Synthesis and anticonvulsant activity of novel and potent 1-aryl-7,8-methylenedioxy-1,2,3,5-tetrahydro-4H-2,3-benzodiazepin-4-ones

The synthesis and anticonvulsant activity of 1-aryl-7,8-methylenedioxy-1,2,3,5-tetrahydro-4H-2,3-benzodiazepin-4-(thi)ones (4a-d) and their 3-N-alkylcarbamoyl derivatives (4e-h) are reported. The new compounds possess marked anticonvulsant properties, comparable to those of the dehydro analogues 3 and higher than that of GYKI 52466 (1). Noteworthy, compound 4c shows a longer-lasting anticonvulsant activity. Electrophysiological experiments show that derivative 4c is less effective than 1 and 3c to reduce the KA-evoked currents in cerebellar granule neurons.     

Exploration of antimicrobial and antioxidant potential of newly synthesized 2,3-disubstituted quinazoline-4(3H)-ones

A series of 2-(chloromethyl)-3-(4-methyl-6-oxo-5-[(E)-phenyldiazenyl]-2-thioxo-5,6-dihydropyrimidine-1(2H)-yl)quinazoline-4(3H)-ones 9a-j was synthesized by treating 2-(chloroacetyl)amino benzoic acid with 3-amino-6-methyl-5-[(E)-phenyldiazenyl]-2-thioxo-2,5-dihydropyrimidine-4(3H)-one 8a-j and was screened for in vitro antibacterial activities against a representative panel of Gram-positive and Gram-negative bacteria. The compounds were synthesized in excellent yields and the structures were corroborated on the basis of IR, ¹H NMR, Mass and elemental analysis data. All the synthesized compounds elicited the potent inhibitory action against all the tested bacterial stains. Furthermore, in order to explore the antioxidant potential of newly synthesized compounds, the free radical scavenging activity measurement were performed by the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay method. It is revealed from the antioxidant screening results that the compounds 9c and f manifested profound antioxidant potential.     

Synthesis and anticonvulsant activity of 3-aryl-5H-2,3-benzodiazephine AMPA antagonists.

A novel series of 3-aryl-5H-2,3-benzodiazepines with N-3 aromatic substituents has been synthesized. Good in vivo anticonvulsant activity of the new compounds has been demonstrated employing the maximal electroshock seizure test in mice. Evaluation of a subset of the compounds in the cortical wedge assay confirmed the new structures to be AMPA antagonists.     

The 4',4'-difluoro analog of 5'-noraristeromycin: a new structural prototype for possible antiviral drug development toward orthopoxvirus and cytomegalovirus

As a surrogate for 4'-hydroxy-5'-noraristeromycin and related carbocyclic nucleosides, an efficient, enantiodivergent synthetic route to both enantiomers of 5-(6-amino-9H-purin-9-yl)-3,3-difluorocyclopentane-1,2-diol (6 and ent-6) has been developed from a common starting material ((+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate, 10). Both compounds were assayed versus a series of viruses. The only response found was for compound 6 toward vaccinia and cowpox (EC50 of 143 and 94 microM, respectively) and human cytomegalovirus (EC50 of 6.2 microM). Both compounds were non-cytotoxic. While not as active as cidofovir toward the orthopox viruses and ganciclovir toward cytomegalovirus, compound 6 offers a new structural prototype upon which to build for uncovering new agents effective against these viral types.     

TEAC antioxidant activity of 4-hydroxybenzoates

The influence of pH, intrinsic electron donating capacity, and intrinsic hydrogen atom donating capacity on the antioxidant potential of series of hydroxy and fluorine substituted 4-hydroxybenzoates was investigated experimentally and also on the basis of computer calculations. The pH-dependent behavior of the compounds in the TEAC assay revealed different antioxidant behavior of the nondissociated monoanionic form and the deprotonated dianionic form of the 4-hydroxybenzoates. Upon deprotonation the radical scavenging ability of the 4-hydroxybenzoates increases significantly. For mechanistic comparison a series of fluorobenzoates was synthesized and included in the studies. The fluorine substituents were shown to affect the proton and electron donating abilities of 4-hydroxybenzoate in the same way as hydroxyl substituents. In contrast, the fluorine substituents influenced the TEAC value and the hydrogen atom donating capacity of 4-hydroxybenzoate in a way different from the hydroxyl moieties. Comparison of these experimental data to computer-calculated characteristics indicates that the antioxidant behavior of the monoanionic forms of the 4-hydroxybenzoates is not determined by the tendency of the molecule to donate an electron, but by its ability to donate a hydrogen atom. Altogether, the results explain qualitatively and quantitatively how the number and position of OH moieties affect the antioxidant behavior of 4-hydroxybenzoates.     

Caroverine, a multifunctional drug with antioxidant functions

Here we show that lipid peroxidation of liposomal membranes was suppressed in the presence of Caroverine, a spasmolytic drug used in some countries. In order to understand the mechanism of this antioxidant action of Caroverine we studied the interaction of Caroverine with superoxide radicals, hydroxyl radicals and peroxynitrite. The results of the study show that the reaction of Caroverine with O2-* radicals is of marginal significance. However, it is efficient in removing peroxynitrite and a particular high reaction constant was found for reaction with hydroxyl radicals. The strong antioxidant activity of Caroverine is therefore based both on the partial prevention of the formation and the highly active scavenging of hydroxyl radicals.     

Synthesis and antiplasmodial activity of new 4-aryl-2-trichloromethylquinazolines

A series of original 4-aryl-substituted 2-trichloromethylquinazoline derivatives was synthesized using a microwave-assisted Suzuki-Miyaura cross-coupling approach. Antiplasmodial activity was evaluated on both chloroquino-resistant and -sensitive Plasmodium falciparum strains, and the selectivity indexes for THP1 and HepG2 human cells were also calculated, revealing their antiplasmodial potential.     

Design,synthesis and bioevaluation of 3-oxo-6-aryl-2,3-dihydropyridazine-4-carbohydrazide derivatives as novel xanthine oxidase inhibitors

In view of expanding the structure activity relationship of xanthine oxidase inhibitors, a series of 3-oxo-6-aryl-2,3-dihydropyridazine-4-carbohydrazide/carboxylic acid derivatives were designed by molecular docking and synthesized. All the target compounds were evaluated for their in vitro XO inhibition by using febuxostat and allopurinol as the standard controls. Most of the hydrazide derivatives exhibited potency levels in the micromolar range. From the view of docking study, hydrazide derivatives bind to the active site of XO through a novel interaction mode, which is different from that of febuxostat bearing a carboxyl group. The most promising compound 8b was further subjected to kinetic analysis to deduce their modes of inhibition.     

The complete genome sequence of Bifidobacterium longum LTBL16, a potential probiotic strain from healthy centenarians with strong antioxidant activity

B. longum LTBL16 is a potential probiotic strain that was isolated from healthy centenarians in Bama, China. In vitro experiments show that B. longum LTBL16 has a strong antioxidant activity and the complete genome of B. longum LTBL16 was sequenced in this work. The genome consists of one 2,430,682 bp circular chromosome that is plasmid free. The circular chromosome has a GC content of 61.23% and contains 2071 coding sequences (CDSs), 4 rRNA manipulators and 55 tRNA coding genes. Genetic analysis showed that at least five protein-coding genes were associated with antioxidant activity, and the abundance of these genes may be related to free radical scavenging rates and oxygen tolerance. In addition, the safety of B. longum LTBL16 was evaluated using a virulence factor database and antibiotic resistance gene database. The results indicate that B. longum LTBL16 has the good potential for the development and utilization as a probiotic.     

The antioxidant activity of cyclohistidylproline

A cyclohistidyl-proline, cyclopeptide possessing a hormonal and neurotrophic activity is shown to be an inhibitor of the (Fe + ascorbic acid)-induced peroxidation of membrane lipids, its effect being dependent on its concentration. Inhibition of the malondialdehyde formation by cyclohistidil-proline is accompanied by protection of the membrane bound Ca-pump. In the test of the free radical cumole oxidation antioxidative effect of cyclohistidyl-proline is 4 times higher than that of the hydrophilic antioxidant carnosine. After peritoneal injection of cyclohistidil-proline (15 mg/kg of body weight) to rats the stationary level of thiobarbituric acid reactive products in rat brain or serum is pronouncedly decreased, this effect being in progress up to 6 h after injection. Antioxidative action of cyclohistidyl-proline suggests to be on the basis of a variety of its biological effects.     

The interaction of tylophorinidine,a potential leukemic drug,with bovine serum albumin

Association of tylophorinidine with bovine serum albumin was indioated by the quenching of the protein fluorescence above pH 7.0. The association constant, Ka, at pH 9.2 was calculated to be 5 × 10⁴ litres/mole. The Ka increased with increasing temperature, and the change in enthalpy, ΔH, was calculated to be 4.5 Kcals. The stoichionetry of binding obtained from Job's plot was 1:1. The data suggest involvement of tryptophan and hydrophobic forces in the albumintylophorinidine complex.     

The antioxidant properties and microbial load of Moringa oleifera leaves dried using a prototype convective air-dryer

The recent COVID-19 pandemic resulted in major postharvest losses because most fresh produce could not be sold. Drying is an important thermal-based food preservation method which could have prolonged the shelf-life of these produce, but most drying technologies are costly, and cannot be afforded by small-time farmers. From this context, we were interested in evaluating the drying of Moringa oleifera leaves (MOL) using a low-cost self-built prototype convective-air dryer (CAD), alongside conventional drying methods for its antioxidant properties, microbial load and phytoconstituents. Results showed total polyphenol content was the highest (p < 0.05) in our CAD samples, and it retained among the highest total flavonoid content, total antioxidant capacity, total alkaloid content and DPPH radical scavenging activity. Furthermore, methanolic CAD extract presented lower coliform and yeast and mold count than the aqueous CAD extract. We also briefly explored MOL as a sanitizer where the microbial load of the methanolic extract was comparable (p > 0.05) with several commercial non-alcoholic sanitizers, indicating its commercialization potential as a bio-friendly sanitizer. Finally, using GC–MS, we are the first to report (best of our knowledge) on the presence of caprolactam, an important bio-medical field compound, in the CAD sample’s aqueous extract.     

The antioxidant action of anticataract drug preparations

In our days the role of lens lipid peroxidation in cataract development is under discussion. It is important to establish if anticataract preparations hinder this process. Antioxidation action of different anticataract drugs in phosphate buffer--rat serum--FeSO4 system was studied. It was established that only part of anticataract drugs are able to hinder lipid peroxidation.     

The activator-binding site of Onchocerca volvulus S-adenosylmethionine decarboxylase,a potential drug target

S-Adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in polyamine biosynthesis. In many eukaryotes its activity is stimulated specifically by putrescine. The AdoMetDC of the filarial parasite Onchocerca volvulus, however, is not only stimulated by putrescine but also by the naturally occuring polyamines spermidine and spermine. Several diamines, acetylated polyamines and polyamine analogues were used to analyse what molecular prerequisites are needed to stimulate nematode AdoMetDC activity. In the absence of an activator, the O. volvulus enzyme exhibits an extremely low specific activity. This fact, together with the unspecificity of activator binding, was thought to be useful for a new strategy to inhibit nematode AdoMetDC activity. Therefore, different polyamine analogues were tested as competitive inhibitors towards the stimulatory effect putrescine has on the O. volvulus and, in comparison, on the Caenorhabditis elegans and human AdoMetDC. Bis(aralkyl)- and bis(alkyl)-substituted polyamine analogues with a 3-7-3 backbone were found to inhibit AdoMetDC activities, however, probably without interfering with the putrescine stimulation. The best inhibitor, BW-1, was about 10-fold more effective against O. volvulus AdoMetDC than against the human enzyme. Unexpectedly, BW-1 was determined to be a competitive inhibitor with respect to AdoMet, having a Ki value of 310 microM for the putrescine-stimulated human AdoMetDC. Furthermore, we show for the O. volvulus and the human enzyme that the degree of inhibition by BW-1 depends on the actual putrescine concentration.     

Anti-ulcer and antioxidant activity of Normacid, a herbomineral formulation

Effect of various doses (125, 250, 500 and 1000 mg/kg, po) of Normacid was studied on gastric secretion and gastric ulcers in pylorus-ligation and on ethanol-induced gastric mucosal injury in rats. The reduction in ulcer index in both the models along with the reduction in total acidity and an increase in the pH of gastric fluid in pylorus-ligated rats proved the anti-ulcer activity of Normacid. The increase in the levels of superoxide dismutase, catalase, reduced glutathione and membrane bound enzymes like Ca2+ ATPase, Mg2+ ATPase and Na+K+ ATPase and decrease in lipid peroxidation in both the models showed the antioxidant activity of the formulation. Thus it can be concluded that the anti-ulcer activity shown by Normacid may be due to the modulation of defensive factors by improvenent in gastric cytoprotection and partly due to antioxidant property.     

The antioxidant activity of phloretin: the disclosure of a new antioxidant pharmacophore in flavonoids

Phloretin is a dihydrochalcone flavonoid that displays a potent antioxidant activity in peroxynitrite scavenging and the inhibition of lipid peroxidation. Comparison with structurally related compounds revealed that the antioxidant pharmacophore of phloretin is 2,6-dihydroxyacetophenone. The potent activity of 2,6-dihydroxyacetophenone is due to stabilisation of its radical via tautomerisation. The antioxidant pharmacophore in the dihydrochalcone phloretin, i.e., the 2,6-dihydroxyacetophenone group, is different from the antioxidant pharmacophores previously reported in flavonoids.     

Morphine,a potential inhibitor of myeloperoxidase activity

Morphine is an opioid alkaloid commonly used in clinical practice for its analgesic properties. The phenolic hydroxyl group of that phenanthrene derivative is pivotal for binding to opioid receptors but it may also be responsible for the antioxidant behavior of morphine reported in several in vitro experiments. In this study, we assessed the effect of morphine on myeloperoxidase (MPO), a hemic enzyme from azurophilic granules of polymorphonuclear neutrophils involved in the production of cytotoxic and microbicidal reactive oxidants during inflammatory response. Specific immunological extraction followed by enzyme detection (SIEFED) and molecular modeling (docking) were performed to study the potential anti-catalytic action of morphine on MPO in comparison with the inhibitory effects of reference antioxidant molecules quercetin, gallic acid and ascorbic acid. The reducing action of morphine on the MPO peroxidase cycle has been investigated using electron paramagnetic resonance (EPR) and UV-visible absorption spectroscopy. Morphine acted as a reducing substrate in the peroxidase cycle of MPO and therefore protected the enzyme against the suicide action of its natural substrate, hydrogen peroxide. The SIEFED experiments associated with the docking study, further demonstrated a lack of strong and sustained anti-catalytic activity of morphine. In summary, from the results of this study, it appears that morphine acts as a weak and reversible inhibitor of MPO that may nonetheless contribute to immunomodulatory and antioxidant effects of this opioid analgesic in vivo.     

Artesunate,a potential drug for treatment of Babesia infection

The effects of artesunate, a water-soluble artemisinin derivative, against Babesia species, including Babesia bovis, Babesia gibsoni and Babesia microti were studied. Cultures of B. bovis and B. gibsoni were treated with 0.26, 2.6, 26 and 260 μM artesunate, showing inhibition of parasite growth at concentrations equal to and greater than 2.6 μM artesunate by days 3 post-treatment for B. gibsoni and B. bovis in a dose-dependent manner. Consistent with in vitro experiments, artesunate was effective in the treatment of mice infected with B. microti at doses equal to and greater than 10 mg/kg of body weight on days 8–10 post-infection. Taken together, these results suggest that artesunate could be a potential drug against Babesia infection.     

Evaluation of antioxidant activity and potential toxicity of 1-buthyltelurenyl-2-methylthioheptene

The aim of the present study was to evaluate pharmacological and toxicological properties of 1-buthyltelurenyl-2-methylthioheptene (compound 1). In vitro, compound 1 at 1 μM was effective in reducing lipid peroxidation induced by Fe/EDTA. Compound 1 presented neither thiol peroxidase nor thiol oxidase activity and did not change δ-ALA-D (δ-aminolevulinate dehydratase) activity (10-400 μM). Calculated LD₅₀ of compound 1, administered by oral route, was 65.1 μmol/kg. Rats treated with compound 1 did not reveal any motor impairment in the open field. Hepatic, renal and cerebral lipid peroxidation in treated rats did not differ from those in control rats. Conversely, 0.5 μmol/kg of compound 1 decreased lipid peroxidation in spleen. δ-ALA-D activity in liver and spleen was inhibited in rats treated with the higher dose of compound 1 but no significant differences were detected in renal δ-ALA-D activity. AST (aspartate aminotransferase) and ALT (alanine aminotransferase) activities as well as urea and creatinine levels were increased by high doses of compound 1 (50-75 μmol/kg). Compound 1 induced a significant decrease in plasma triglyceride levels but none of the doses tested changed the cholesterol level. This is a promising compound for more detailed pharmacological studies involving organotellurium compounds.