Biological activity of new aza analogues of quinolones

A series of novel derivatives of 4H-pyrido[1,2-a]pyrimidine, 1,4-dihydro-4-oxo-1,5-naphthyridine and 1,4-dihydro-4-oxo-1,6-naphthyridine were prepared and their biological activity was compared with that of nalidixic acid. Thein vitro antibacterial activity of the tested compounds was lower than that of nalidixic acid except for two agents,1b and2c, with a higher activity againstEnterococcus faecalis. The compounds were tested for their ability to cure four plasmids from two species ofEnterobacteriaceae. The derivatives eliminated three plasmids (pKM101, pBR322, F'lac) at one-half or one-quarter of the minimal inhibitory concentration. Plasmid RP4 was unaffected by the treatment. None of these compounds showed better antichloroplast activity than nalidixic acid.     

Antimicrobial activities of 2-arylthio-N-alkylmaleimides

Summary A variety of 2-arylthio-N-alkylmaleimides were prepared, and their antimicrobial activities were examined. Almost all of these compounds exhibited antibacterial activity against Gram-positive bacteria such asBacillus subtilis andStaphylococcus aureus. Some compounds such as 2-(halogeno-phenyl)-thio-N-methylmaleimides (4, 5, 6, 8 and 10) and 2-(2-carbamoylphenyl)thio-N-methylmaleimide(35) exhibited antibacterial activity againstEscherichia coli. All compounds tested were inactive againstPseudomonas aeruginosa except 2-(2-carbamoylphenyl)thio-N-methylmaleimide(35) which was marginally active. Activities against Gram-positive bacteria were not due to the effect of the substituent on the benzene ring, except in the instances 2-carboxy, 2-carbomethoxy, 2-amino groups and alkyl chains, however, activities against Gram-negative bacteria were due to phenylthio and the alkyl substituents. Some of 2-arylthio-N-alkylmaleimides were examined for their antifungal activities using eight strains of fungi, and they showed activity against these.     

Antimicrobial activity of naphthoquinones from Fusaria

Twenty-two naphthoquinone compounds isolated or derived synthetically from culture extracts ofFusarium solani andF. oxysporum were examined for antimicrobial activity. Fifteen exhibited antibiotic activity againstStaphylococcus aureus, and 12 were active againstStreptococcus pyogenes, but none were active at the highest rate of 128 g/ml againstEscherichia coli, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, Serratia marcescens, orPseudomonas aeruginosa. Of 8 plant pathogenic bacteria tested against 11 naphthoquinones,Corynebacterium poinsettiae was inhibited by 6 compounds, andPseudomonas viridiflava was weakly inhibited by one. Only one of a group of 6 fluorescent soil pseudomonads was inhibited by one naphthoquinone. Antifungal activity of 10 compounds against 8 fungal plant pathogens was limited to inhibition ofPhytophthora parasitica by one naphthopyran.South Atlantic, Agricultural Research Service, U.S. Department of Agriculture. Mention of a trademark or proprietary product is for identification only and does not imply a warranty or guarantee of the product by the U.S. Department of Agriculture over other products which may also be suitable.     

Synthesis,antimicrobial and antiviral activity of substituted benzimidazoles

In the present study we have synthesized (4-nitrophenyl)-[2-(substituted phenyl)-benzoimidazol-1-yl]-methanones, (2-bromophenyl)-[2-(substituted phenyl)-benzoimidazol-1-yl]-methanone analogues (1–14) and evaluated them for their antimicrobial and antiviral potential. The results of antimicrobial screening indicated that none of the synthesized compounds were effective against the tested bacterial strains. Compounds 3, 11, 13 and compounds 5, 11, 12 were found to be active against Aspergillus niger and Candida albicans respectively, and may be further developed as antifungal agents. Furthermore, evaluation against a panel of different viruses pointed out the selective activity of compounds 5 and 6 against vaccinia virus and Coxsackie virus B4.     

Antiviral activity of substituted 5-chlorodiphenylamine-2-carboxylic acid hydrazides and their N-benzylidene derivatives

The substituted 5-chlorodiphenylamine-2-carboxylic acid hydrazides and their N-benzylidene derivatives were tested for their antiviral activity against gomphrena mosaic virus in a hypersensitive hostin vitro as well asin vivo. Most of the compounds exhibited potential antiviral activity. These compounds may be useful in controlling viral infections in garden as well as in field crops.     

Reconfirmation of antimicrobial activity in the coelomic fluid of the earthwormEisenia fetida andrei by colorimetric assay

A novel tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS) was used in the assessment of antimicrobial activity in earthworm in the presence of phenazine methosulphate (PMS) as an electron coupling reagent. This activity was purified from the coelomic fluid of the earthworm (ECF),Eisenia fetida andrei (Oligochaeta, Lumbricidae, annelids) using a series of column chromatography techniques and was tested against three Gram-negative strains ofEscherichia coli, Pseudomonas aeruginosa, Aeromonas hydrophila and three Gram-positive strains ofStaphylococcus aureus, Bacillus megaterium, Arthrobacter sp., respectively. Only the pigment-free eluate of coelomic fluid of the earthworm (ECFPE) showed activity againstB. megaterium amongst three isolated active fractions. The anion (DEAE-52) exchange effluent of the ECFPE was reported to have the strongest activity againstP. aeruginosa amongst the three active fractions. The 20% acetonitrile eluate (AE) by Sep-Pak C₁₈ cartridge was also tested and showed fair resistance againstE. coli, P. aeruginosa andArthrobacter sp., respectively.     

Anthelmintic activity of 3,6-dibenzyl-2,5-dioxopiperazine, cyclo(L-Phe-L-Phe)

Summary After oral administration, dipeptide Phe-Phe-OMe1 exhibits anthelmintic activity againstEchinococcus multilocularis larvae, cestoda, in mongolian gerbils (intraperitoneal localization), but not againstHymenolepis nana, cestoda, in fasted mice (gastro-intestinal localization). This compound rapidly provides its cyclization product dioxopiperazine2 in pH 7.4 buffer at 37°C, but was stable at pH 2.4 during 16h at 30°C. It was postulated that dipeptide1 could act as a prodrug of2. Initial pharmacokinetics studies were carried out in mice and dogs. After oral administration, biotransformation of1 into2 occurred to some extent in mice but not in fasted dogs. Results of these studies did not allow to ascertain that1 is a prodrug of2. Compound2 has been tested in mice againstH. nana andSchistosoma mansoni, a gastrointestinal trematoda. Albeit less active than the reference compound praziquantel,2 has shown a good activity against both worms. 2,5dioxopiperazines represent therefore a new class of anthelmintics.     

Synthesis,antiviral activity and structure–activity relationship of 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorosulfonylureas and products of their cyclization

Novel 1-(1-aryl-4,5dihydro-1H-imidazoline)-3-chlorosulfonylourea derivatives 3a–3f were synthesized in the reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with chlorosulfonyl isocyanate. The second series of compounds 4a–4f was prepared from the respective 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorsulfonylureas 3a–3f and 1,1′-carbonyldiimidazole (CDI). The selected compounds were tested for their activity against Herpes simplex virus and coxsackievirus B3 (CVB3). It was determined that three derivatives, i.e 3d, 4a and 4d are active against Herpes simplex virus (HSV-1). Compounds 3d and 4c are active against CVB3. Their favorable activity can be primarily attributed to their low lipophilicity values. Moreover, the lack of substituent in the phenyl moiety or 4-methoxy substitution can be considered as the most beneficial for the antiviral activity.     

Antimicrobial activities ofStreptomyces pulcher,S. canescens andS. citreofluorescens against fungal and bacterial pathogens of tomatoin vitro

Thirty-seven actinomycete species isolated from fertile cultivated soils in Egypt were screened for the production of antimicrobial compounds against a variety of test organisms. Most of the isolates exhibited antimicrobial activities against Gram-positive, Gram-negative, and acid-fast bacteria, yeasts and filamentous fungi, with special attention to fungal and bacterial pathogens of tomato. On starch-nitrate agar, 14 strains were active againstFusarium oxysporum f.sp.lycopersici (the cause ofFusarium wilt), 18 againstVerticillium albo-atrum (the cause ofVerticillium wilt), and 18 againstAlternaria solani (the cause of early blight). In liquid media, 14 isolates antagonizedPseudomonas solanacearum (the cause of bacterial wilt) and 20 antagonizedClavibacter michiganensis ssp.michiganensis (the cause of bacterial canker). The most active antagonists of the pathogenic microorganisms studied were found to beStreptomyces pulcher, S. canescens (syn.S. albidoflavus) andS. citreofluorescens (syn.S. anulatus). The antagonistic activities ofS. pulcher andS. citreofluorescens against pathogenic bacteria in liquid media under shaking conditions. The optimum culture conditions were determined.     

Biological activity of hydroxyanthraquinones and their glucosides toward microorganisms

Five mono- and dihydroxyanthraquinones as well as 12 of their glucosides (both free and acetylated) were tested with six different microbial species using the plate-diffusion method. None of the tested substances was active againstEscherichia coli, 15 of the 17 substances displayed an activity towardBacillus subtilis, Bacillus cereus, Candida albicans, Saccharomyces cerevisiae andStreptomyces aurecfaciens. Relationships between the substance type and biological activity are discussed.     

Insecticidal properties of nonactic acid and homononactic acid,the precursors of macrotetrolide antibiotics

(±)-Nonactic acid (1) and (±)-homononactic acid (2), the non-antibiotic precursors of macrotetrolide antibiotics, showed significant insecticidal effects (comparable with those of the commercial synthetic pesticide Metathion) onLeptinotarsa decemlineata, Epilachna varivestis andEuproctis chrysorrhoea. Anisoplia austriaca, Aphis fabae andCalandra granaria were less sensitive in this respect. A low acaricidal activity againstTetranychus urticae (not reaching that of the commercial miticide Acarition) was also found. Both1 and2 exhibited growth-stimulating properties for plants.     

Synthesis and antiviral activity of 1-(1,3-disubstitutedimidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives

Novel 1-(1,3-disubstituted-imidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives (3a–3j) were obtained from appropriate 1-aryl-3-arylsulfonyl-1H-imidazolidine-2-imines (1a–1j) and ethyl isocyanatoacetate (2), which were subjected to condensation. Seven compounds were tested for their antiviral activity against HSV-1 and CVB3 viruses. Among the tested compounds, 3c was found to be active against HSV-1, proving that 4-methoxy substituent as R and 4-methyl substituent as R₁ are most beneficial for activity against this virus. Furthermore, 3e and 3g were active against CVB3, which demonstrated that both 4-methyl and 4-chloro substitution is tolerated as R₁, whereas 4-chloro and 2-methoxy substituents are best as R. It was also shown that the active compounds are characterized by relatively big surface area, small ovality, and greatest HOMO and LUMO energies in comparison to the rest of the compounds.     

Antibiotic activity of lectins from marine algae against marine vibrios

Saline and aqueous ethanol extracts of marine algae and the lectins from two red algal species were assayed for their antibiotic activity against marine vibrios. Experimental studies were also carried out on the influence of environmental factors on such activity, using batch cultures. The results indicated that many of the saline extracts of the algal species were active and that the activity was selective against those vibrios assayed. The algal extracts were active against Vibrio pelagius and the fish pathogen V. vulnificus, but inactive against V. neresis. Algal lectins from Eucheuma serra (ESA) and Galaxaura marginata (GMA) strongly inhibited V. vulnificus but were inactive against the other two vibrios. The antibacterial activity of algal extracts was inhibited by pretreatment with various sugars and glycoprotein. Extracts of the two red algae, E. serra and Pterocladia capillacea, in saline and aqueous ethanol, inhibited markedly the growth rate of V. vulnificus at very low concentrations. Culture results indicated that metabolites active against V. vulnificus were invariably produced in P. capillacea over a wide range of temperature, light intensity, and nutritional conditions. Enhanced antibacterial activity occurred when P. capillacea was grown under higher irradiance, severe nutrient stress and moderate temperature (20 °C), reflecting the specific antibiotic characteristics of this alga. The strong antibiotic activity of lectins towards fish pathogenic bacteria reveals one of the important roles played by algal lectins, as well as the potential high economic value of those marine algae assayed for aquaculture and for biomedical purposes.     

Antibiotic activity of epiphytic bacteria isolated from intertidal seaweeds

A survey of antibiotic-producing bacteria from the microbial flora attached to seaweeds and the study of their antibiotic capacities were carried out. From 5 species of green and brown marine algae, 224 bacterial strains were isolated and tested for antibiotic production. A total of 38 strains displayed antibiotic activity, withEnteromorpha intestinalis being the source of the highest number of producer strains. All epiphytic bacteria with antibiotic activity were assigned to thePseudomonas-Alteromonas group. Antagonism assays among the isolates demonstrated that each producer strain inhibits the growth of the other producers, as well as of some nonproducer strains also isolated from seaweeds. Likewise, an autoinhibitory effect was observed in all antibiotic-producing strains. Antibacterial spectra of all the strains include activity againstStaphylococcus, Alcaligenes, Pseudomonas, Vibrio, Pasteurella, andAchromobacter. A preliminary characterization of the antibiotic substances produced by these epiphytic bacteria demonstrated that they are low molecular weight compounds, thermolabile, and anionic and are not affected by proteolytic enzymes. The role that these inhibitory substances can play in the natural environment is discussed.     

Synthesis and biological evaluation of novel 3-substituted amino-4-hydroxylcoumarin derivatives as chitin synthase inhibitors and antifungal agents

A series of novel 3-substituted amino-4-hydroxycoumarin derivatives have been designed and synthesized as chitin synthase (CHS) inhibitors. All the synthesized compounds have been screened for their CHS inhibition activity and antimicrobial activity in vitro. The enzymatic assay indicated that most of the compounds have good inhibitory activity against CHS, in which compound 6o with IC₅₀ of 0.10?mmol/L had stronger activity than that of polyoxins B, which acts as control drug with IC₅₀ of 0.18?mmol/L. As far as the antifungal activity is concerned, most of the compounds possessed moderate to excellent activity against some representative pathogenic fungi. Especially, compound 6b was found to be the most potent agent against Cryptococcus neoformans with minimal inhibitory concentration (MIC) of 4?μg/mL. Moreover, the results of antibacterial screening showed that these compounds have negligible actions to some tested bacteria. Therefore, these compounds would be promising to develop selective antifungal agents.     

Biological evaluation of 10-(diphenylmethylene)- 4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives

Antibacterial and antifungal activity of 10-(diphenylmethylene)-4-azatricyclo[5.2.1.0^2,6]dec-8-ene-3,5-dione derivatives were examined by the disc-diffusion method (growth inhibition zone diameter in agar medium). The MIC’s for the most active agents were determined. Title compounds were also evaluated in vitro against representatives of different virus classes. Most of the tested compounds exhibit activity against CVB-2 virus.     

SYNTHESIS OF 3-ALKYL PIPERAZIN-2-ONE NUCLEOSIDES WITH POTENTIAL ANTIRETROVIRAL ACTIVITY

Abstract

Piperazinone nucleosides can be formed by N-glycosylation with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose of either piperazin-2-ones or pyrazin-2-ones followed by reduction of the heterocycle with rhodium on alumina. All the prepared compounds were tested for their activity against the Visna virus, but did not show significant antiviral activity.     

Antimicrobial activity of FeIII,CuII, AgI,ZnII and HgII complexes of 2-(2-hydroxy-5-bromo/nitro-phenyl)-1H- and 2-(2-hydroxyphenyl)-5-methyl/chloro/nitro-1H-benzimidazoles

Antimicrobial activity of 2-(2-hydroxyphenyl)-5-R⁵-1H-benzimidazoles, 2-(2-hydroxy-5-R^5′-phenyl)-1H-benzimidazoles and their Fe^III, Cu^II, Ag^I, Zn^II and Hg^II nitrate complexes was tested towardStaphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella typhi, Shigella flexneri, andProteus mirabilis. Antifungal activity was tested againstCandida albicans. Benzimidazole benzene ring substituents increase the antimicrobial activity, phenol ring substituents decrease it. The ligands show an antibacterial effect against onlyS. aureus whereas Ag^I and Hg^II complexes of the ligands have a higher activity with respect to the other complexes to all the bacteria. On the other hand, Fe^III complexes show a considerable activity againstS. aureus andS. epidermidis.     

Synthesis and Anti-juvenile Hormone Activity of 1-Citronellyl-5-substituted Imidazoles

A number of 1-citronellyl-5-substituted imidazoles were synthesized and bioassayed on the silkworm, Bombyx mori, in order to assess their anti-juvenile hormone activity. Most of the 1-citronellyl-5-substituted imidazoles induced precocious metamorphosis in the 3rd and 4th instar larvae of B. mori by topical application. The percentage of precocious metamorphosis correlated well with the dosage. Among the compounds tested, l-citronellyl-5-(2-chlorophenyl)imidazole (8) and the 2-methylphenyl analog 10 showed the highest activity. When compounds 8 and 10 were applied to the 4th instar larvae at 10 μg/larva, precocious pupation was induced in 100% without any lethal effects.     

The Selection of an Isolate of the Hyphomycete Fungus,Metarhizium anisopliae,for Control of Termites in Australia

Ninety-three isolates ofMetarhizium anisopliae,mostly derived from a survey of termite material, were screened for activity againstNasutitermes exitiosusandCoptotermes frenchiorC. acinaciformisusing a grooming assay technique. Twenty-six of the most promising isolates were further evaluated by bioassay againstN. exitiosusandC. acinaciformis.All isolates were pathogenic withCoptotermesspp. being more susceptible thanN. exitiosus.A group of nine isolates, chosen for their level of pathogenicity for one or other genus of termites and to represent a genetically diverse group, was finally compared in a minicolony test using termite colonies in 1 liter jars. The isolate, code-named FI-610 (derived from nest-mound material ofC. lacteusin SE New South Wales), was one of the most effective isolates against termites from both of the two colonies tested. This isolate also grew relatively well on agar plates at 36°C. FI-610 was thus selected for field trials and was found to be effective in killing colonies ofC. acinaciformiswhen 10 g (=3 × 10¹¹conidia) or more of conidial powder was blown into the center of the large mound colonies.