesis. The principal pterocarpans isolated were phaseollidin and phaseollin and ORD spectra indicate that these compounds have the same (6aR, 11aR)-configuration as 3,9-dihydroxypterocarpan. A pathway leading to phaseollidin and phaseollin is proposed involving 2′-hydroxylation of daidzein, reduction to the isoflavanone, further reduction, dehydration and cyclization to the pterocarpan, and prenylation to give phaseollidin and then cyclization and dehydrogenation to give phaseollin. No evidence of prenylation at the isoflavone or isoflavanone stage was obtained. The phaseollin metabolite, (6aS, 11aS)-6a-hydroxyphaseollin, was also detected.