Synthesis of Halopyrazole Matrine Derivatives and Their Insecticidal and Fungicidal Activities

Matrine is a traditional botanical pesticide with a broad-spectrum biological activity that is widely applied in agriculture. Halopyrazole groups are successfully introduced to the C13 of matrine to synthesize eight new derivatives with a yield of 78–87%. The insecticidal activity results show that the introduction of halopyrazole groups can significantly improve the insecticidal activity of matrine on Plutella xylostella, Mythimna separata and Spodoptera frugiperda with a corrected mortality rate of 100%, which is 25–65% higher than matrine. The fungicidal activity results indicate that derivatives have a high inhibitory effect on Ceratobasidium cornigerum, Cibberella sanbinetti, Gibberrlla zeae and Collectot tichum gloeosporioides. Thereinto, 4-Cl-Pyr-Mat has the best result, with an inhibition rate of 23–33% higher than that of matrine. Therefore, the introduction of halogenated pyrazole groups can improve the agricultural activity of matrine.     

Evaluation of bactericidal and fungicidal activity of ferrocenyl or phenyl derivatives in the diphenyl butene series

Some ferrocene compounds, such as tamoxifen derivatives hydroxyferrocifen 1 and ferrociphenol 2, show strong antiproliferative activity on hormone-dependent and hormone-independent breast cancer cells. In order to evaluate their antimicrobial activity, they were tested, together with their purely organic analogs, on the bacteria Pseudomonas aeruginosa and Staphylococcus aureus and the fungus Candida albicans. It has been found that the compounds bearing alkylamino chains are active, and in these cases the antimicrobial activity increases for compounds bearing two amino chains. These dialkyamino compounds are equally as active as doxycycline on P. aeruginosa and S. aureus but superior to it on C. albicans. The results show that there are no general correlation between the antitumoral activity and the bactericidal and fungicidal activities of these compounds. The ferrocene derivatives and their organic analogs have similar activity on bacteria and fungus. This bactericidal and fungicidal behaviour is a novel area of activity for these entities.     

A Novel Antifungal Protein with Lysozyme-Like Activity from Seeds of Clitoria ternatea

An antifungal protein with a molecular mass of 14.3 kDa was isolated from the seeds of butterfly pea (Clitoria ternatea) and designated as Ct protein. The antifungal protein was purified using different methods including ammonium sulphate precipitation, ion exchange chromatography on DEAE-cellulose and gel filtration on Sephadex G-50 column. Ct protein formed a single colourless rod-shaped crystal by hanging drop method after 7 days of sample loading. The protein showed lytic activity against Micrococcus luteus and broad-spectrum, fungicidal activity, particularly against the most clinically relevant yeasts, such as Cryptococcus neoformans, Cryptococcus albidus, Cryptococcus laurentii, Candida albicans and Candida parapsilosis. It also exerted an inhibitory activity on mycelial growth in several mould species including Curvularia sp., Alternaria sp., Cladosporium sp., Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Rhizopus sp., and Sclerotium sp. The present study adds to the literature on novel seed proteins with antifungal activity.     

Chiral derivatives of Butenafine and Terbinafine: synthesis and antifungal activity

Two series of allylamines/benzylamines have been synthesised and evaluated for their antifungal activity towards Cryptococcus neoformans. All compounds are chiral derivatives of Butenafine and Terbinafine, having additional substituents at the carbon connected to the central nitrogen atom. In both series, the antifungal activity was strongly dependent on both the steric bulk and the electronic nature of the substituents. Compared to the parent compounds (Butenafine and Terbinafine), the activity was maintained when the hydrogen was replaced with a methyl group. Lower activity was observed for ethyl, whereas introduction of -CH₂F, -CHF₂, -CF₃ or -CN substituents removed all antifungal activity. Testing of (R)- and (S)-N-(4-tert-butylbenzyl)-N-methyl-1-(naphthalen-1-yl)ethanamine against C. neoformans, Cryptococcus diffluens and Trichosporon cutaneum revealed that most of the activity resides in the (R)-enantiomer. The (R)-enantiomer performed as well as, or better (lower MIC values) than Butenafine against each test strain, suggesting that antimycotics based on this compound might be an improvement of existing Butenafine-based formulations.     

A novel synthesis of (−)-callicarpenal

Callicarpenal, isolated from the leaves of American beautyberry (Callicarpa americana) and Japanese beautyberry (Callicarpa japonica), exhibits significant mosquito bite-deterring activity and repellent activity against ticks and fire ants. The mosquito bite-deterring activity level of callicarpenal was reported to be similar to that of N,N-diethyl-m-toluamide. The novel synthesis of (?)-callicarpenal reported herein was accomplished by starting from (+)-pulegone. In our original approach, a novel Prins-type cyclization based on Meyer–Schuster rearrangement was featured as a key step.     

Effect of gamma irradiation on antioxidant activity of Amoora rohitaka

The effect of a medium dose of gamma radiation on antioxidant activity of Amoora rohitaka was studied. Radiation doses were 0, 1, 3 and 5?kGy. Antioxidant activity was screened by using different assay. With increasing dose the formation of Maillard reaction products (MRPs) contributes to the increase in the antioxidant activity. MRPs are formed as a result of Maillard reaction. In ABTS [2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid di-ammonium salt] assay, ethanol extract showed increase in scavenging activity. It also showed a marked increase in polyphenolic contents. The present study reveals that gamma irradiation can be an efficient process to increase antioxidant activity of Amoora rohitaka.     

Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity

The almiramide N-methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure–activity relationship study has been performed to examine the influences of N-methylation and conformation on activity against various strains of leishmaniasis protozoan and on cytotoxicity. The synthesis and biological analysis of twenty-five analogs demonstrated that derivatives with a single methyl group on either the first or fifth residue amide nitrogen exhibited greater activity than the permethylated peptides and relatively high potency against resistant strains. Replacement of amino amide residues in the peptide, by turn inducing α amino γ lactam (Agl) and N-aminoimidazalone (Nai) counterparts, reduced typically anti-parasitic activity; however, peptide amides possessing Agl residues at the second residue retained significant potency in the unmethylated and permethylated series. Systematic study of the effects of methylation and turn geometry on anti-parasitic activity indicated the relevance of an extended conformer about the central residues, and conformational mobility by tertiary amide isomerization and turn geometry at the extremities of the active peptides.     

Bioassay-Guided Isolation of Anti-Alzheimer Active Components from the Aerial Parts of Hedyotis diffusa and Simultaneous Analysis for Marker Compounds

Previous studies have reported that Hedyotis diffusa Willdenow extract shows various biological activities on cerebropathia, such as neuroprotection and short-term memory enhancement. However, there has been a lack of studies on the inhibitory activity on neurodegenerative diseases such as Alzheimer’s disease (AD) through enzyme assays of H. diffusa. Therefore, H. diffusa extract and fractions were evaluated for their inhibitory effects through assays of enzymes related to AD, including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1), and on the formation of advanced glycation end-product (AGE). In this study, ten bioactive compounds, including nine iridoid glycosides 1–9 and one flavonol glycoside 10, were isolated from the ethyl acetate and n-butanol fractions of H. diffusa using a bioassay-guided approach. Compound 10 was the strongest inhibitor of cholinesterase, BACE1, and the formation of AGEs of all isolated compounds, while compound 5 had the lowest inhibitory activity. Compounds 3, 6, and 9 exhibited better inhibitory activity than other compounds on AChE, and two pairs of diastereomeric iridoid glycoside structures (compounds 4, 8, and 6, 7) showed higher inhibitory activity than others on BChE. In the BACE1 inhibitory assay, compounds 1–3 were good inhibitors, and compound 10 showed higher inhibitory activity than quercetin, the positive control. Moreover, compounds 1 and 3 were stronger inhibitors of the formation of AGE than aminoguanidine (AMG), the positive control. In conclusion, this study is significant since it demonstrated that the potential inhibitory activity of H. diffusa on enzymes related to AD and showed the potential use for further study as a natural medicine for AD treatment on the basis of the bioactive components isolated from H. diffusa.     

Peagol and peagoldione, two new strigolactone-like metabolites isolated from pea root exudates

Two new strigolactone-like metabolites, named peagol and peagoldione, with germinative activity for root parasitic plants, were isolated from pea root exudates and were characterized by spectroscopic methods. Peagol was more active on Orobanche foetida and Phelipanche aegyptiaca seeds, while peagoldione was active on P. aegyptiaca only. Low activity was found on Orobanche crenata and Orobanche minor. Stimulatory activity of peagol on O. foetida seeds is most relevant as this species does not respond to the synthetic strigolactone analogue GR24, usually used as Orobanche germination standard.     

Effects of electron-withdrawing substituents on DPPH radical scavenging reactions of protocatechuic acid and its analogues in alcoholic solvents

The DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging activity of protocatechuic acid (3,4-dihydroxybenzoic acid) and its related catechols was examined. Compounds possessing strong electron-withdrawing substituents showed high activity. NMR analysis of the reaction mixtures of catechols and DPPH radical in methanol showed the formation of methanol adducts. The results suggest that high radical scavenging activity of catechols in alcohol is due to a nucleophilic addition of an alcohol molecule on o-quinones, which leads to a regeneration of a catechol structure. Furthermore, the radical scavenging activity in alcohols would largely depend on the electron-withdrawing/donating substituents, since they affect the susceptibility toward nucleophilic attacks on o-quinone.     

Antifeedant Mechanism of Dodonaea viscosa Saponin A Isolated from the Seeds of Dodonaea viscosa

Dodonaea viscosa is a medicinal plant which has been used to treat various diseases in humans. However, the anti-insect activity of extracts from D. viscosa has not been evaluated. Here, we found that the total saponins from D. viscosa (TSDV) had strong antifeedant and growth inhibition activities against 4th-instar larvae of Spodoptera litura. The median antifeeding concentration (AFC₅₀) value of TSDV on larvae was 1621.81 μg/mL. TSDV affected the detoxification enzyme system of the larvae and also exerted antifeedant activity possibly through targeting the γ-aminobutyric acid (GABA) system. The AFC₅₀ concentration, the carboxylesterase activity, glutathione S-transferases activity, and cytochrome P450 content increased to 258%, 205%, and 215%, respectively, and likewise the glutamate decarboxylase activity and GABA content to 195% and 230%, respectively, in larvae which fed on TSDV. However, D. viscosa saponin A (DVSA) showed better antifeedant activity and growth inhibition activity in larvae, compared to TSDV. DVSA also exerted their antifeedant activity possibly through targeting the GABA system and subsequently affected the detoxification enzyme system. Further, DVSA directly affected the medial sensillum and the lateral sensillum of the 4th-instar larvae. Stimulation of Spodoptera litura. with DVSA elicited clear, consistent, and robust excitatory responses in a single taste cell.     

10-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-3-methyl-1H,10H-pyrano[4,3-b] chromen-1-ones from a pseudo-multicomponent reaction and evaluation of their antioxidant activity

A series of novel 10-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-3-methyl-1H,10H-pyrano[4,3-b]chromen-1-ones were synthesized by a pseudo-three-component reaction of 4-hydroxy-6-methyl-2-oxo-2H-pyran-2-one (TAL) with 2-hydroxyarylaldehydes using different acids as catalysts and solvents. The approach relies on a regioselective cascade reaction involving two molar equiv of the TAL iteratively acting as active methylene in a Knoevenagel condensation and in a Michael addition. The antioxidant activity of the synthesized compounds were determined using the DPPH scavenging assay, being the results dependent on the nature and number of chromone substituents. The compound bearing an ortho-dihydroxy (catechol) moiety showed excellent activity at lower concentrations, while derivatives bearing alkoxy groups as substituents present pro-oxidant activity.     

Evaluation of substituent effects on activity and enantioselectivity in the enzymatic reduction of aryl ketones

The enzymatic reduction of a series of substituted aryl ketones catalyzed by 24 isolated recombinant ketoreductases was studied and the substituent effects on activity and enantioselectivity were evaluated. When comparing p- and m-substituted acetophenones, the substituent significantly affects the activity of some of the tested ketoreductases, while it has little effect on the activity of other ketoreductases. Most of the tested ketoreductases were highly enantioselective in the reduction of these aryl ketones. The electronic properties, steric factors, and the ability to form a hydrogen bond to the substituents at the ortho-position play a significant role in determining both the activity and enantioselectivity of the ketoreductase-catalyzed reductions. From an applicability point of view, both enantiomers of the product aryl alcohols could be prepared via reduction catalyzed by one or more of the ketoreductases in most cases.     

Lipid bilayer composition influences small multidrug transporters

Background

Reversible phosphorylation events within a polymerisation complex have been proposed to modulate capsular polysaccharide synthesis in Streptococcus pneumoniae. Similar phosphatase and kinase genes are present in the exopolysaccharide (EPS) biosynthesis loci of numerous lactic acid bacteria genomes.

Results

The protein sequence deduced from the wzb gene in Lactobacillus rhamnosus ATCC 9595 reveals four motifs of the polymerase and histidinol phosphatase (PHP) superfamily of prokaryotic O-phosphatases. Native and modified His-tag fusion Wzb proteins were purified from Escherichia coli cultures. Extracts showed phosphatase activity towards tyrosine-containing peptides. The purified fusion protein Wzb was active on p-nitrophenyl-phosphate (pNPP), with an optimal activity in presence of bovine serum albumin (BSA 1%) at pH 7.3 and a temperature of 75°C. At 50°C, residual activity decreased to 10 %. Copper ions were essential for phosphatase activity, which was significantly increased by addition of cobalt. Mutated fusion Wzb proteins exhibited reduced phosphatase activity on p-nitrophenyl-phosphate. However, one variant (C6S) showed close to 20% increase in phosphatase activity.

Conclusion

These characteristics reveal significant differences with the manganese-dependent CpsB protein tyrosine phosphatase described for Streptococcus pneumoniae as well as with the polysaccharide-related phosphatases of Gram negative bacteria.     

Chemical Composition and Anti-Urolithiatic Activity of Extracts from Argania spinosa (L.) Skeels Press-Cake and Acacia senegal (L.) Willd

Ethnobotanical studies have reported the traditional medicinal uses of Acacia senegal (L.) Willd. and Argania spinosa (L.) Skeels against kidney stone formation and other chronic kidney diseases. The present work is undertaken to study the litholytic activity and the inhibiting activity of calcium oxalate crystallization by bioactive compounds identified in Argania spinosa (L.) Skeels press-cake (residue of Argan oil) and in Acacia senegal (L.) Willd. The litholytic activity was studied in vitro on cystine and uric acid stones using a porous bag and an Erlenmeyer glass. The study of the inhibiting activity of calcium oxalate crystallization, was based on temporal measurements of the optical density, registered at a 620 nm wavelength for 30 min using an ultraviolet–visible spectrophotometer. The silylation method was performed to identify phytochemicals, followed by gas chromatography coupled with mass spectrophotometry (GC/MS) analysis. The results show significant litholytic activity of Argania Spinosa press-cake hydro-ethanolic extract on uric acid and cystine stones, respectively, with dissolution rates (DR) of 86.38% and 60.42% versus 3.23% and 9.48% for the hydro-ethanolic extract of Acacia senegal exudate. Furthermore, the percentages of nucleation inhibition are 83.78% and 43.77% (p ˂ 0.05) for Argania spinosa and Acacia senegal, respectively. The results point to the detection of 17 phytochemicals in Argania spinosa press-cake extract, the majority of which are phenolic acids and have potent anti-urolithiatic action.     

Synthesis,biological activities and 3D-QSAR studies of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfur ether moiety

A series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfur ether moiety were designed, synthesized, and tested for their antifungal activities against several phytopathogenic fungi. The established CoMSIA model could predict the antifungal activity.     

Synthesis, characterization and antimicrobial activity of palladium(II) complexes with some alkyl derivates of thiosalicylic acids: Crystal structure of the bis(S-benzyl-thiosalicylate)-palladium(II) complex, [Pd(S-bz-thiosal)2]

S-Alkyl (R = benzyl, methyl, ethyl, propyl and butyl) derivatives of thiosalicylic acid and the corresponding palladium(II) complexes were prepared and their structures were proposed on the basis of infrared, ¹H and ¹³C NMR spectroscopy. The cis geometrical configurations of the isolated complexes were proposed on the basis of an X-ray structural study of the bis(S-benzyl-thiosalicylate)-palladium(II), [Pd(S-bz-thiosal)₂] complex.Antimicrobial activity of the tested compounds was evaluated by determining the minimum inhibitory concentration (MIC) and minimum microbicidal concentration (MMC) in relation to 26 species of microorganisms. The tested ligands, with a few exceptions, show low antimicrobial activity. The palladium(II) complexes, [Pd(S-R-thiosal)₂], have statistically significant higher activity than the corresponding ligands. The complexes [Pd(S-et-thiosal)₂] and [Pd(S-pro-thiosal)₂] displayed the strongest activity amongst the all tested compounds. The palladium(II) complexes show selective and moderate antibacterial activity and significant antifungal activity. The most sensitive were Aspergillus fumigatus and Aspergillus flavus.     

Application of Yeast Candida utilis to Ferment Eisenia bicyclis for Enhanced Antibacterial Effect

In this study, fermentation broth of Eisenia bicyclis with Candia utilis YM-1 exhibited enhanced antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) and food-borne pathogenic bacteria. To perform a more detailed investigation on the antibacterial activity, the fermented broth of E. bicyclis was extracted with methanol and further fractionated with organic solvents. After 1-day fermentation, the ethyl acetate (EtOAc)-soluble extract exhibited the highest anti-MRSA activity with minimum inhibitory concentration values ranging from 128 to 512 μg/mL, suggesting that the fermentation of E. bicyclis with C. utilis YM-1 may enhance antibacterial activity against MRSA. This effect was correlated to the result obtained by an increase in total phenolic contents in EtOAc-soluble extract. In addition, high-performance liquid chromatography analysis revealed that eckol, dieckol, dioxinodehydroeckol, and phlorofucofuroeckol-A contents in the EtOAc-soluble extract increased significantly. Thus, these results show that anti-MRSA activity of E. bicyclis fermented with C. utilis most likely originated from phlorotannins and allow the possible application of a variety of seaweed functional foods.     

Synthesis,Biological Evaluation,and Structure–Activity Relationships of 4-Aminopiperidines as Novel Antifungal Agents Targeting Ergosterol Biosynthesis

The aliphatic heterocycles piperidine and morpholine are core structures of well-known antifungals such as fenpropidin and fenpropimorph, commonly used as agrofungicides, and the related morpholine amorolfine is approved for the treatment of dermal mycoses in humans. Inspired by these lead structures, we describe here the synthesis and biological evaluation of 4-aminopiperidines as a novel chemotype of antifungals with remarkable antifungal activity. A library of more than 30 4-aminopiperidines was synthesized, starting from N-substituted 4-piperidone derivatives by reductive amination with appropriate amines using sodium triacetoxyborohydride. Antifungal activity was determined on the model strain Yarrowia lipolytica, and some compounds showed interesting growth-inhibiting activity. These compounds were tested on 20 clinically relevant fungal isolates (Aspergillus spp., Candida spp., Mucormycetes) by standardized microbroth dilution assays. Two of the six compounds, 1-benzyl-N-dodecylpiperidin-4-amine and N-dodecyl-1-phenethylpiperidin-4-amine, were identified as promising candidates for further development based on their in vitro antifungal activity against Candida spp. and Aspergillus spp. Antifungal activity was determined for 18 Aspergillus spp. and 19 Candida spp., and their impact on ergosterol and cholesterol biosynthesis was determined. Toxicity was determined on HL-60, HUVEC, and MCF10A cells, and in the alternative in vivo model Galleria mellonella. Analysis of sterol patterns after incubation gave valuable insights into the putative molecular mechanism of action, indicating inhibition of the enzymes sterol C14-reductase and sterol C8-isomerase in fungal ergosterol biosynthesis.     

Phenol oxidases production and wood degradation by a thermophilic fungusThermoascus aurantiacus

The ability of a Brazilian strain ofThermoascus aurantiacus, a thermophilic fungus, to produce extracellular phenol oxidases and to degradeEucalyptus grandis sawdust was studied.T. aurantiacus was capable of good growth in liquid culture containing 1.5% (w/v) of various lignocellulosic substrates (sugar cane bagasse, rice hulls, and chips and sawdust ofE. grandis) plus 5 mg/mL of glucose. When lignocellulosic substrates were used, enzymes involved in cellulose and hemicellulose metabolism were stimulated inT. aurantiacus. It was also found that these substrates have an inductive effect on phenol oxidase production. The most effective inducer of phenol oxidase activity wasE. grandis sawdust, which led to the production of 0.80 U/mL (o-dianisidine oxidation) on day 12. Low phenol oxidase activity was observed at cultures when only glucose was used. Cultures ofT. aurantiacus also exhibited cellobiose-quinone oxidoreductase activity when lignocellulosic materials were used as substrate. However, under our experimental conditions, lignin peroxidase activity was not detected.E. grandis sawdust supplemented with 5 mg/mL of glucose suffered a total weight loss of 6.7% accompanied by 15% lignin loss and 64.4% extractive loss after 21 d incubation withT. aurantiacus.