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AbstractSeven uncommon types of essential oils obtained from Pinus nigra, Hyssopus officinalis, Sison amomum, Smyrnium olusatrum, Helosciadium nodiflorum, Pelargonium graveolensand Vepris macrophyllawere tested against a panel of thirty bacterial strains that cause serious infectious diseases. Among these bacterial species, the most dangerous for human health were five documented multi-drug-resistant strains belonging to the Acinetobacterand Klebsiellagenera and derived from clinical isolation. The chemical composition of essential oils was achieved by GC-MS analysis, whereas the antibacterial efficacy was evaluated by the microdilution technique according to CLSI document M7-A9. The Vepris macrophyllaessential oil, which contains geranial (33.2%), neral (23.1%) and citronellol (14.5%), exhibited the strongest inhibition against the multi-resistant strains A. baumannii, K. pneumoniaeand S. aureus,with MIC values of 4.1, 2.05 and 4.1 mg/ml, respectively.

A novel class of antibacterial and antifungal agents is here identified by means of dockings and virtual screening techniques. Biological data proved the initial effort, formulated on the structure similarity of nuclear receptors binders with known quinolones or thiazole derivatives, to reposition PPARs agonists as likely bacterial type II topoisomerases inhibitors.

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The 2H-1,4-benzoxazine derivatives are novel drugs structurally similar to nucleotides; however, their actions on the pancreatic β cell ATP-sensitive K+ (KATP) channel and on glucose disposal are unknown. Therefore, the effects of the linear/branched alkyl substituents and the aliphatic/aromatic rings at position 2 of the 2H-1,4-benzoxazine nucleus on the activity of these molecules against the pancreatic β cell KATP channel and the Kir6.2ΔC36 subunit were investigated using a patch-clamp technique. The effects of these compounds on glucose disposal that followed glucose loading by intraperitoneal glucose tolerance test and on fasting glycemia were investigated in normal mice. The 2-n-hexyl analog blocked the KATP (IC₅₀ = 10.1 × 10⁻⁹ M) and Kir6.2ΔC36 (IC₅₀ = 9.6 × 10⁻⁹ M) channels, which induced depolarization. In contrast, the 2-phenyl analog was a potent opener (drug concentration needed to enhance the current by 50% = 0.04 × 10⁻⁹ M), which induced hyperpolarization. The ranked order of the potency/efficacy of the analog openers was 2-phenyl > 2-benzyl > 2-cyclohexylmethyl. The 2-phenylethyl and 2-isopropyl analogs were not effective as blockers/openers. The 2-n-hexyl (2-10 mg/kg) and 2-phenyl analogs (2-30 mg/kg) reduced and enhanced the glucose areas under the curves, respectively, after glucose loading in mice. These compounds did not affect the fasting glycemia as is observed with glibenclamide. The linear alkyl chain and the aromatic ring at position 2 of the 1,4-benzoxazine nucleus are the determinants, which confer the KATP channel blocking action with glucose-lowering effects and the opening action with increased glucose levels, respectively. The opening/blocking actions of these compounds mimic those that were observed with ATP and ADP. The results support the use of these compounds as novel antidiabetic drugs.

The human kidney-specific chloride channels ClC-Ka (rodent ClC-K1) and ClC-Kb (rodent ClC-K2) are important determinants of renal function, participating to urine concentration and blood pressure regulation mechanisms. Here we tested the hypothesis that these chloride channels could represent new drug targets for inducing diuretic and antihypertensive effects.

A series of experiments was performed to test a theoretical model that we have recently proposed to explain the highly enantioselective oxidation of aryl benzyl sulfides with tert‐butyl hydroperoxide in the presence of a complex between titanium and (S,S)‐ or (R,R)‐hydrobenzoin. The studied variations involved the sulfides, the ligands, and the order of addition of reactants. The reaction path predicted by our model was confirmed in every experiment. In particular, aryl benzyl sulfides behaved as the ideal substrate for this type of asymmetric oxidation, which yields synthetically useful, enantiopure aryl benzyl sulfoxides in a straightforward manner.

The 2H-1,4-benzoxazine derivatives are modulators of the skeletal muscle ATP-sensitive-K+channels (KATP), activating it in the presence of ATP but inhibiting it in the absence of nucleotide. To investigate the molecular determinants for the activating/blocking actions of these compounds, novel molecules with different alkyl or aryl-alkyl substitutes at position 2 of the 1,4-benzoxazine ring were prepared. The effects of the lengthening of the alkyl chain and of branched substitutes, as well as of the introduction of aliphatic/aromatic rings on the activity of the molecules, were investigated on the skeletal muscle KATPchannels of the rat, in excised-patch experiments, in the presence or absence of internal ATP (10-4M). In the presence of ATP, the 2-n-hexyl analog was the most potent activator (DE50= 1.08 x 10-10M), whereas the 2-phenylethyl was not effective. The rank order of efficacy of the openers was 2-n-hexyl ≥2-cyclohexylmethyl >2-isopropyl = 2-n-butyl ≥ 2-phenyl ≥ 2-benzyl = 2-isobutyl analogs. In the absence of ATP, the 2-phenyl analog was the most potent inhibitor (IC50= 2.5 x 10-11M); the rank order of efficacy of the blockers was 2-phenyl ≥ 2-n-hexyl > 2-n-butyl > 2-cyclohexylmethyl, whereas the 2-phenylethyl, 2-benzyl, and 2-isobutyl 1,4-benzoxazine analogs were not effective; the 2-isopropyl analog activated the KATPchannel even in the absence of nucleotide. Therefore, distinct molecular determinants for the activating or blocking actions for these compounds can be found. For example, the replacement of the linear with the branched alkyl substitutes at the position 2 of the 1,4-benzoxazine nucleus determines the molecular switch from blockers to openers. These compounds were 100-fold more potent and effective as openers than other KCO against the muscle KATPchannels.

CLC-K Cl– channels are selectively expressed in kidney and ear, where they are pivotal for salt homeostasis, and loss-of-function mutations of CLC-Kb produce Bartter's syndrome type III. The only ligand known for CLC-K channels is a derivative of the 2-p-chlorophenoxypropionic acid (CPP), 3-phenyl-CPP, which blocks CLC-Ka, but not CLC-Kb. Here we show that in addition to this blocking site, CLC-K channels bear an activating binding site that controls channel opening. Using the voltage-clamp technique on channels expressed in Xenopus laevis oocytes, we found that niflumic acid (NFA) increases CLC-Ka and CLC-Kb currents in the 10 to 1000 µM range. Flufenamic acid (FFA) derivatives or high doses of NFA produced instead an inhibitory effect on CLC-Ka, but not on CLC-Kb, and on blocker-insensitive CLC-Ka mutants, indicating that the activating binding site is distinct from the blocker site. Evaluation of the sensitivity of CLC-Ka to derivatives of NFA and FFA together with a modeling study of these ligands allow us to conclude that one major characteristic of activating compounds is the coplanarity of the two rings of the molecules, whereas block requires a noncoplanar configuration. These molecules provide a starting point for identification of diuretics or drugs useful in the treatment of Bartter's syndrome.

A series of structurally related 2‐aryloxy‐2‐arylacetic acids (1–3, 5–16) together with a thioisostere derivative (4) have been synthesized and characterized by GC‐MS and 1H NMR. The designed compounds were analyzed on a Penicillin G Acylase chiral stationary phase (PGA‐CSP) and the influence of the structure variations on retention and enantioselectivity was investigated. The chromatographic study includes the direct separation of the enantiomers of the synthesized compounds and the determination of the elution order of selected racemic mixtures. 10 out of 16 racemates were separated; high chromatographic enantioseparation factors (α > 2) were achieved for some compounds. For the enantiomers of four compounds whose absolute configuration was known (1, 3, 12, 16), the elution order was R:Swith the exception of 2‐(4‐chloro‐phenoxy)phenylacetic acid (1), for which the elution order was reversed. Preliminary molecular modeling studies suggest that both polar and charge‐transfer interactions as well as steric effects play an important role in determining the retention factors and the enantioselectivities observed. Chirality, 2006. © 2006 Wiley‐Liss, Inc.

Both enantiomers of “para-hydroxymexiletine” (PHM), one of the main metabolites of mexiletine, were synthesized and fully characterized. Properties of (R)- and (S)-PHM, in terms of blocking potency and stereoselectivity on frog skeletal muscle Na⁺ channels, were evaluated. The presence of a hydroxy group on the aryloxy moiety in the 4-position, as in PHM, reduced potency with respect to mexiletine in reducing INa max. However, PHM showed clear use-dependent behavior similar to that of mexiletine and, in contrast with what is observed with the parent compound, maintained its stereoselectivity during the use-dependent block. Chirality 16:72–78, 2004. © 2004 Wiley-Liss, Inc.

Both enantiomers of “para‐hydroxymexiletine” (PHM), one of the main metabolites of mexiletine, were synthesized and fully characterized. Properties of (R)‐ and (S)‐PHM, in terms of blocking potency and stereoselectivity on frog skeletal muscle Na+channels, were evaluated. The presence of a hydroxy group on the aryloxy moiety in the 4‐position, as in PHM, reduced potency with respect to mexiletine in reducing INa max. However, PHM showed clear use‐dependent behavior similar to that of mexiletine and, in contrast with what is observed with the parent compound, maintained its stereoselectivity during the use‐dependent block. Chirality 16:72–78, 2004. © 2004 Wiley‐Liss, Inc.

The reaction of diphenyl(methoxymethyl)phosphine oxide 1with organometallic reagents was found to lead to substitution of the methoxymethyl group. The P-phenyl substituent showed a lower propensity to undergo a displacement.

The reaction gives poor results, when acetophenone or benzaldehyde derivatives are used as starting material, cf.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.