Carbohydrazones of substituted salicylaldehydes as potential lead compounds for the development of narrow-spectrum antimicrobials

Certain substituted salicylaldehydes are known to have highly potent antimicrobial activity against bacteria and fungi, but the mechanism underlying this remarkable activity is not known, and almost nothing has been reported on the effects of further modification of the structures, such as the formation of hydrazone-type derivatives. We report now a study on the antimicrobial properties of the carbohydrazone derivatives of several substituted salicylaldehydes. The compounds studied were synthesized from ring-substituted salicylaldehydes and carbohydrazide in the mole ratio 2:1. They were tested against Aspergillus niger, Bacillus cereus, Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Saccharomyces cerevisiae and Staphylococcus epidermidis using the agar diffusion method. The carbohydrazone derived from 2,3,4-trihydroxybenzaldehyde had distinctly higher activity than the parent aldehyde in the same molar concentration. This activity was limited to one test organism (S. epidermidis), while the free aldehyde had at least some (in some cases even high) activity against all of the microbes studied. All other ones of the effective carbohydrazone compounds were distinctly less active than the parent salicylaldehydes as such. The hydrazones studied had in general a narrower antimicrobial spectrum than the free aldehydes and are thus of interest as potential lead compounds for the development of narrow-spectrum anti-microbial drugs. The mechanism of action of the aldehydes as well as that of the carbohydrazones is discussed.     

Substituted salicylaldehydes as potential antimicrobial drugs: minimal inhibitory and microbicidal concentrations

Substituted salicylaldehydes are potent antibacterial and antifungal agents and may have chemotherapeutic potential. In the clinical setting, the minimal inhibitory concentration (MIC) as well as the minimal bactericidal and fungicidal concentrations (MBC and MFC, respectively) are of fundamental interest. Therefore, we have now, using a panel of five microbial species (Bacillus cereus, Candida albicans, Escherichia coli, Saccharomyces cerevisiae, and Staphylococcus aureus), determined the MIC and MBC/MFC values of a total of 22 aromatic aldehydes, including 19 substituted salicylaldehydes and the unsubstituted parent compounds benzaldehyde and salicylaldehyde (2-hydroxybenzaldehyde). The results clearly indicate that both of the yeasts studied are remarkably sensitive to various salicylaldehydes and, especially, to halogenated ones. Some congeners clearly merit consideration as potential therapeutic agents for Candida infections. The MIC values of the most potent congeners are of roughly the same magnitude as that of amphotericin B, and the results of the MFC measurements indicate that the compounds are fungicidal. All of the bacteria studied are also sensitive to at least some of the compounds tested but, clearly, this class of antimicrobials has superior activity against yeasts. Structure-activity relationships are discussed for each microbial species and compared with each other. The comparison of the results of MIC and MBC/MFC measurements with those of agar diffusion tests revealed aspects that are of interest concerning the methodology of antimicrobial activity screening. Unexpectedly, it was found that some compounds that are completely devoid of activity in agar diffusion tests had potent activity in MIC tests, indicating that if only agar diffusion methodology is used in drug discovery, some highly active compounds may be missed.     

Antimicrobial activity of the marine alkaloids haminol and pulo'upone and related compounds

The marine alkaloids haminol A, haminol B and pulo'upone as well as 17 related compounds (twelve 2-substituted pyridine derivatives, four 3-substituted ones and one analogue of the bicyclic terminus of pulo'upone) were tested for antimicrobial activity against a panel of six microbes (Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, Candida albicans and Saccharomyces cerevisiae) using the paper disc agar diffusion method. Six compounds were tested also against the mold Aspergillus niger. Some of the compounds displayed noteworthy antimicrobial activity, only one congener being completely devoid of activity. Nearly all compounds had activity against B. cereus and S. epidermidis. The growth of E. coli, C albicans and S. cerevisiae was also distinctly inhibited by many compounds. In contrast, most compounds were inactive or had minimal activity against P. aeruginosa. Interestingly, most of the compounds tested against the opportunistic pathogen A. niger were active, one of them having noteworthy inhibitory potency.     

Design, synthesis, synergistic antimicrobial activity and cytotoxicity of 4-aryl substituted 3,4-dihydropyrimidinones of curcumin

3,4-Dihydropyrimidinones of curcumin were synthesized in excellent yield by multi-component one-pot condensation of curcumin, substituted aromatic aldehydes and urea/thiourea under solvent free conditions using SnCl(2)·2H(2)O catalyst. All the synthesized compounds have been characterized by IR, (1)H NMR, (13)C NMR, Mass spectra as well as elemental analyses. The synthesized compounds 4a-n were evaluated for their synergistic antimicrobial (antibacterial and antifungal) activity against bacteria and fungi. Zone of inhibition was measured by adopting disc diffusion method. In vitro minimum inhibitory concentrations were measured using broth microdilution and food poisoning method. In addition to this in vitro cytotoxicity of synthesized compounds against three human cancer lines Hep-G2, HCT-116 and QG-56 were also evaluated. Most of the compounds showed interesting antimicrobial and cytotoxic activity as compared to curcumin, that is, the compounds derived from 2-hydroxy benzaldehyde, 4-hydroxy benzaldehyde and 4-hydroxy-3-methoxy benzaldehyde showed the highest biological activity as compared to other compounds.     

N/C-4 substituted azetidin-2-ones: synthesis and preliminary evaluation as new class of antimicrobial agents

A series of 3-chloro-4-(3-methoxy-4-acetyloxyphenyl)-1-[3-oxo-3-(phenylamino)propanamido] azetidin-2-ones 3a-g and 3-chloro-4-[2-hydroxy-5-(nitro substituted phenylazo)phenyl]-1-phenylazetidin-2-ones 6a-h were synthesized using appropriate synthetic route. Structures of all the synthesized compounds were established on the basis of elemental analysis and spectroscopic data. The antimicrobial activity of the synthesized compounds was screened against several microbes. Several of these molecules showed potent antimicrobial activity against Bacillus anthracis, Staphylococcus aureus and Candida albicans and significant structure-activity relationship (SAR) trends.     

Biological activity of a new series of tertiary alcohols

The in vitro antimicrobial activity of a new series of synthetic fluorine-substituted triaryl alcohols against the human pathogens Staphylococcus aureus, Escherichia coli, and Candida albicans was studied with the aim of overcoming multiple drug resistance and improving the clinical usefulness of antimicrobial drugs. The nature and positions of substituents attached to aromatic rings, as well as their electronegativities and sizes, seem to affect the preferred molecular conformations and, hence, the binding of the compounds to the corresponding cell receptors.     

Antimicrobial activity of two antitumour agents and ribonucleotide reductase inhibitors, pyridine-2-carboxaldehyde thiosemicarbazone and the acetate form of its copper(II) chelate

Some copper chelates have potent antitumour activity, and in some cases also the free ligands have activity in vivo. Yet, little is known about their antimicrobial properties. Copper(II) chelates of the thiosemicarbazones of a-N-heterocyclic carboxaldehydes constitute one important group of such agents, also their ligands having marked antitumour activity. Both the ligands and chelates inhibit ribonucleotide reductase. Some ligands have been or are under clinical trials as antineoplastic agents. I report here a study on the antimicrobial properties of the prototype compounds of this group, pyridine-2-carboxaldehyde thiosemicarbazone and its copper(II) chelate. They were tested against nine microbes, including bacteria (Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus lactis), yeasts (Candida albicans and Saccharomyces cerevisiae) and one mold (Aspergillus niger). Two clinical isolates of Bacillus sp. and one reference strain were also studied. Both the ligand and the chelate had marked activity. The ligand displayed considerable activity against all bacteria except for S. lactis, and its activity against E. coli and P. aeruginosa was that high that practical applications might be considued. It was highly active against A. niger and moderately active against C. albicans. The chelate was highly active against S. epidermidis and S. cerevisiae. Both compounds inhibited the clinical isolates markedly. Since some related ligands have been or are in clinical trials on humans or are entering them, their route to clinical use, also as antimicrobials, might be much more straightforward than that of substances, whose toxicity in humans is wholly unexplored.     

Synthesis and in vitro antimicrobial studies of some new 3-[phenyldiazenyl] benzaldehyde N-phenyl thiosemicarbazones

The increasing clinical importance of drug resistant microbial pathogens has lent additional urgency to microbiological research and new antimicrobial compound development. For this purpose, a new series of 3-[phenyldiazenyl] benzaldehyde N-phenylthiosemicarbazones were synthesized and evaluated for antifungal and antibacterial activity. The reaction of 2-hydroxy-5-[phenyldiazenyl] benzaldehyde (I) with N-phenylhydrazinecarbothioamide (II) were carried out in DMF. The antimicrobial activity of the synthesized target compounds (III) were evaluated by screening on different human pathogens using the disc diffusion assay. All the compounds exhibited considerable inhibition against the bacteria and fungi tested.     

Synthesis and antifungal activity of oxygenated cholesterol derivatives

A series of oxygenated cholesterol derivatives were prepared from new synthetic methods and evaluated for their in vitro antimicrobial properties against human pathogens. The activity was highly dependent on the structure of the different compounds involved. The best results were obtained with hydroxy ketones 2, 4 and 5 and diketone 7 exhibiting activities against S. cerevisiae (ATCC 28383) and Candida albicans (CIP 1663-86). For example, compound 2 exhibited high activities against C. albicans (CIP 1663-86) and Amphotericine B and miconazole resistant strain C. albicans (CIP 1180-79) at a concentration of 1.5 microg/mL.     

Antimicrobial Activity of 3-Phenylimidazolidine-2,4-diones and Related Compounds

The structure-activity relationships of 3-(3′,5′-dichlorophenyl)imidazolidine-2,4-dione derivatives were investigated by the agar dilution method using Sclerotinia sclerotiorum as a test microbe. Several compounds were tested for antimicrobial spectrum in vitro with other pathogenic microbes and for foliage protective activity in green house tests with rice sheath blight, rice brown spot, damping-off of cucumber and kidney bean stem rot. It was found that the antimicrobial activity was enhanced when the 1-position of imidazolidine ring was substituted by an alkyl group but was reduced when the 5-position was substituted by alkyl groups. Generally, 3-(3′,5′-dichlorophenyl)imidazolidine-2,4-dione derivatives were active against Scierotiniaceae, Corticiaceae, Dematiaceae, Polystigmataceae or Pleosporaceae. In green house tests, some of these compounds showed high protective activity against rice sheath blight, rice brown spot, damping-off of cucumber and kidney bean stem rot. Results of the green house tests on the above mentioned diseases correlate well with those of in vitro tests except in the case of kidney bean stem rot.     

Enhancement of mycobactericidal activity of glutaraldehyde with α,β-unsaturated and aromatic aldehydes

Summary Several ,-unsaturated and aromatic aldehydes were evaluated for antimicrobial activity usingMycobacterium bovis as the test strain. Activity of most of the compounds was determined in the presence and absence of 2% glutaraldehyde. Several compounds highly active against this organism, e.g. 2-pentenal, benzaldehyde, ando-phthalaldehyde showed rapid kill of >10⁵ CFU ml^–1 in 5 min. Activity of ,-unsaturated compounds substituted in the ₁ position showed increasing activity with increasing chain length. Of the aromatic aldehydes tested, benzaldehyde andp-dimethylamino benzaldehyde showed little activity alone, but when combined with 2% glutaraldehyde showed increased activity. Substituents added to the benzaldehyde ring (nitro, chloro, methyl, and methoxy) all detracted from the synergism, but still showed increased activity over the activity of 2% glutaraldehyde. The same affect was noted with disubstituted benzaldehyde compounds but not with substitutedo-phthaladehyde (2-formylformaldehyde).     

Bromophenols as Candida albicans isocitrate lyase inhibitors

A new series of bromophenols was synthesized by reactions of corresponding phenol analogs with bromine. The synthesized compounds were tested for inhibitory activity against isocitrate lyase (ICL) of Candida albicans and antimicrobial activity against gram-positive and, gram-negative bacteria and fungi. Among the synthesized bromophenols, bis(3-bromo-4,5-dihydroxyphenyl)methanone (11) and (3-bromo-4,5-dihydroxyphenyl)(2,3-dibromo-4,5-dihydroxyphenyl)methanone (12) displayed potent inhibitory activities against ICL, showing a stronger inhibitory effects than were found with natural bromophenol 1. The preliminary structure-activity relationships were investigated in order to determine the essential structural requirements for the inhibitory activities of these compounds against ICL of C. albicans.     

Antimicrobial activity of some Salvia species essential oils from Iran

The aerial parts of Salvia multicaulis, S. sclarea and S. verticillata were collected at full flowering stage. The essential oils were isolated by hydrodistillation and analyzed by combination of capillary GC and GC-MS. The in vitro antimicrobial activity of the essential oils were studied against eight Gram-positive and Gram-negative bacteria (Bacillus subtilis, Bacillus pumulis, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae) and three fungi (Candida albicans, Saccharomyces cerevisiae and Aspergillus niger). The results of antibacterial activity tests of the essential oils according to the disc diffusion method and MIC values indicated that all the samples have moderate to high inhibitory activity against the tested bacteria except for P. aeruginosa which was totally resistant. In contrast to antibacterial activity, the oils exhibited no or slight antifungal property, in which only the oil of S. multicaulis showed weak activity against two tested yeasts, C. albicans and S. cerevisiae.     

Screening of antimicrobial activity of diarylamines in the 2,3,5-trimethylbenzo[b]thiophene series: a structure-activity evaluation study

Gram positive (Bacillus cereus, B. subtilis), Gram negative (Pseudomonas aeruginosa, Escherichia coli) bacteria, and Candida albicans as a representative of fungi were used for screening the in vitro antimicrobial activity of diarylamines in the 2,3,5-trimethylbenzo[b]thiophene series bearing different substituents, synthesized by us using the palladium-catalyzed C-N coupling methodology. The minimal inhibitory concentration (MIC) and structure-activity relationships (SARs) were evaluated.     

Antimicrobial and antiviral screening of novel indole carboxamide and propanamide derivatives

A few series of indole derivatives were screened for antimicrobial, antifungal and anti-HBV activities. The compounds were tested for their in vitro antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and for their antifungal activity against Candida albicans using a disc diffusion method, which measures the diameter of the inhibition zone around a paper disc soaked in a solution of the test compounds. The antimicrobial activity results showed that all compounds are as a active as the standard compound ampicillin against Staphylococcus aureus. It was also found that indole carboxamide derivatives, substituted at 3-position with several benzyl groups, showed better inhibition of Bacillus subtilis than their congeners substituted at 2-position. Activity patterns of the compounds against Escherichia coli and Staphylococcus aureus were found slightly different by the same method. In this case, there was no correlation between structure and activity of the compounds. The antifungal activity of carboxamide derivatives was found higher compared to that of the propanamide derivatives. The minimum inhibitory concentration (MIC) values of some indole derivatives were also determined by the tube dilution technique. The MIC values of the compounds were found nearly 20- to 100-fold smaller compared to the standard compounds ciprofloxacin and ampicillin (1.56-3.13 microg/ml and 1.56-12.5 microg/ml, respectively) against Staphylococcus aureus, Bacillus subtilis and Escherichia coli. The MIC values of the tested compounds showed that these are better inhibitors for Candida albicans. Indole derivatives were screened by the anti-HBV susceptibility test. No compound showed good inhibition against the HBV virus.     

Allelopathic effects of water hyacinth [Eichhornia crassipes

Eichhornia crassipes (Mart) Solms is an invasive weed known to out-compete native plants and negatively affect microbes including phytoplankton. The spread and population density of E. crassipes will be favored by global warming. The aim here was to identify compounds that underlie the effects on microbes. The entire plant of E. crassipes was collected from El Zomor canal, River Nile (Egypt), washed clean, then air dried. Plant tissue was extracted three times with methanol and fractionated by thin layer chromatography (TLC). The crude methanolic extract and five fractions from TLC (A-E) were tested for antimicrobial (bacteria and fungal) and anti-algal activities (green microalgae and cyanobacteria) using paper disc diffusion bioassay. The crude extract as well as all five TLC fractions exhibited antibacterial activities against both the gram positive bacteria; Bacillus subtilis and Streptococcus faecalis; and the gram negative bacteria; Escherichia coli and Staphylococcus aureus. Growth of Aspergillus flavus and Aspergillus niger were not inhibited by either E. crassipes crude extract nor its five fractions. In contrast, Candida albicans (yeast) was inhibited by all. Some antialgal activity of the crude extract and its fractions was manifest against the green microalgae; Chlorella vulgaris and Dictyochloropsis splendida as well as the cyanobacteria; Spirulina platensis and Nostoc piscinale. High antialgal activity was only recorded against Chlorella vulgaris. Identifications of the active antimicrobial and antialgal compounds of the crude extract as well as the five TLC fractions were carried out using gas chromatography combined with mass spectroscopy. The analyses showed the presence of an alkaloid (fraction A) and four phthalate derivatives (Fractions B-E) that exhibited the antimicrobial and antialgal activities.     

Food-mediated modulation of immunity in a phytophagous insect: An effect of nutrition rather than parasitic contamination

Inherent to the cost of immunity, the immune system itself can exhibit tradeoffs between its arms. Phytophagous insects face a wide range of microbial and eukaryotic parasites, each activating different immune pathways that could compromise the activity of the others. Feeding larvae are primarily exposed to microbes, which growth is controlled by antibiotic secondary metabolites produced by the host plant. The resulting variation in abundance of microbes on plants is expected to differentially stimulate the insect antimicrobial immune defenses. Under the above tradeoff hypothesis, stimulation of the insect antimicrobial defenses is expected to compromise immune activity against eukaryote parasites. In the European grape berry moth, Eupoecilia ambiguella, immune effectors directed towards microbes are negatively correlated to those directed towards eukaryotic parasites among host plants. Here, we hypothesize this relationship is caused by a variable control of the microbial community among host plants by their antibiotic metabolites. To test this hypothesis, we first quantified antimicrobial activity in berries of several grape varieties. We then measured immune defenses of E. ambiguella larvae raised on artificial diets in which we mimicked levels of antimicrobial activity of grape berries using tetracycline to control the abundance of growing microbes. Another group of larvae was raised on artificial diets made of berry extracts only to control for the effect of nutrition. We found that controlling microbe abundance with tetracycline in diets did not explain variation in the immune function whereas the presence of berry extracts did. This suggests that variation in immune defenses of E. ambiguella among grape varieties is caused by nutritional difference among host plants rather than microbe abundance. Further study of the effects of berry compounds on larval immune parameters will be needed to explain the observed tradeoff among immune system components.     

The antimicrobial activity of essential oil from Dracocephalum foetidum against pathogenic microorganisms

A number of essential oils from Mongolian aromatic plants are claimed to have antimicrobial activities. The essential oil of Dracocephalum foetidum, a popular essential oil used in Mongolian traditional medicine, was examined for its antimicrobial activity. Eight human pathogenic microorganisms including B. subtilis, S. aureus, M. lutens, E. hirae, S. mutans, E. coli, C. albicans, and S. cerevisiae were examined. The essential oil of Dracocephalum foetidum exhibited strong antimicrobial activity against most of the pathogenic bacteria and yeast strains that were tested; by both the agar diffusion method and the minimum inhibitory concentration (MIC) assay (MIC range was 26-2592 microg/ml). Interestingly, Dracocephalum foetidum even showed antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. We also analyzed the chemical composition of the oil by GC-MS and identified several major components, including n-Mentha-1,8-dien-10-al, limonene, geranial, and neral.     

The synthesis and antibacterial activity of totarol derivatives. Part 2: Modifications at C-12 and O-13

Alterations of the C-12 and C-13 aromatic ring substituents of totarol (1) afforded the series of derivatives 2-14, and introduction of substituents at C-12 gave exclusively 2a-14a. The majority of these analogues were tested in vitro against the following organisms: beta-lactamase-positive and high level gentamycin-resistant Enterococcus faecalis, penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), and multiresistant Klebsiella pneumoniae. The results were evaluated in terms of structure-activity relationship which reveals that: (a) the phenolic moiety at C-13, in general, is essential for antibacterial activity at < 32 microg/mL against gram-positive species, and (b) derivatization at C-12 has an undesirable effect on the antibacterial activity of this class of compounds, while (c) all compounds tested are ineffective against the gram-negative Klebsiella pneumoniae.