Synthesis and evaluation of anticonvulsant activity of N-(2,5-dimethylphenoxy)- and N-[(2,3,5-trimethylphenoxy)alkyl]aminoalkanols

A series of new N-(2,5-dimethylphenoxy)- and N-(2,3,5-trimethylphenoxy)alkylaminoalkanols [I-XVII] was synthesized and evaluated for anticonvulsant activity. Pharmacological tests included maximal electroshock (MES) and subcutaneous pentetrazole seizure threshold (scMet) assays as well as neurotoxicity (TOX) evaluation in mice after intraperitoneal (i.p.) administration and/or in rats after oral (p.o.) administration. The most active compound was R-2N-[(2,3,5-trimethylphenoxy)ethyl]aminobutan-1-ol, which exhibited 100% activity in MES at the dose of 30 mg/kg body weight (mice, i.p.) and 75% activity in MES at 30 mg/kg b.w. (rats, p.o.) without neurotoxicity at the active doses

Skin metabolism established with the use of MetaSite for selected retinoids employed in topical and systemic treatment of various skin disorders and found in cosmeceuticals

Purpose. Besides being widely used in cosmetics, retinoids are potent therapeutic agents used topically and systemically as anti-acne agents. The aim of this study was to predict with the use of MetaSite the skin metabolism of selected retinoids employed in treatment of skin disorders and found in cosmeceuticals. The following compounds were studied: retinol, retinaldehyde, retinoic acid, retinyl acetate, retinyl palmitate, acitretin, etretinate, adapalene and bexarotene. Methods. MetaSite, Molecular Discovery Ltd. is a computational model that enables prediction of cytochrome P450-dependant metabolism. This software indicates atoms in the molecule structure that are mostly vulnerable to metabolic changes and predicts the metabolite structures. Results. MetaSite indicated that retinol and retinal metabolites were obtained through hydroxylation of the methyl group located in the position 3 of the aliphatic chain, whereas retinoic acid biotransformation would occur principally in the carbon atom situated in the position 4 in the cyclohexene ring. In acitretin molecule, carbon atom of the methoxy group attached to the benzene ring displayed the highest probability of biotransformation. In etretinate, metabolic reactions would occur principally on the carbon atom of the final ethyl group of the molecule. Conclusions. MetaSite metabolism predictions for retinoic acid, acitretin, etretinate, adapalene and bexarotene were in agreement with experimental findings. In case of compounds being converted by catalysts other than cytochrome P450 enzymes, the primary metabolites predicted by MetaSite differ from those reported previously. In conclusion, MetaSite is a useful tool that can aid identification of the major metabolites of compounds being administered topically

Trans-cinnamaldehyde : biological properties and applications in cosmetology.

Trans-cynamoaldehyd (aldehyd cynamonowy, 3-fenyloprop-2-enal) jest związkiem organicznym, nienasyconym aldehydem naturalnie występującym w gatunkach roślin z rodzaju Cinnamomum. Największe jego ilości znajdują się w olejkach eterycznych pozyskiwanych z Cinnamomum zeylanicum oraz Cinnamomum cassia. Ma postać żółtej cieczy o charakterystycznym, intensywnym cynamonowym zapachu. Z powodu interesujących walorów zapachowych oraz wielokierunkowej aktywności biologicznej jest wykorzystywany między innymi jako składnik wielu produktów kosmetycznych. Wykazuje działanie przeciwdrobnoustrojowe, przeciwzapalne, antyoksydacyjne. Ponadto istnieją doniesienia na temat jego działania przeciwnowotworowego, pozytywnego wpływu na pracę serca oraz w leczeniu cukrzycy. Pomimo wielu korzystnych właściwości trans-cynamoaldehydu, w literaturze można znaleźć informacje na temat licznych działań niepożądanych wywołanych przez jego wysokie stężenia. Związek ten jest opisywany jako czynnik uczulający, a jego działanie drażniące skierowane głównie na skórę. Spośród substancji zapachowych wykorzystywanych do produkcji kosmetyków, trans-cynamoaldehyd jest jednym z głównych składników wykazujących działanie alergizujące. Jest agonistą receptora TRPA1 oraz może być przyczyną alergicznego kontaktowego zapalenia skóry i pokrzywki nieimmunologicznej, zaliczanych do chorób z grupy wyprysku kontaktowego. Aldehyd cynamonowy jest również wykorzystywany w testach płatkowych, które stanowią podstawę diagnostyki alergii na składniki kosmetyków.Trans-cinnamaldehyde (cinnamic aldehyde; (2E)-3-phenylprop-2-enal) is an simple organic compound, an unsaturated aldehyde, naturally occurring in plant species of the genus Cinnamomum. The greatest quantities are found in essential oils obtained from Cinnamomum zeylanicum and Cinnamomum cassia. It is a tree of the laurel family (Lauraceae), native to Ceylon. It occurs in the form of a yellow liquid with a characteristic, intense cinnamon scent. In laboratory and industrial conditions, it is obtained using many patented methods. The most common of these is the condensation of benzaldehyde with acetaldehyde. Due to its interesting aromatic qualities and multidirectional biological activity, it is widely used in food products and household chemicals. In the pharmaceutical industry it is used to improve the odor and the taste of drugs, especially those containing bitter substances. However it is also an important ingredient of many cosmetic products. It has antimicrobial, anti-inflammatory and antioxidant properties. In addition, there are reports of its anti-cancer effect, a positive effect on the heart function and in the treatment of diabetes. Trans-cinnamaldehyde is considered as Generally Recognized As Safe (GRAS) by the US Food and Drug Administration (FDA). However, despite the many positive aspects of trans-cinnamaldehyde, in the literature data on numerous side effects caused by its high concentrations can be found. This compound is described as a sensitizing agent and its irritating action is mainly directed at the skin. In cosmetics it is significant allergenic substance. Trans-cinnamaldehyde is an agonist of the TRPA1 receptor and can cause allergic contact dermatitis and non-immune contact urticaria, which are classified as contact eczema. Cinnamaldehyde is also used in patch tests, which are the basis for diagnosing allergies to cosmetic ingredients. Therefore, although it is considered a safe substance, due to its allergenic and irritating effects, its content in cosmetic products is subject to certain restrictions and it should not exceed 0.05%

Preliminary evaluation of anticonvulsant activity and neurotoxicity of some 1,4-substituted piperazine derivatives

A series of 1,4-piperazine derivatives was synthesized and evaluated for anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure threshold (ScMet) assays and for neurotoxicity (TOX). The compounds were only moderately effective. The anticonvulsant activity was accompanied by neurotoxicity. 1-[(4-Chlor-3-methylphenoxy)-acetyl]-4-(2-methoxyphenyl)-piperazine was also evaluated in six hertz seizure test (6-Hz) and showed good activity. At the dose of 100 mg/kg b. w. the compound produced 100% protection after 0.5 h without neurotoxic effect

The influence of some xanthone derivatives on the activity of J-774A.1 cells

The chemiluminescence of stimulated cells with phorbol myristate acetate and the production of nitric oxide after stimulation with lipopolisaccharide in the presence of the parent compounds FAA (flavone-8-acetic acid = (4-oxo-2- phenyl-4H-chromen-8-yl)acetic acid), XAA (xanthone-4-acetic acid = (9-oxo-9Hxanthen-4-yl)acetic acid), and appropriate xanthone derivatives (1-7) was determined. Also the toxicity of the FAA, MFAA ((6-methyl-4-oxo-2-aryl-4Hchromen-8-yl)acetic acid), XAA and 1–7 against J-774A.1 cultured cells was evaluated. Compound 5 (2-methyl-2-{[(9-oxo-9H-xanthen-2-yl)methyl]sulfanyl}- propanoic acid) was effective in inhibiting chemiluminescence of J-774A.1 cells but most of the other tested compounds stimulated the reaction. FAA and two xanthones with a methoxycarbonyl moeity slightly decreased the generation of nitric oxide at 50 μM. Most of the tested compounds (1-7) showed weak toxicity at concentration of 100 μM

Metabolic stability and its role in the discovery of new chemical entities

Determination of metabolic profiles of new chemical entities is a key step in the process of drug discovery, since it influences pharmacokinetic characteristics of therapeutic compounds. One of the main challenges of medicinal chemistry is not only to design compounds demonstrating beneficial activity, but also molecules exhibiting favourable pharmacokinetic parameters. Chemical compounds can be divided into those which are metabolized relatively fast and those which undergo slow biotransformation. Rapid biotransformation reduces exposure to the maternal compound and may lead to the generation of active, non-active or toxic metabolites. In contrast, high metabolic stability may promote interactions between drugs and lead to parent compound toxicity. In the present paper, issues of compound metabolic stability will be discussed, with special emphasis on its significance, in vitro metabolic stability testing, dilemmas regarding in vitro-in vivo extrapolation of the results and some aspects relating to different preclinical species used in in vitro metabolic stability assessment of compounds

S(+)-(2E)-N-(2-Hydroxypropyl)-3-Phenylprop-2-Enamide (KM-568) : a novel cinnamamide derivative with anticonvulsant activity in animal nodels of seizures and epilepsy

Epilepsy is one of the most frequent neurological disorders affecting about 1% of the world’s human population. Despite availability of multiple treatment options including antiseizure drugs, it is estimated that about 30% of seizures still remain resistant to pharmacotherapy. Searching for new antiseizure and antiepileptic agents constitutes an important issue within modern medicinal chemistry. Cinnamamide derivatives were identified in preclinical as well as clinical studies as important drug candidates for the treatment of epilepsy. The cinnamamide derivative presented here: S(+)-(2E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide (S(+)-N-(2-hydroxypropyl)cinnamamide, compound KM-568) showed anticonvulsant activity in several models of epilepsy and seizures in mice and rats. It was active in a genetic animal model of epilepsy (Frings audiogenic seizure-susceptible mouse model, ED50 = 13.21 mg/kg, i.p.), acute seizures induced electrically (maximal electroshock test ED50 = 44.46 mg/kg mice i.p., ED50 = 86.6 mg/kg mice p.o., ED50 = 27.58 mg/kg rats i.p., ED50 = 30.81 mg/kg rats p.o., 6-Hz psychomotor seizure model 32 mA ED50 = 71.55 mg/kg mice i.p., 44 mA ED50 = 114.4 mg/kg mice i.p.), chronic seizures induced electrically (corneal kindled mouse model ED50 = 79.17 mg/kg i.p., hippocampal kindled rat model ED50 = 24.21 mg/kg i.p., lamotrigine-resistant amygdala kindled seizure model in rats ED50 = 58.59 mg/kg i.p.), acute seizures induced chemically (subcutaneous metrazol seizure threshold test ED50 = 104.29 mg/kg mice i.p., ED50 = 107.27 mg/kg mice p.o., ED50 = 41.72 mg/kg rats i.p., seizures induced by picrotoxin in mice ED50 = 94.11 mg/kg i.p.) and the pilocarpine-induced status epilepticus model in rats (ED50 = 279.45 mg/kg i.p., ED97 = 498.2 mg/kg i.p.). The chemical structure of the compound including configuration of the chiral center was confirmed by NMR spectroscopy, LC/MS spectroscopy, elemental analysis, and crystallography. Compound KM-568 was identified as a moderately stable derivative in an in vitro mouse liver microsome system. According to the Ames microplate format mutagenicity assay performed, KM-568 was not a base substitution or frameshift mutagen. Cytotoxicity evaluation in two cell lines (HepG2 and H9c2) proved the safety of the compound in concentrations up to 100 µM. Based on the results of anticonvulsant activity and safety profile, S(+)-(2E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide could be proposed as a new lead compound for further preclinical studies on novel treatment options for epilepsy

Preliminary evaluation of central nervous system activity of (E)-N-2-methyl-3-phenylprop-2-enyl ((E)-N- α-methylcinnamyl) derivatives of selected aminoalkanols

A series of (E)-α-methylcinnamyl derivatives of selected aminoalkanols was synthetized and evaluated for activity in central nervous system. All compounds were tested as anticonvulsants and one additionally in antidepressant- and anxiolytic-like assays. The compounds possessed pharmacophoric elements regarded as beneficial for anticonvulsant activity: hydrophobic unit and two hydrogen bonds donor/acceptor features. The compounds were verified in mice after intraperitoneal (i.p.) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scPTZ) induced seizures as well as neurotoxicity assessments. Eight of the tested substances showed protection in MES test at the dose of 100 mg/kg. The derivative of 2 aminopropan-1-ol was also tested in 6-Hz test in mice i.p. and showed anticonvulsant activity but at the same time the neurotoxicity was noted. The derivative of 2-amino-1-phenylethanol which possessed additional hydrophobic unit in aminoalkanol moiety was tested in other in vivo assays to evaluate antidepressant- and anxiolytic-like activity. The compound proved beneficial properties especially as anxiolytic agent remaining active in four-plate test in mice at the dose of 2.5 mg/kg (i.p.). In vitro biotransformation studies of 2-amino-1-phenylethanol derivative carried out in mouse liver microsomal assay indicated two main metabolites as a result of aliphatic and aromatic hydroxylation or aliphatic carbonylation. To identify possible mechanism of action, we evaluated serotonin receptors (5-HT1A, 5-HT6 and 5-HT7) binding affinities of the compounds but none of them proved to bind to any of tested receptors