Neue phloroglucin-derivate aus Leontonyx-arten sowie weitere verbindungen aus vertretern der tribus inuleae

The investigation of several South African species of the tribe Inuleae afforded in addition to known compounds 16 new constituents. From Leontonyx a group of 9 new phloroglucinol derivatives, from Stoebe species two new p-hydroxyacetophenone, two thymol and two coumaric acid derivatives and from Relhania a new euparine-derivative were isolated. The structures are elucidated mainly by spectroscopic methods. The chemotaxonomic aspects are discussed briefly. The phloroglucinol derivatives, which in part are derived from geraniol, seem to be especially characteristic.     

The effect of polyhexamethylene guanidine hydrochloride (PHMG) derivatives introduced into polylactide (PLA) on the activity of bacterial enzymes

The present study was aimed at investigating bactericidal properties of polylactide (PLA) films containing three different polyhexamethylene guanidine hydrochloride (PHMG) derivatives and effect of the derivatives on extracellular hydrolytic enzymes and intracellular dehydrogenases. All PHMG derivatives had a slightly stronger bactericidal effect on Staphylococcus aureus than on E. coli but only PHMG granular polyethylene wax (at the concentration of at least 0.6 %) has a bactericidal effect. PHMG derivatives introduced into PLA affected the activity of microbial hydrolases to a small extent. This means that the introduction of PHMG derivatives into PLA will not reduce its enzymatic biodegradation significantly. On the other hand, PHMG derivatives introduced into PLA strongly affected dehydrogenases activity in S. aureus than in E. coli.     

Design,synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors

By targeting the ThDP binding site of Escherichia coli PDHc-E1, two new ‘open-chain’ classes of E. coli PDHc-E1 inhibitors, amide and urea derivatives, were designed, synthesized, and evaluated. The amide derivatives of compound 6d, with 4-NO₂ in the benzene ring, showed the most potent inhibition of E. coli PDHc-E1. The urea derivatives displayed more potent inhibitory activity than the corresponding amide derivatives with the same substituent. Molecular docking studies confirmed that the urea derivatives have more potency due to the two hydrogen bonds formed by two NH of urea with Glu522. The docking results also indicate it might help us to design more efficient PDHc-E1 inhibitors that could interact with Glu522.     

1-O-2′-hydroxyalkyl and 1-O-2′-ketoalkyl glycerols

1-O-2′-Hydroxyalkyl glycerols were synthesized from 1,2-alkanediols and, alternatively, from 1,2-epoxyalkanes. Their 2,3-isopropylidene derivatives, 2′-acetoxy-2,3-isopropylidene derivatives and 2′,2,3-triacetoxy derivatives were prepared. 1-O-2′-Ketoalkyl-2,3-isopropylidene glycerols were prepared from the corresponding 2′-hydroxy derivatives; they were hydrolyzed to 1-O-2′-ketoalkyl glycerols. The compounds were characterized by thin-layer and gas-liquid chromatography, by infrared spectroscopy and mass spectrometry.     

Efficacy of novel antibacterial compounds targeting histidine kinase YycG protein

Treating staphylococcal biofilm-associated infections is challenging. Based on the findings that compound 2 targeting the HK domain of Staphylococcus epidermidis YycG has bactericidal and antibiofilm activities against staphylococci, six newly synthesized derivatives were evaluated for their antibacterial activities. The six derivatives of compound 2 inhibited autophosphorylation of recombinant YycG′ and the IC₅₀ values ranged from 24.2 to 71.2 μM. The derivatives displayed bactericidal activity against planktonic S. epidermidis or Staphylococcus aureus strains in the MIC range of 1.5–3.1 μM. All the derivatives had antibiofilm activities against the 6- and 24-h biofilms of S. epidermidis. Compared to the prototype compound 2, they had less cytotoxicity for Vero cells and less hemolytic activity for human erythrocytes. The derivatives showed antibacterial activities against clinical methicillin-resistant staphylococcal isolates. The structural modification of YycG inhibitors will assist the discovery of novel agents to eliminate biofilm infections and multidrug-resistant staphylococcal infections.     

Synthesis and Topoisomerase I inhibitory properties of klavuzon derivatives

Klavuzon is a naphthalen-1-yl substituted α,β-unsaturated δ-lactone derivative, and is one of the anti-proliferative members of this class of compounds. Asymmetric and racemic syntheses of novel α,β-unsaturated δ-lactone derivatives are important to investigate their potential for the treatment of cancer. In this study, asymmetric and racemic syntheses of heteroatom-substituted klavuzon derivatives are reported. The syntheses were completed by a well-known three-step procedure. Anti-proliferative activity of seven novel racemic klavuzon derivatives were reported against MCF-7, PC3, HCT116 p53+/+ and HCT116 p53−/− cancer cell lines. Topoisomerase I inhibitory properties of 5,6-dihydro-2H-pyran-2-one derivatives were also studied.     

The significance of arbutin and its derivatives in therapy and cosmetics

The ongoing studies on biological activity of arbutin and its derivatives show a wide range of their possible applications. Arbutin containing plant substances are used mostly in the treatment of urinary tract infections (UTI). However, several in vitro and in vivo studies revealed anti-melanogenic activity of arbutin, which can be useful in hyperpigmentation therapy. Moreover, it was found that the modifications in arbutin structure lead to an increase of the above-mentioned activity. The lack of significant adverse effects of arbutin and its derivatives makes them a valuable alternative to hydroquinone. Therefore, an increasing interest in arbutin and its derivatives is observed especially in the cosmetics industry.The scope of biological activity covered by the findings of in vivo and in vitro studies on arbutin and its derivatives are discussed.     

Separation and identification of O-acetyl-O-methyl-galactononitriles by gas-liquid chromatography and mass spectrometry

The gas-liquid-chromatographic retention-times and the mass-spectral features of partially methylated d-galactononitrile acetates are reported. Distinctive fragmentation of each of the mono-O-methyl derivatives allows their identification, and the results are applicable to the same substituted derivatives of the other aldohexoses. A new fragmentation-pathway, typical of the acetylated and the O-acetyl-O-methylaldononitriles, is proposed in order to justify previously unexplained fragments. This fragmentation competes with the known ones in derivatives that do not carry vicinal methoxyl groups.     

Inhibition of Candida albicans virulence factors by novel levofloxacin derivatives

Candida albicans is an important opportunistic fungal pathogen, responsible for biofilm associated infections in immunocompromised patients. The aim of the present study was to investigate the antibiofilm properties of novel levofloxacin derivatives on C. albicans biofilms. The levofloxacin derivatives at their Biofilm Inhibitory Concentrations (BIC) were able to inhibit the biofilms of C. albicans, the yeast-to-hyphal transition and were also able to disrupt their mature biofilms. Furthermore, Real-time PCR analysis showed that the expression of ergosterol biosynthesis pathway gene (ERG11) and the efflux pump-encoding genes (CDR1 and MDR1) was decreased upon treatment with the levofloxacin derivatives. The total ergosterol content quantified using UV spectrophotomer showed decrease in ergosterol in the presence of levofloxacin derivatives. Overall, levofloxacin derivatives (6a, 6c and 7d) are capable of inhibiting C. albicans virulence factors. Therefore, these compounds with potential therapeutic implications can be used as new strategy to treat biofilm-related candidal infections.     

Neue ent-labdan-derivate aus Austroeupatorium chaparense

The aerial parts of A. chaparense afforded, in addition to known compounds, five new ent-labdane derivatives, while Campovassouria bupleurifolia contains mainly kaurene derivatives. The chemotaxonomic situation is briefly discussed.     

Constituents of the genus Oxylobus

The aerial parts of Oxylobus arbutifolius and O. adscendens gave eudesmanolides and labdane derivatives as well as two new euparin derivatives.     

Biological activities of novel derivatives of DIF-1 isolated from Dictyostelium

The differentiation-inducing factor-1 (DIF-1) is a lipophilic signal molecule (chlorinated alkylphenone) that induces stalk cell differentiation in the cellular slime mold Dictyostelium discoideum. In addition, DIF-1 and its derivatives have been shown to possess anti-leukemic activity and glucose consumption-promoting activity in vitro in mammalian cells. In this study, to assess the chemical structure-effect relationship of DIF-1, we synthesized eight derivatives of DIF-1 and investigated their stalk cell-inducing activity in Dictyostelium cells and pharmacological activities in mammalian cells. Of the derivatives, two amide derivatives of DIF-1, whose hydrophobic indexes are close to that of DIF-1, induced stalk cell differentiation as strongly as DIF-1 in Dictyostelium cells. It was also found that some derivatives suppressed cell growth in human K562 leukemia cells and promoted glucose consumption in mouse 3T3-L1 cells. These results give us valuable information as to the chemical structure-effect relationship of DIF-1.     

Ciprofloxacin Derivatives Affect Parasite Cell Division and Increase the Survival of Mice Infected with Toxoplasma gondii

Toxoplasmosis, caused by the protozoan Toxoplasma gondii, is a worldwide disease whose clinical manifestations include encephalitis and congenital malformations in newborns. Previously, we described the synthesis of new ethyl-ester derivatives of the antibiotic ciprofloxacin with ~40-fold increased activity against T. gondii in vitro, compared with the original compound. Cipro derivatives are expected to target the parasite’s DNA gyrase complex in the apicoplast. The activity of these compounds in vivo, as well as their mode of action, remained thus far uncharacterized. Here, we examined the activity of the Cipro derivatives in vivo, in a model of acute murine toxoplasmosis. In addition, we investigated the cellular effects T. gondii tachyzoites in vitro, by immunofluorescence and transmission electron microscopy (TEM). When compared with Cipro treatment, 7-day treatments with Cipro derivatives increased mouse survival significantly, with 13–25% of mice surviving for up to 60 days post-infection (vs. complete lethality 10 days post-infection, with Cipro treatment). Light microscopy examination early (6 and 24h) post-infection revealed that 6-h treatments with Cipro derivatives inhibited the initial event of parasite cell division inside host cells, in an irreversible manner. By TEM and immunofluorescence, the main cellular effects observed after treatment with Cipro derivatives and Cipro were cell scission inhibition - with the appearance of ‘tethered’ parasites – malformation of the inner membrane complex, and apicoplast enlargement and missegregation. Interestingly, tethered daughter cells resulting from Cipro derivatives, and also Cipro, treatment did not show MORN1 cap or centrocone localization. The biological activity of Cipro derivatives against C. parvum, an apicomplexan species that lacks the apicoplast, is, approximately, 50 fold lower than that in T. gondii tachyzoites, supporting that these compounds targets the apicoplast. Our results show that Cipro derivatives improved the survival of mice acutely infected with T. gondii and inhibited parasite replication early in the first cycle of infection in vitro, highlighting their therapeutic potential for the treatment of toxoplasmosis.     

Synthesis and antimicrobial activity of some new substituted pyrido[3′,2′:4,5]thieno[3,2-d]-pyrimidinone derivatives

A series of new 3-substituted-7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,4-dichlorophenyl)-2-methylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one derivatives were synthesized as antimicrobial agents using 7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,4-dichlorophenyl)-2-methyl-4H-pyrido[3′,2′:4,5]thieno[3,2-d]-[1,3]oxazin-4-one as a starting compound. Its condensation with substituted aniline derivatives or phenyl hydrazine gave the corresponding N-substituted derivatives. Treatment of the starting compound with hydrazine hydrate afforded the corresponding N-amino derivative, which was reacted with substituted phenylisocyanate and phenylisothiocyanate derivatives to give the corresponding semicarbazides and thiosemicarbazide derivatives. All the newly synthesized compounds were evaluated for their antimicrobial activities in comparison to streptomycin and fusidic acid as positive controls. The structure assignments of the new compounds are based on chemical and spectroscopic evidence.     

Synthesis and acetylcholinesterase inhibitory activities of tabersonine derivatives

Tabersonine, the main alkaloid in Voacanga seeds, was used as a lead compound to semi-synthesize tabersonine derivatives. In total, 13 compounds, containing 10 novel tabersonine derivatives, were synthesized by introducing substituent groups R₁–R₅. The acetylcholinesterase (AChE) inhibitory activities of tabersnonine derivatives were evaluated using Ellman’s method. Among them, compound (7) showed the highest AChE inhibitory activity with the IC₅₀ value was 5.32 μM. The substituent groups R₁–R₅ showed different influences on the AChE inhibitory activities of tabersonine derivatives. The AChE inhibitory activities of tabersonine derivatives increased with the introduction of group R₁ and/or combined groups R₃, R₄, while decreased with the introduction of group R₅. And the group R₂ showed no significant influence on the AChE inhibitory activities of tabersonine derivatives.     

Syntheses and chiroptical properties of some derivatives of 1-thioglycerol

A modified synthesis of 3-thio-sn-glycerol which leads to a product of high optical purity is described. The purity was demonstrated by the use of a chiral shift reagent. 3-S-Acetyl- and 3-S-oleyl-3-thio-sn-glycerol as well as 3-acyl derivatives of 3-thio-sn-glycerol have been synthesized. The ORD and CD curves of these compounds as well as of some other derivatives of 3-thio-sn-glycerol were analyzed and discussed. The CD curves of the triacyl derivatives show a positive effect at 260 nm and a negative effect at 230–250 nm.     

Labdane and dehydronerolidol derivatives from Brickellia diffusa

An investigation of Brickellia diffusa afforded three new dehydronerolidol derivatives and five new labdane derivatives, all highly oxygenated. The structures were elucidated by spectroscopic methods and a few chemical transformations. The compounds isolated showed close relationships to those isolated from Brickellia sp.     

G.L.C.-M.S. of partially methylated and acetylated derivatives of 3-deoxyoctitols

Partially methylated and acetylated 3-deoxyoctitols were prepared from derivatives of 3-deoxy-d-manno-2-octulosonic acid (KDO), and identified as the d-glycero-d-talo and d-glycero-d-galacto isomers by g.l.c.-m.s. Mono- and oligosaccharide derivatives of KDO were subjected in sequence to methylation, carboxyl-reduction, hydrolysis, carbonyl-reduction, and acetylation to yield 1,2,6-tri-O-acetyl-3-deoxyoctitol derivatives. Carboxyl-reduction and then methylation gave the series of 2,6-di-O-acetyl derivatives. Oligosaccharides with KDO at the reducing end, e.g., β-d-ribofuranosyl-(1→7)-KDO, α-l-glycero-d-manno-heptopyranosyl-(1→5)-KDO, and α-KDOp-(2→4)-KDO, yielded, after carbonyl-reduction, methylation, carboxyl-reduction, hydrolysis, and acetylation, the 1,7-, 1,5-, and 1,4-di-O-acetyl derivatives, whereas remethylation after carboxyl-reduction gave the 7-, 5-, and 4-O-acetyl derivatives of 3-deoxyoctitol. General rules for the fragmentation of 3-deoxyoctitols during e.i.-m.s. were established.     

Specificity of thrombin: I. Esterolytic properties of thrombin,plasma, trypsin,and chymotrypsin with Nβ-substituted guanidino derivatives of p-nitrophenyl-p′-guanidinobenzoate

Thrombin exhibits a restricted specificity, relative to plasmin, trypsin, and chymotrypsin, for a series of derivatives of the titrant substrate p-nitrophenyl-p′-guanidinobenzoate (NPGB). Substitution on the beta guanidino nitrogen of NPGB with an n-butyl, n-hexyl, cyclo-hexyl, or benzyl residue does not prevent the esterolytic cleavage of these derivatives but does markedly alter their substrate properties with the four enzymes investigated.All four enzymes cleave NPGB at equivalent concentrations by releasing p-nitrophenol as pre-steady-state burst reactions followed by its steady-state production. Both chymotrypsin and trypsin similarly display burst reactions with the derivatives at corresponding concentrations. The acyl-enzyme intermediates formed with chymotrypsin, however, are more stable for the derivatives than for NPGB, and those formed with trypsin are less stable. In contrast, plasmin and thrombin exhibit incomplete burst reactions with the derivatives at these concentrations. Except for the cyclo-hexyl derivative, with which plasmin does not react, the derivatives relative to NPGB were cleaved faster by plasmin than by thrombin. These cleavages with thrombin, moreover, were competitively inhibited by benzamidine. Kinetic data obtained for thrombin further indicated that the substituent groups of derivatives hindered the initial formation of enzyme-substrate complexes. These results suggest that thrombin and, most likely, plasmin have restricted primary binding-site regions for small molecule substrates which do not readily accommodate bulky substituent groups.In addition, increasing concentrations of glycerol were found to greatly alter the esterolytic properties of thrombin for the compounds studied. This effect was demonstrated by increased deacylation rates with NPGB and by decreased cleavage rates with the n-butyl derivative.     

Further sesquiterpene lactones from the genus Dittrichia

The aerial parts of Dittrichia graveolens afforded in addition to compounds isolated previously five new sesquiterpene lactones, two benzoic acid derivatives while D. viscosa gave two further derivatives of costic acid. The structures were elucidated by high field NMR spectroscopy.