Kinetics and metabolism of (+)-, (−)- and (±)-bufuralol

Summary Single oral doses of (+)-, (–)- and (±)-bufuralol were administered to a healthy volunteer to compare the disposition and metabolism of the individual isomers and the racemate. Plasma levels and area under plasma curve (AUC) of the active isomer, (–)-bufuralol, were higher than those of the (+)-isomer; plasma clearance was correspondingly lower. Intermediate values were found for the racemate. The elimination half-life of (–)-bufuralol was shorter than that of (+)-bufuralol, but similar to the racemate. Both isomers were cleared almost entirely by metabolism. The main metabolic pathway for (–)-bufuralol was aromatic hydroxylation, whereas the principal route for (+)-bufuralol was conjugation. Phenol metabolites in the systemic circulation were present mainly as conjugates. Both isomers also underwent aliphatic hydroxylation. This pathway was more favoured by the (+)-isomer, although plasma levels and AUC of the principal product, 2-hydroxy-bufuralol, were almost identical for the two forms. Major differences in metabolic fate thus had relatively little effect on the disposition of pharmacologically active metabolites.     

Pyridine-2,5-dicarboxylate complexes with 2,2′-bipyridine and Co(II), Zn(II), Cu(II): syntheses, characterization, antimicrobial, and cytotoxic effects

In this study, three novel mononuclear M(II)-pyridine-2,5-dicarboxylate (M = Co(II), Cu(II), and Zn(II)) complexes with pyridine-2,5-dicarboxylic acid or (isocinchomeronic acid, H₂pydc) and 2,2′-bipyridine (bipy), [Co(pydc)(bipy)₂]·5H₂O (1), [Cu(pydc)(bipy)₂]·6H₂O (3), and [Zn(pydc)(bipy)₂]·6H₂O (4) have been synthesized. Elemental, thermal, and mass analysis; magnetic susceptibilities; molar conductance; IR and UV/vis spectroscopic studies have been performed to characterize the complexes. Subsequently, the results of antimicrobial activity of the two ligands H₂pydc and bipy, and the four compounds (1), (2), (3), and (4) were obtained by the agar disk diffusion method. Furthermore, the cytotoxic activity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay for 24 and 48 h on rat glioma cells (C6).     

Synthesis, characterization, and antitumor activities of 1,1′-diacetylferrocene dihydrazone containing phenolic group and its complexes with Pd(II) and Pt(II)

A ferrocenyl ligand was prepared from condensation of 1,1′-diacetylferrocene dihydrazone with salicylaldehyde. The ligand forms 1:1 complexes with Pd(II) and Pt(II) in good yield. Characterization of the ligand and complexes was carried out using elemental analysis, infrared study, ¹H and ¹³C nuclear magnetic resonance, and electronic absorption spectra. Anticancer activity of the prepared ligand and its complexes against human breast cancer cell line MCF-7 was determined, and the results were compared with the activity of the commonly used anticancer drug cisplatin. The results suggested that the prepared compounds possess significant antitumor activity comparable to the activity of cisplatin.     

Synthesis and antifungal activity of sulfides,sulfoxides, and sulfones based on (1S)-(-)-β-pinene

Attachment of 2-mercaptoethanol and thioglycolic acid methyl ester to the double bond of (1S)-(-)-β-pinene yielded pinane sulfides with the cis configuration. Oxidation of sulfides with m-chloroperbenzoic acid yielded the corresponding sulfoxides and sulfones. The resulting compounds were screened for antimycotic activity and the dynamics of changes in antifungal properties in sulfides-sulfoxide-sulfone series were studied.     

Design,synthesis and bioevaluation of N-hydroxyquinolinones as potential anti-plasmodial,anti-bacterial and iron(Ⅱ)-chelating agents

OBJECTIVE To establish a small compound library via a versatile synthetic route for the investigation of natural-inspiring compounds containing N-hydroxypyridones motif as potential anti-plasmodial,anti-bacterial and iron(Ⅱ)-chelating agents.METHODS An amidation/cyclization approach was adopted to synthesize a library of N-hydroxyquinolinones.The anti-plasmodial susceptibility of lab clone 3D7 P.falciparum was measured using aprotocol modified from the WHO microtest.The minimum bactericidal concentration(MBC)values were determined against Escherichia coli and Staphylococcus arueus.Nine compounds were selected to test their iron(Ⅱ)-chelating abilities.The iron(Ⅱ)-chelating ability was determined by measuring the absorbance of ferrozine-iron complex at 562 nm.RESULTS A new route for the facile synthesis of a library of N-hydroxyquinolinones based on one-pot palladium catalyzed C-N amidation/dehydrocyclizationsequence was implemented.Four compounds show anti-plasmodial activities with the range of 1.1-1.4μmol·L-1,50% chelation abilities of the nine selected compounds were shown to be 0.24-0.29mmol·L-1.CONCLUSION Alibrary of N-hydroxyquinolinones was synthesized via a novel synthetic route.The anti-plasmodial and anti-bacterial activities of these compounds were evaluated.Four compounds show potent anti-plasmodial activities Nine compounds were examined for their propensities to undergo iron chelation and these compounds were shown to be promising iron(Ⅱ)chelators as compared to EDTA.     

Microwave-accelerated preparation and analytical characterization of 5-ethoxy-N,N-dialkyl-[α,α,β,β-H(4) ]- and [α,α,β,β-D(4) ]-tryptamines

The increased interest in N,N-dialkyl tryptamines is a reflection of their diverse range of biologically active properties. Deuterated derivatives are of interest for use as internal standards in bioanalytical or pharmacological assays. The present study reports on the synthesis of twelve novel 5-ethoxy-N,N-dialkyl-[α,α,β,β-H(4) ]-tryptamines and their [α,α,β,β-D(4) ]-counterparts following the Speeter and Anthony procedure. The normally time-consuming reduction step was carried out in 5 min under microwave-accelerated conditions. Good yields were obtained using tetrahydrofuran as the solvent at 150 °C. The resulting 24 tryptamines have been characterized by 1D/2D nuclear magnetic resonance spectroscopy and gas chromatography ion trap mass spectrometry. Differential fragmentation of side-chain-related iminium ions has been observed as a key principle. Because many N,N-dialkyltryptamines are available outside of traditional pharmaceutical supply chains as so-called 'research chemicals', the availability, as standards, of these new N,N-dialkyltryptamines will aid in identifiying novel tryptamines arising from these other souces. They should therefore be of immediate value within forensic, research, and public health contexts.     

Non-alcoholic fatty liver disease (NAFLD) – pathogenesis,classification, and effect on drug metabolizing enzymes and transporters

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a “three-hit” process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 has been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may result in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters.

Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 is more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 is up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major DMEs and transporters. We also discuss the potential mechanisms underlying these alterations.     

Synthesis, stereochemistry, and antimicrobial evaluation of t(3)-isopropyl-r(2), c(6)-di-2′-furanylpiperidin- 4-one and its derivatives

In a wide search program for new and efficient antimicrobial agents, a series of t(3)-isopropyl-r(2),r(6)-di-2′-furanylpiperidin-4-one 1 and its derivatives 2–7 were synthesized; characterized by IR, ¹H NMR, ¹H-¹H COSY, ¹³C NMR, and mass and elemental analysis; and their antibacterial activity against Streptococcus faecalis, Bacillus subtilis, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa and antifungal activity against Candida-6, Candida albicans, Aspergillus niger, Candida-51 and Aspergillus flavus was evaluated. Compound 6 exerted potent in vitro antibacterial activity against B. subtilis while compound 6 exhibited in vitro antifungal activity against Candida-6.     

Synthesis, characterization, and antimicrobial activity of copper(II) complexes with N,N′-propanediyl-bis-benzenesulfonamide and N,N′-ethanediyl-bis-2-methylbenzenesulfonamide

Copper(II) complexes of new aryldisulfonamides (L ₁  = N,N′-bis[(2-methylphenyl)sulfonyl]ethylenediamine) and L ₂  = N,N′-propanediyl-bis-benzenesulfonamide with 1,10-phenanthroline have been synthesized and characterized by using elemental analyses, FT-IR, LCMS, conductivity, and magnetic susceptibility techniques. The structures of [Cu(phen)₂]L₁ (1) and [CuL₂(phen)₂] (2) compounds have been determined. Complex (1) has also been characterized by single crystal X-ray diffraction. The complex (1) crystallizes in the triclinic system, space group P1, with cell constants a = 12.9353(8) Å, b = 13.8543(9) Å, c = 14.4513(10) Å, α = 103.593(5)°, β = 113.713(5)°, γ = 106.104(5)°, and Z = 1. The antibacterial activities of synthesized compounds were studied against Gram-positive bacteria: Staphylococcus aureus, Bacillus subtilis, and B. cereus and Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa, and Yersinia enterocolitica by microdilution (as MICs in μg/mL) and disk diffusion (as diameter zone in mm) method. The biological activity screening showed that (1) has more activity than (2) against the tested bacteria.     

Synthesis and activity of a potent α-glucosidase inhibitor, (1R, 6R, 8S)-cis-1,6-dihydroxypyrrolizidine, and its isomer

The synthesis ofcis- and trans-1,6-dihydroxypyrrolizidine starting fromtrans-4-hydroxyl-L-proline and their evaluation as glycosidase inhibitors are reported. Thecis-isomer was found to be a potent inhibitor against α-glucosidase and showed weak inhibitory effect against other glycosidases. Thetrans-isomer exhibited weak inhibitions of b-glucosidase and amyloglucosidase and poor inhibition of other glycosidases.     

Anti-mycobacterial, cytotoxic activities of Knoevenagel and (E)-α,β-unsaturated esters and ketones from 2-chloronicotinaldehydes

Series of 2-chloronicotinaldehyde Knoevenagel derivatives 3a–r; (E)-α,β-unsaturated esters and ketones 5a–k were prepared and evaluated for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H₃₇Rv (Mtb). Compounds 3e, 5b, 5d, 5e, 5g and 5i–k were shown potent to significant activity. Compound 5j is the most potent Mtb inhibitor (MIC: 4.89 μM) when compared to standard drugs Ethambutol (MIC: 7.63 μM) and Ciprofloxacin (MIC: 9.44 μM). Eight compounds displayed potent/significant activity against M. tuberculosis were chosen for the cytotoxicity against three cell lines (Raw 264.7, MCF7, and HeLa). Compound 5j displayed low toxicity with high selective index (15–30) and is an interesting new compound may serve for the development of therapeutics targeted against anti-mycobacterial compounds. This is the first report assigning in vitro anti-mycobacterial inhibitory activity and structure–activity relationship for this class of substituted 2-chloronicotinaldehyde derivatives and presents new family of compounds.     

Synthesis, cytotoxicity, and structure–activity insight of NH- and N-methyl-3,5-bis-(arylidenyl)-4-piperidones

Twenty-one NH- and N-methyl-3,5-bis-(arylidenyl)-4-piperidone analogs of curcumin, 12 of which are novel, were synthesized and evaluated for their cytotoxicity against B16 (murine melanoma) and L1210 (murine lymphoma) cells grown in culture. These curcumin analogs are related to a known anticancer STAT3 inhibitor 3,5-bis-(4-fluorobenzyl)-4-piperidone (3). The compounds showed remarkable cytotoxicity, especially against B16 cells. The dimethoxy substituted analogs 4e and 4f and dihydroxy analog 4i emerged as the most active compounds with IC₅₀ values in the range of 0.2–2.3 μM. 4e, f, and i were about 10-times more cytotoxic against both cell lines than 3. Analysis of the results demonstrates that the position of the hydroxyl group is crucial for cytotoxicity. Amino-containing analogs are generally less active than their halogenated and oxygen-containing analogs, and N-substitution in the 4-piperidone moiety adds value to the cytotoxicity of the compounds.     

Pleurotus opuntiae (Durieu et Lév.) Sacc. (higher Basidiomycetes) and other species related to Agave and Opuntia plants in Mexico-taxonomy, distribution, and applications

Pleurotus opuntiae is an important mushroom from xerophytic temperate regions of Mexico, as parasite or saprobe on Agave and Opuntia. Discussions on the taxonomic relationships of P opuntiae with P djamor, P. agaves, P. levis, and P. yuccae are presented, of which P. agaves is a synonym of P. opuntiae, and P. yuccae is a synonym of P. djamor. This latter and P levis are close species of P. opuntiae. The traditional uses of P opuntiae and P. djamor as food and remedy for several health problems, and also to get a traditional alcoholic drink from the Agave, are also considered.     

Hydrolysis of Carbonates,Thiocarbonates, Carbamates,and Carboxylic Esters of α-Naphthol, β-Naphthol,and p-Nitrophenol by Human,Rat, and Mouse Liver Carboxylesterases

Thirty carbonates, thiocarbonates, carbamates, and carboxylic esters of -naphthol, -naphthol, and p-nitrophenol were synthesized and tested as substrates for liver carboxylesterases from the crude microsomal fractions of human and mouse, and purified isozymes, hydrolases A and B, from rat liver microsomes. The carbonates, thiocarbonates, and carboxylic esters of -naphthol were cleaved more rapidly than the corresponding -naphthol isomers by the mammalian liver esterases. -Naphthyl esters of acetic, propionic, and butyric acids were among the best substrates tested for these enzymes. The majority of the substrates was consistently hydrolyzed at higher rates by hydrolase B compared with hydrolase A, although the Michaelis–Menten constant (K _m) values of selected substrates differed widely with these two isozymes. Malathion was a 15-fold better substrate for hydrolase B than for hydrolase A. Compared with the corresponding carboxylates, the carbonate moiety of - and -naphthol and p-nitrophenol lowered the specific activities of the enzymes by about fivefold but improved stability under basic conditions. The optimum pH of mouse liver esterase with the acetate, methylcarbonate, and ethylthiocarbonate of -naphthol was between pH 7.0 and pH 7.6. Human and mouse liver microsomal esterase activities were about five orders of magnitude lower than the esterase activities of purified rat liver hydrolase B. A relationship between the catalytic activity of the enzymes and the lipophilicity of the naphthyl substrates indicated that (i) in the - and -naphthyl carbonate series, an inverse relationship between enzyme activity and lipophilicity of the substrates was observed, whereas (ii) in the -naphthyl carboxylate series, an increase in enzyme activity with increasing lipophilicity of the substrates up to a log P value of about 4.0 was observed, after which the enzyme activity decreased.     

The first total syntheses of (±)-norphoebine,dehydrophoebine, oxophoebine,dehydrocrebanine, oxocrebanine and uthongine and their cytotoxicity against three human cancer cell lines

The first total syntheses of (±)-norphoebine, dehydrophoebine, oxophoebine, dehydrocrebanine, oxocrebanine and uthongine have been achieved. The crucial step involved the formation of ring C by a microwave-assisted direct biaryl coupling to produce the aporphine skeleton in high yields. The synthetic alkaloids were evaluated for their cytotoxicity against three human cancer cell lines MCF7, KB and NCI-H187. The results showed that uthongine was the best candidate of the series and it exhibited cytotoxicity against a human breast cancer MCF7 line with an IC₅₀ = 3.05 μM     

Methylene blue and vasoplegia: who, when, and how?

Systemic inflammatory response can be associated with clinically significant and, at times, refractory hypotension. Despite the lack of uniform definitions, this condition is frequently called vasoplegia or vasoplegic syndrome (VS), and is thought to be due to dysregulation of endothelial homeostasis and subsequent endothelial dysfunction secondary to direct and indirect effects of multiple inflammatory mediators. Vasoplegia has been observed in all age groups and in various clinical settings, such as anaphylaxis (including protamine reaction), sepsis, hemorrhagic shock, hemodialysis, and cardiac surgery. Among mechanisms thought to be contributory to VS, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway appears to play a prominent role. In search of effective treatment for vasoplegia, methylene blue (MB), an inhibitor of nitric oxide synthase (NOS) and guanylate cyclase (GC), has been found to improve the refractory hypotension associated with endothelial dysfunction of VS. There is evidence that MB may indeed be effective in improving systemic hemodynamics in the setting of vasoplegia, with reportedly few side effects. This review describes the current state of clinical and experimental knowledge relating to MB use in the setting of VS, highlighting the potential risks and benefits of therapeutic MB administration in refractory hypotensive states.     

Pharmacokinetic properties of γ-hydroxybutyrate (GHB) in whole blood, serum, and urine

Over the last 10-15 years, γ-hydroxybutyrate (GHB) and γ-butyrolactone have become increasingly popular "club drugs", but they have also gained attention as potential agents of drug-facilitated sexual assault (DFSA). Several studies have attempted to characterize GHB's pharmacokinetic properties in humans, and the aim of this paper is to build on this research with an emphasis on DFSA cases. A 25 mg/kg dose of GHB was given to 12 GHB-na?ve volunteers (6 men and 6 women). Urine and blood samples (serum and whole blood) were collected and analyzed by gas chromatography-mass spectrometry following liquid-liquid extraction. The urinary T(max) was 1 h in 11 volunteers with a mean C(max) of 67.6 mg/L (32.6-161.3 mg/L). Urinary concentrations rapidly decreased to < 10 mg/L (interpretive limit) for 11 volunteers after just 4 h. Data derived from whole blood (mean C(max) = 48.0 mg/L, T(max) = 24.6 min) closely matched that from serum (mean C(max) = 59.4 mg/L, T(max) = 23.3 min), suggesting GHB is distributed into erythrocytes. All 12 volunteers had GHB concentrations of less than 5 mg/L in both whole blood and serum after 3 h. Results verify the rapid elimination of GHB and the limited retrospective power of a concentration-based approach to prove GHB administration in blood and urine and confirm that, in DFSA cases, samples should be collected as soon as possible.