Synthesis and in vitro trypanocide activity of several polycyclic drimane-quinone derivatives

The Diels-Alder reaction between two polygodial-derived dienes and simple quinones to yield substituted naphtho- and anthraquinones, is described. The in vitro trypanocide activity for the series was determined. Two of the new compounds showed an activity ten and two times higher, respectively, than nifurtimox and benznidazole, the medicines of choice for the treatment of the acute Chagas' disease.     

Novel vanillin derivatives containing a 1,3,4-thiadiazole moiety as potential antibacterial agents

In this study, thirty-four novel vanillin derivatives containing a 1,3,4-thiadiazole structure were obtained and their antibacterial activities were evaluated. The results indicate that most of the title compounds displayed inhibitory effects on Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas oryzae pv. oryzicola (Xoc). Among them, compound 29 exhibited excellent antibacterial activities against Xoo and Xoc in vitro, with the EC₅₀ values of 3.14 and 8.83 μg/mL, respectively, much superior to thiodiazole copper (87.03 and 108.99 μg/mL) and bismerthiazol (67.64 and 79.26 μg/mL). Under greenhouse condition, the protective efficiency of compound 29 against rice bacterial leaf blight was 49.34%, and curative efficiency was 40.96%. In addition, compound 29 can reduce the exopolysaccharides production of Xoo, increase the permeability of cell membrane and damage cell membrane.     

Bioactivity studies of oxysporone and several derivatives

Recently oxysporone, a phytotoxic dihydrofuropyranone, was isolated along with two closely related compounds, afritoxinones A and B, from liquid cultures of Diplodia africana, an invasive fungal pathogen of Phoenicean juniper. In this study, eight derivatives were hemisynthesized and assayed for their phytotoxic and antifungal activities in comparison to the parent compound. Each compound was tested on non-host plants and on four destructive plant pathogens such as Athelia rolfsii, Diplodia corticola, Phytophthora cinnamomi and P. plurivora. The results on the phytotoxic activity showed that the dihydrofuropyranone carbon skeleton and both the double bond the hydroxy group of dihydropyran ring appeared to be structural features important in conferring activity. Although the data concerning the antifungal activity did not allow to extract any structure–activity relationships, it should be underlined that the conversion of oxysporone into the corresponding 4-O-benzoyl derivative led to a compound showing a good antifungal activity towards three out of the four organisms tested.     

Rational design of pyridyl derivatives of vanillin for the treatment of sickle cell disease

Hypoxia-induced polymerization of sickle hemoglobin (Hb S) is the principal phenomenon that underlays the pathophysiology and morbidity associated with sickle cell disease (SCD). Opportunely, as an allosteric protein, hemoglobin (Hb) serves as a convenient and potentially critical druggable target. Consequently, molecules that prevent Hb S polymerization (Hb modifiers), and the associated erythrocyte sickling have been investigated–and retain significant interest–as a viable therapeutic strategy for SCD. This group of molecules, including aromatic aldehydes, form high oxygen affinity Schiff-base adducts with Hb S, which are resistant to polymerization. Here, we report the design and synthesis of novel potent antisickling agents (SAJ-009, SAJ-310 and SAJ-270) based on the pharmacophore of vanillin and INN-312, a previously reported pyridyl derivative of vanillin. These novel derivatives exhibited superior in vitro binding and pharmacokinetic properties compared to vanillin, which translated into significantly enhanced allosteric and antisickling properties. Crystal structure studies of liganded Hb in the R2 quaternary state in complex with SAJ-310 provided important insights into the allosteric and antisickling properties of this group of compounds. While these derivatives generally show similar in vitro biological potency, significant structure-dependent differences in their biochemical profiles would help predict the most promising candidates for successful in vivo pre-clinical translational studies and inform further structural modifications to improve on their pharmacologic properties.     

Enantioselective recognition of 2,3-benzodiazepin-4-one derivatives with anticonvulsant activity on several polysaccharide chiral stationary phases

The dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501) has potent in vitro cytotoxicity and in vivo antitumor activity. SJG-136 binds in the minor groove of DNA and produces G-G interstrand cross-links via reactive N(10)-C(11)/N(10')-C(ll') imine/carbinolamine moieties. We have developed a sensitive, specific liquid chromatography tandem mass spectrometry (LC/MS/MS) method for the quantitative determination of SJG-136 in plasma. SJG-136 was isolated by solid phase extraction through a C8 column, reverse-phase HPLC separation was accomplished on a C18 column with isocratic elution and MS/MS detection, monitoring the m/z 557-m/z 476 transition after electrospray ionization. The linear range and lower limit of quantitation from plasma standard curves were 2.8-1800 nM, and 5 nM, respectively. SJG-136 plasma protein binding was species-dependent. Values of the unbound fraction in human, rat and mouse were 25%, 16.2% and <1%, respectively. Protein binding was saturable in dog plasma where the unbound fraction increased from 10.8% to 22.3% over a 22-720 nM concentration range. SJG-136 pharmacokinetics after a single intravenous dose were best fit to a two-compartment open model with elimination half-life and plasma clearance values of 97 min and 6.1 mL/min/kg, respectively. SJG-136 did not accumulate in plasma following intravenous administration of 1.0 microg/kg doses for five consecutive days.     

Biocatalytic synthesis of vanillin

The conversions of vanillic acid and O-benzylvanillic acid to vanillin were examined by using whole cells and enzyme preparations of Nocardia sp. strain NRRL 5646. With growing cultures, vanillic acid was decarboxylated (69% yield) to guaiacol and reduced (11% yield) to vanillyl alcohol. In resting Nocardia cells in buffer, 4-O-benzylvanillic acid was converted to the corresponding alcohol product without decarboxylation. Purified Nocardia carboxylic acid reductase, an ATP and NADPH-dependent enzyme, quantitatively reduced vanillic acid to vanillin. Structures of metabolites were established by (1)H nuclear magnetic resonance and mass spectral analyses.     

omega-Hydroxyacid derivatives in the epidermis of several mammalian species

1. omega-Hydroxyacids from the acylceramides and acylglucosylceramides of mammalian epidermis were examined by thin-layer and gas-liquid chromatography to determine their degree of unsaturation and chain-length distributions. The species examined included human (Homo sapiens), pig (Sus scrofa), mouse (Mus musculus) and rat (Rattus rattus). 2. Within a species, the omega-hydroxyacids from the acylceramide and acylglucosylceramide were essentially identical. 3. The human omega-hydroxyacids proved to be mainly saturated with C30:0 being the major entity. 4. The pig contained similar saturated, monoenoic and small amounts of dienoic omega-hydroxyacids, with C30:0, C32:1 being the major entities. 5. The mouse and rat contained C32:0 and C34:1 as the major components.     

Biotechnological production of vanillin

Vanillin is one of the most important aromatic flavor compounds used in foods, beverages, perfumes, and pharmaceuticals and is produced on a scale of more than 10 thousand tons per year by the industry through chemical synthesis. Alternative biotechnology-based approaches for the production are based on bioconversion of lignin, phenolic stilbenes, isoeugenol, eugenol, ferulic acid, or aromatic amino acids, and on de novo biosynthesis, applying fungi, bacteria, plant cells, or genetically engineered microorganisms. Here, the different biosynthesis routes involved in biotechnological vanillin production are discussed.     

Sensitivity of Rhizobia to vanillin

The sensitivity of Rhizobia isolated from pea, fenugreek, gram, cowpea, urid andRhizobium meliloti, Rhizobium trifolii andRhizobium japonicum was studied in asparagine-mannitol, salt-mannitol and salt media. It was observed that Rhizobia from gram were most resistant.Rhizobium japonicum was found to be resistant up to 50 mg vanillin/100 ml. Vanillin-resistant strains could utilize vanillin as the sole carbon source. In the case of pea, gram and fenugreek vanillin was found to be utilized in the presence of mannitol.     

Synthesis and characterization of several carbamoyl- and methylcarbamoyl-substituted EMPO derivatives

The spin trapping behavior of four novel carbamoyl-substituted EMPO derivatives, namely 5-carbamoyl-3,5-dimethyl-pyrroline N-oxide (CADMPO), 3,5-dimethyl-5-methylcarbamoyl-pyrroline N-oxide (DMMCAPO), 5-carbamoyl-3-ethyl-5-methyl-pyrroline N-oxide (CAEMPO), and 3-ethyl-5-methyl-5-methylcarbamoyl-pyrroline N-oxide (EMMCAPO), towards different oxygen- and carbon-centered radicals is described, the half lives of the respective superoxide adducts ranging from about 10 to 20 min. The most characteristic adducts were, however, formed from methyl, hydroxymethyl, hydroxyethyl, and carbon dioxide anion radicals.     

Choleretic activity and biliary elimination of lipids and bile acids induced by an artichoke leaf extract in rats

The therapeutic properties of artichoke (Cynara scolymus L.) preparations have been known since ancient times. The traditional use of artichoke leaf extract (ALE) in gastroenterology is mainly based upon its strong antidyspeptic actions which are mediated by its choleretic activity. The aim of this study was to investigate the effects of ALE on bile flow and the formation of bile compounds in anaesthetised Wistar rats after acute and repeated (twice a day for 7 consecutive days) oral administration. A significant increase in bile flow was observed after acute treatment with ALE as well as after repeated administration. The choleretic effects of ALE were similar to those of the reference compound dehydrocholic acid (DHCA). Total bile acids, cholesterol and phospholipid were determined by enzymatic assays. There was a strong ALE-induced increase in total bile acid concentration over the entire experiment. With the highest dose (400 mg/kg), a significant increase was obtained after single and repeated administration. The bile acids-increased effects of ALE were much more pronounced than those of reference (DHCA). No significant differences in cholesterol and phospholipid content could be found.     

Anticalcium activity of several antidepressive agents]

In experiments in white mice and rats the antidepressants pyrazidol (pirlindole), moclobemide and especially tetrindole possess anticalcium activity in tests of calcium chloride-induced lethality in mice and arrhythmia in rats. Tetrindole is as active as verapamil. Imipramine, azaphen and incazane were not active in these experiments. In vitro on isolated intestinal segments of guinea-pigs tetrindole exerts anticalcium action, but in less degree than verapamil. In all probability the anticalcium activity of tetrindole may play some role in the mechanism of action of this compound on the central nervous system.     

Antiviral activity of benzimidazole derivatives. II. Antiviral activity of 2-phenylbenzimidazole derivatives

Seventy-six 2-phenylbenzimidazole derivatives were synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against a panel of 10 RNA and DNA viruses. The most commonly affected viruses were, in decreasing order, CVB-2, BVDV, Sb-1, HSV-1, and YFV, while HIV-1 and VSV were not affected, and RSV, VV and Reo-1 were only susceptible to a few compounds. Thirty-nine compounds exhibited high activity (EC₅₀ = 0.1–10 μM) against at least one virus, and four of them were outstanding for their high and selective activity against VV (24, EC₅₀ = 0.1 μM) and BVDV (50, 51, and 53 with EC₅₀ = 1.5, 0.8, and 1.0 μM, respectively). The last compounds inhibited at low micromolar concentrations the NS5B RdRp of BVDV and also of HCV, the latter sharing structural similarity with the former. The considered compounds represent attractive leads for the development of antiviral agents against poxviruses, pestiviruses and even HCV, which are important human and veterinary pathogens.