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Modern cosmetology is an advanced discipline related to other areas of science, such as chemistry, pharmacy, biology, molecular biology or biotechnology. Available cosmetics are well-tested and safe products that meet the expectations of consumers in terms of quality and activity. In accordance with current law regulations, manufacturers are required to include a list of cosmetic ingredients on the cosmetic’s container using the International Nomenclature of Cosmetic Ingredients (INCI) rules, common for the entire European Union. This allows to analyze the composition of the product by the consumers, in terms of the presence of specific ingredients that will meet their expectations, as well as exclusion from use, for example due to their beliefs. This article provides examples of surprising cosmetic ingredients, the use of which is probably not obvious for the majority of the consumers. The raw materials obtained from snails are used because of their protective properties as well a positive effect on the condition of the skin, including anti-aging, antioxidant and regenerating activity. Ambergris, a waxy substance derived from the intestine of the sperm whales, is used as a fragrance and stabilizer of the scent of some perfumes. Fats and oils obtained from minks or domestic animals possess a softening and soothing effect. Animal fats are also used in the production of popular soaps. Hen eggs are also used in cosmetology. The shells used in peelings possess exfoliating functions. In addition, eggs whites, yolks, as well as numerous substances isolated from eggs are used. Stem cells used in cosmetology are obtained from in vitro cultivation of areas of dividing tissues. Cosmetic raw materials, which are the content of the cultured cells, have anti-aging, protective and regenerative properties. The knowledge of examples of surprising cosmetic ingredients will allow a better insight into the used cosmetic products as well as will encourage to broaden the interest in modern cosmetology.

Background Epilepsy frequently coexists with neuropathic pain. Our approach is based on the search for active compounds with multitarget profiles beneficial in terms of potential side effects and on the implementation of screening for potential multidirectional central activity. Methods Compounds were synthesized by means of chemical synthesis. After antiseizure and neurotoxicity screening in vivo, KM-408 and its enantiomers were chosen for analgesic activity evaluations. Further safety studies included acute toxicity in mice, the effect on normal electrocardiogram and on blood pressure in rats, whole body plethysmography in rats, and in vitro and biochemical assays. Pharmacokinetics has been studied in rats after iv and po administration. Metabolism has been studied in vivo in rat serum and urine. Radioligand binding studies were performed as part of the mechanism of action investigation. Results Selected results for KM-408: Ki sigma = 7.2*10–8; Ki 5-HT1A = 8.0*10–7; ED50 MES (mice, ip) = 13.3 mg/kg; formalin test (I phase, mice, ip)—active at 30 mg/kg; SNL (rats, ip)—active at 6 mg/kg; STZ-induced pain (mice, ip)—active at 1 mg/kg (von Frey) and 10 mg/kg (hot plate); hot plate test (mice, ip)—active at 30 mg/kg; ED50 capsaicin test (mice, ip) = 18.99 mg/kg; tail immersion test (mice)—active at 0.5%; corneal anesthesia (guinea pigs)—active at 0.125%; infiltration anesthesia (guinea pigs)—active at 0.125%. Conclusions Within the presented study a novel compound, R,S-2-((2-(2-chloro-6-methylphenoxy)ethyl)amino)butan-1-ol hydrochloride (KM-408) with dual antiseizure and analgesic activity has been developed for potential use in neuropathic pain treatment. Graphical abstract

Background: Our previous studies showed that xanthone derivatives with N-(2-methoxyphenyl)piperazine fragment have an affinity to the 5-HT1A receptor and show antidepressant-like properties in rodents. In this study, we tested three xanthone derivatives, HBK-1 (R, S) and its enantiomers, in which we increased the distance between the piperazine and xanthone fragments by using a hydroxypropoxy linker. We hypothesized that this would increase the binding to the 5-HT1A receptor and consequently, pharmacological activity. Aims: We aimed to assess the in vitro and in vivo pharmacological activity of the xanthone derivatives. Methods: We evaluated the in vitro affinity for serotonin 5-HT1A and 5-HT2A receptors and serotonin transporter. We also determined the intrinsic activity at the 5-HT1A receptor. We investigated the antidepressant-like properties and safety after acute administration (dose range: 1.25–20 mg/kg) using the forced swim, tail suspension, locomotor activity, rotarod and chimney tests in mice. We also evaluated the basic pharmacokinetic parameters. Results: Our results indicated that the compounds showed a high affinity for the 5-HT1A receptor but very weak antagonistic properties in the Ca2+ mobilization assay; however, they showed significant agonistic properties in the β-arrestin recruitment assay. In both behavioural tests the studied xanthone derivatives showed antidepressant-like activity. Pre-treatment with p-chlorophenylalanine or WAY-100635 abolished their antidepressant-like activity. None of the compounds caused motor impairments at antidepressant-like doses. The racemate penetrated the blood–brain barrier and had a relatively high bioavailability after intraperitoneal administration. Conclusions: Xanthone derivatives with N-(2-methoxyphenyl)piperazine fragment and hydroxypropoxy linker show increased binding to the 5-HT1A receptor and may represent an attractive putative treatment candidate for depression.

Aminoalkanol derivatives have attracted much interest in the field of medicinal chemistry as part of the search for new anticonvulsant drugs. In order to study the influence of the methyl substituent and N-oxide formation on the geometry of molecules and intermolecular interactions in their crystals, three new examples have been prepared and their crystal structures determined by X-ray diffraction. 1-[(2,6-Dimethylphenoxy)ethyl]piperidin-4-ol, C15H23NO2, 1, and 1-[(2,3-dimethylphenoxy)ethyl]piperidin-4-ol, C15H23NO2, 2, crystallize in the orthorhombic system (space groups P212121 and Pbca, respectively), with one molecule in the asymmetric unit, whereas the N-oxide 1-[(2,3-dimethylphenoxy)ethyl]piperidin-4-ol N-oxide monohydrate, C15H23NO3·H2O, 3, crystallizes in the monoclinic space group P21/c, with one N-oxide molecule and one water molecule in the asymmetric unit. The geometries of the investigated compounds differ significantly with respect to the conformation of the O—C—C linker, the location of the hydroxy group in the piperidine ring and the nature of the intermolecular interactions, which were investigated by Hirshfeld surface and corresponding fingerprint analyses. The crystal packing of 1 and 2 is dominated by a network of O—H...N hydrogen bonds, while in 3, it is dominated by O—H...O hydrogen bonds and results in the formation of chains.

Excessive UV exposure contributes to several pathological conditions like skin burns, erythema, premature skin aging, photodermatoses, immunosuppression, and skin carcinogenesis. Effective protection from UV radiation may be achieved with the use of sunscreens containing UV filters. Currently used UV filters are characterized by some limitations including systemic absorption, endocrine disruption, skin allergy induction, and cytotoxicity. In the research centers all over the world new molecules are developed to improve the safety, photostability, solubility, and absorption profile of new derivatives. In our study, we designed and synthesized seventeen novel molecules by combining in the structures two chromophores: xanthone and (E)-cinnamoyl moiety. The ultraviolet spectroscopic properties of the tested compounds were confirmed in chloroform solutions. They acted as UVB or UVA/UVB absorbers. The most promising compound 9 (6-methoxy-9-oxo-9H-xanthen-2-yl)methyl (E)-3-(2,4-dimethoxyphenyl)acrylate) absorbed UV radiation in the range 290&ndash, 369 nm. Its photoprotective activity and functional photostability were further evaluated after wet milling and incorporation in the cream base. This tested formulation with compound 9 possessed very beneficial UV protection parameters (SPFin vitro of 19.69 &plusmn, 0.46 and UVA PF of 12.64 &plusmn, 0.32) which were similar as broad-spectrum UV filter tris-biphenyl triazine. Additionally, compound 9 was characterized by high values of critical wavelength (381 nm) and UVA/UVB ratio (0.830) thus it was a good candidate for broad-spectrum UV filter and it might protect skin against UVA-induced photoaging. Compound 9 were also shown to be photostable, non-cytotoxic at concentrations up to 50 &micro, M when tested on five cell lines, and non-mutagenic in Ames test. It also possessed no estrogenic activity, according to the results of MCF-7 breast cancer model. Additionally, its favorable lipophilicity (miLogP = 5.62) does not predispose it to penetrate across the skin after topical application.

The aroxyalkylaminoalcohol derivatives are a group of compounds known for their pharmacological action. The crystal structures of four new xylenoxyaminoalcohol derivatives having anticonvulsant activity are reported, namely, 2-{[2-(2,6-dimethylphenoxy)ethyl]amino}-1-phenylethan-1-ol, C18H23NO2, 1, the salt N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxy-1-phenylethan-2-aminium 3-hydroxybenzoate, C18H24NO2 +·C7H5O3 −, 2, and two polymorphs of the salt (R)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxy-1-phenylethan-2-aminium chloride, C18H24NO2 +·Cl−, 3 and 3p. Both polymorphs crystallize in the space group P21212 and each has two cations and two anions in the asymmetric unit (Z′ = 2). The molecules in the polymorphs show differences in their molecular conformations and intermolecular interactions. The crystal packing of neutral 1 is dominated by intermolecular O—H...N hydrogen bonds, resulting in the formation of one-dimensional chains. In the crystal structures of the salt forms (2, 3 and 3p), each protonated N atom is engaged in a charge-assisted hydrogen bond with the corresponding anion. The protonation of the N atom also influences the conformation of the molecular linker between the two aromatic rings and changes the orientation of the rings. The crystal packing of the salt forms is dominated by intermolecular O—H...O hydrogen bonds, resulting in the creation of chains and rings. Structural studies have been enriched by the calculation of Hirshfeld surfaces and the corresponding fingerprint plots.

The increasing number of patients reporting depressive symptoms requires the design of new antidepressants with higher efficacy and limited side effects. As our previous research showed, 2-methoxyphenylpiperazine derivatives are promising candidates to fulfill these criteria. In this study, we aimed to synthesize a novel 2-methoxyphenylpiperazine derivative, HBK-10, and investigate its in vitro and in vivo pharmacological profile. After assessing the affinity for serotonergic and dopaminergic receptors, and serotonin transporter, we determined intrinsic activity of the compound at the 5-HT1A and D2 receptors. Next, we performed behavioral experiments (forced swim test, tail suspension test) to evaluate the antidepressant-like activity of HBK-10 in naïve and corticosterone-treated mice. We also assessed the safety profile of the compound. We showed that HBK-10 bound strongly to 5-HT1A and D2 receptors and presented antagonistic properties at these receptors in the functional assays. HBK-10 displayed the antidepressant-like effect not only in naïve animals, but also in the corticosterone-induced mouse depression model, i.e., chronic administration of HBK-10 reversed corticosterone-induced changes in behavior. Moreover, the compound’s sedative effect was observed at around 26-fold higher doses than the antidepressant-like ones. Our study showed that HBK-10 displayed a favorable pharmacological profile and may represent an attractive putative treatment candidate for depression.

Excessive UV exposure contributes to several pathological conditions like skin burns, erythema, premature skin aging, photodermatoses, immunosuppression, and skin carcinogenesis. Effective protection from UV radiation may be achieved with the use of sunscreens containing UV filters. Currently used UV filters are characterized by some limitations including systemic absorption, endocrine disruption, skin allergy induction, and cytotoxicity. In the research centers all over the world new molecules are developed to improve the safety, photostability, solubility, and absorption profile of new derivatives. In our study, we designed and synthesized seventeen novel molecules by combining in the structures two chromophores: xanthone and (E)-cinnamoyl moiety. The ultraviolet spectroscopic properties of the tested compounds were confirmed in chloroform solutions. They acted as UVB or UVA/UVB absorbers. The most promising compound 9 (6-methoxy-9-oxo-9H-xanthen-2-yl)methyl (E)-3-(2,4-dimethoxyphenyl)acrylate) absorbed UV radiation in the range 290–369 nm. Its photoprotective activity and functional photostability were further evaluated after wet milling and incorporation in the cream base. This tested formulation with compound 9 possessed very beneficial UV protection parameters (SPFin vitro of 19.69 ± 0.46 and UVA PF of 12.64 ± 0.32) which were similar as broad-spectrum UV filter tris-biphenyl triazine. Additionally, compound 9 was characterized by high values of critical wavelength (381 nm) and UVA/UVB ratio (0.830) thus it was a good candidate for broad-spectrum UV filter and it might protect skin against UVA-induced photoaging. Compound 9 were also shown to be photostable, non-cytotoxic at concentrations up to 50 µM when tested on five cell lines, and non-mutagenic in Ames test. It also possessed no estrogenic activity, according to the results of MCF-7 breast cancer model. Additionally, its favorable lipophilicity (miLogP = 5.62) does not predispose it to penetrate across the skin after topical application.

Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic, neuropathic pain. We obtained a phenoxyalkylaminoalkanol derivative, KM-416 which had previously demonstrated a significant anticonvulsant activity and had also been shown to bind to 5-HT1A, α2-receptors and SERT and not to exhibit mutagenic properties. As KM-416 is a promising compound in our search for drug candidates, in the present study we further assessed its pharmacological profile (analgesic, local anesthetic, and antidepressant-like activities) accompanied with patch-clamp studies. Considering the importance of drug safety, its influence on the cardiovascular system was also evaluated. Moreover, KM-416 was subjected to forced degradation and pharmacokinetic studies to examine its stability and pharmacokinetic parameters. KM-416 revealed a significant antinociceptive activity in the tonic - the formalin test, neurogenic - the capsaicin test, and neuropathic pain model - streptozotocin-induced peripheral neuropathy. Moreover, it exerted a local anesthetic effect. In addition, KM-416 exhibited anti-depressant like activity. The results from the patch-clamp studies indicated that KM-416 can inhibit currents elicited by activation of NMDA receptors, while it also exhibited a voltage-dependent inhibition of Na+ currents. KM-416 did not influence ventricular depolarization and repolarization. Following oral administration, pharmacokinetics of KM-416 was characterized by a rapid absorption in the rat. The brain-to-plasma AUC ratio was 6.7, indicating that KM-416 was well distributed to brain. The forced degradation studies showed that KM-416 was very stable under stress conditions. All these features made KM-416 a promising drug candidate for further development against neuropathic pain and epilepsy.

Four crystal structures of 2-amino-N-(dimethylphenoxyethyl)propan-1-ol derivatives, characterized by X-ray diffraction analysis, are reported. The free base (R,S)-2-amino-N-[2-(2,3-dimethylphenoxy)ethyl]propan-1-ol, C13H21NO2, 1, crystallizes in the space group P21/n, with two independent molecules in the asymmetric unit. The hydrochloride, (S)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium chloride, C13H22NO2 +·Cl−, 2c, crystallizes in the space group P21, with one cation and one chloride anion in the asymmetric unit. The asymmetric unit of two salts of 2-picolinic acid, namely, (R,S)-N-[2-(2,3-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium pyridine-2-carboxylate, C13H22NO2 +·C6H4NO2 −, 1p, and (R)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium pyridine-2-carboxylate, C13H22NO2 +·C6H4NO2 −, 2p, consists of one cation and one 2-picolinate anion. Salt 1p crystallizes in the triclinic centrosymmetric space group P\overline 1, while salt 2p crystallizes in the space group P41212. The conformations of the amine fragments are contrasted and that of 2p is found to have an unusual antiperiplanar arrangement about the ether group. The crystal packing of 1 and 2c is dominated by hydrogen-bonded chains, while the structures of the 2-picolinate salts have hydrogen-bonded rings as the major features. In both salts with 2-picolinic acid, the specific R 1 2(5) hydrogen-bonding motif is observed. Structural studies have been enriched by the generation of fingerprint plots derived from Hirshfeld surfaces.

As part of the presented research, thirteen new aminoalkanol derivatives were designed and obtained by chemical synthesis. In vivo studies (mice, i.p.) showed anticonvulsant activity (MES) of nine compounds, and in the case of one compound (R,S-trans-2-((2-(2,3,5-trimethylphenoxy)ethyl)amino)cyclohexan-1-ol, 4) both anticonvulsant (ED50 MES = 15.67 mg/kg, TD50 rotarod = 78.30 mg.kg, PI = 5.00) and analgesic activity (OXA-induced neuropathic pain, active at 15 mg/kg). For selected active compounds additional in vitro studies have been performed, including receptor studies (5-HT1A), evaluation of antioxidant activity (DPPH assay), metabolism studies as well as safety panel (mutagenicity, safety in relation to the gastrointestinal flora, cytotoxicity towards astrocytes as well as impact on their proliferation and cell cycle).

Aminoalkanol and aroxyalkyl derivatives are known as potential anticonvulsants. Two new salts, namely bis{(R,S)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium} succinate (1s), C13H22NO2 +·0.5C4H4O4 2−, and bis{(S)-(+)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium} succinate (2s), C13H22NO2 +·0.5C4H4O4 2−, have been prepared and characterized by single-crystal X-ray diffraction. The N atoms are protonated by proton transfer from succinic acid. Salt 1s crystallizes in the space group P21/n with one cation and half an anion in the asymmetric unit across an inversion centre, while (2s) crystallizes in the space group P21 with four cations and two anions in the asymmetric unit. The hydroxy group of the cation of 1s is observed in two R/S disorder positions. The crystals of these two salts display similar supramolecular architectures (i.e. two-dimensional networks), built mainly by intermolecular N+—H...Oδ− and O—H...Oδ− hydrogen bonds, where `δ−' represents a partial charge. The succinate anions are engaged in hydrogen bonds, not only with protonated N atoms, but also with hydroxy groups.

Because of numerous indications and high availability, non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed and used medicines in the world. However, long-term therapy with and improper use of NSAIDs may lead to gastrointestinal damage. Therefore, improving the therapeutic index of the existing drugs has become a priority over the past decades. Considerable attention in the field has been concentrated on metal complexes of non-steroidal anti-inflammatory drugs. The aim of this study is to evaluate the effect of complexation with zinc on the anti-inflammatory and ulcerogenic effects of ibuprofen and naproxen after single and triple intragastric administration to rats. The anti-inflammatory effect was assessed in carrageenan-induced inflammatory edema in the hind paw of male albino Wistar rats. The mucosal lesions were inspected and evaluated for gross pathology. Single administration of both the investigated complexes, namely zinc-ibuprofen and zinc-naproxen (20 mg/kg equivalent to ibuprofen and naproxen, respectively) and their parent drugs and physical mixtures with zinc hydroaspartate (ZHA doses: 16.05 and 14.37 mg/kg), caused a significant reduction of the edema after the same time from the carrageenan injection in comparison to the control groups. However, no statistically significant differences between the investigated drugs were observed after their single administration. The mean ulceration score for the mixture of ibuprofen and ZHA was statistically lower than the mean score achieved in rats after treatment with ibuprofen alone. On the other hand, triple intragastric administration of the ZHA-ibuprofen and ZHA- naproxen combination showed substantial enhancement of the anti-inflammatory activity against control groups, as well as against the parent NSAIDs. The most potent anti-inflammatory activity was demonstrated after 2 h from the carrageenan injection in animals receiving ZHA together with naproxen. The edema growth was reduced in these animals by 80.9% as compared to the control group. This result was significantly higher than the results achieved in animals receiving zinc-naproxen (50.2%) or naproxen alone (47.9%). Both NSAID complexes with zinc and mixtures with ZHA alleviated ulcerations caused by parent NSAIDs; however, the mixtures of both ibuprofen and naproxen with ZHA after triple administration were the least damaging. In view of the above results, zinc supplementation during NSAID therapy may have a beneficial effect on ulcer prevention and healing by reducing the effective dose of the parent drug and increasing its potency.

Epilepsy and neuropathic pain are frequent neurological disorders with pathomechanism based on abnormal neuronal discharges. Secondary tissue impairment observed after traumatic brain injury is also connected with neuronal dysfunction. Those three neurological disorders are ineffectively treated with currently available pharmacotherapy options so great effort is made in searching for new effective drugs. Four N-(E)-cinnamoyl (cinnamamide) derivatives of aminoalkanols: S-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (1), R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide (2), R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide (3), (2E)-3-(4-chlorophenyl)-N-(4-hydroxycyclohexyl)prop-2-enamide (4) were evaluated in vivo and in vitro for anticonvulsant, neuroprotective and/or analgesic activity. In intravenous metrazol seizure threshold test compounds 1–3 did not show pro-convulsive effect but proved anticonvulsant potential. In corneal kindled mice model the tested compounds showed beneficial anticonvulsant properties with ED50 of 36.8 mg/kg for 1, 25.7 mg/kg for 2, and 51.1 mg/kg for 3. Compound 2 tested in vitro in spontaneously bursting rat hippocampal slice model significantly reduced burst rate. Compounds 1 and 2 did not decrease lesion volume in acute model of traumatic brain injury. In formalin test of hyperalgesia in mice, compound 1 was active in the acute phase of the test, while compound 4 caused reduction of the time of licking of the affected paw by approx. 88% during the acute phase and 100% during the inflammatory phase. In rat sciatic ligation model of neuropathic pain, compound 1 significantly increased the paw withdrawal threshold starting from one hour after oral administration and the activity continued up to six hours. Reported here four N-(E)-cinnamoyl derivatives of aminoalkanols possess promising activity as anticonvulsant and/or analgesic agents.

Effective protection from the harmful effects of UV radiation may be achieved by using sunscreens containing organic or inorganic UV filters. The number of currently available UV filters is limited and some of the allowed molecules possess limitations such as systemic absorption, endocrine disruption properties, contact and photocontact allergy induction, and low photostability. In the search for new organic UV filters we designed and synthesized a series consisting of 5-benzylidene and 5-(3-phenylprop-2-en-1-ylidene)imidazolidine-2,4-dione (hydantoin) derivatives. The photoprotective activity of the tested compounds was confirmed in methanol solutions and macrogol formulations. The most promising compounds possessed similar UV protection parameter values as selected commercially available UV filters. The compound diethyl 2,2&prime, ((Z)-4-((E)-3-(4-methoxyphenyl)allylidene)-2,5-dioxoimidazolidine-1,3-diyl)diacetate (4g) was characterized as an especially efficient UVA photoprotective agent with a UVA PF of 6.83 &plusmn, 0.05 and favorable photostability. Diethyl 2,2&prime, ((Z)-4-(4-methoxybenzylidene)-2,5-dioxo- imidazolidine-1,3-diyl)diacetate (3b) was the most promising UVB-filter, with a SPFin vitro of 3.07 &plusmn, 0.04 and very good solubility and photostability. The main photodegradation products were geometric isomers of the parent compounds. These compounds were also shown to be non-cytotoxic at concentrations up to 50 &micro, M when tested on three types of human skin cells and possess no estrogenic activity, according to the results of a MCF-7 breast cancer model.

Background and aims Metabolic syndrome associated with insulin resistance and hypertension is often caused by excessive fructose consumption. Treatment of hypertension in patients with metabolic syndrome is a difficult task as many antihypertensive drugs have adverse effects on the metabolic profile. We investigated if MH-76 and MH-79, non-quinazoline α1-adrenoceptor antagonists with an additional ability to stimulate NO/cGMP/K+ pathway, ameliorates metabolic syndrome in fructose-fed rats. As reference compound prazosin was used. Methods and results Male rats were divided into 5 groups (n = 8) and studied for 18 weeks: group control: standard diet and drinking water; group Fructose: high-fructose diet (20% fructose in drinking water); groups Fructose + MH-76, Fructose + MH-79, Fructose + prazosin: high-fructose diet with subsequent MH-76, MH-79 (5 mg/kg/day ip) or prazosin (0.2 mg/kg/day ip) treatment 12 weeks later. In addition to their antihypertensive effect, the studied compounds reversed endothelial dysfunction, decreased hyperglycemia and hypertriglyceridemia, as well as prevented abdominal adiposity. Moreover, MH-76 reduced insulin resistance and decreased TNF-α concentration and lipid peroxidation in adipose tissue. Prazosin treatment exerted an antihypertensive effect, reduced hyperglycemia but did not improve endothelial dysfunction, insulin resistance, and abdominal adiposity. The lower efficacy of prazosin may be the result of its short half-time and the lack of described pleiotropic effects. Conclusions α1–adrenoceptor blockade, endothelial protection, TNF-α suppressing and antioxidant activity together with favorable pharmacokinetic parameters determines high efficacy of MH-76, leading to the effective improvement of hemodynamic and metabolic disturbances in metabolic syndrome. The use of non-quinazoline, multiple-targeted α1-blockers may be an interesting option for treatment of hypertension with metabolic complications.

Background: Natural plant metabolites and their semisynthetic derivatives have been used for years in cancer therapy. Xanthones are oxygenated heterocyclic compounds produced as secondary metabolites by higher plants, fungi or lichens. Xanthone core may serve as a template in the synthesis of many derivatives that have broad biological activities. Objective: This study synthesized a series of 17 new xanthones, and their anticancer potential was also evaluated. Methods: The anticancer potential was evaluated in vitro using a highly invasive T24 cancer cell line. Direct cytotoxic effects of the xanthones were established by IC50 estimation based on XTT assay. Results: 5 compounds of the total 17 showed significant cytotoxicity toward the studied cancer cultures and were submitted to further detailed analysis, including studies examining their influence on gelatinase A and B expression, as well as on the cancer cells migration and adhesion to an extracellular matrix. These analyses were carried out on five human tumor cell lines: A2780 (ovarian cancer), A549 (lung cancer), HeLa (cervical cancer), Hep G2 (liver cancer), and T24 (urinary bladder cancer). All the compounds, especially 4, showed promising anticancer activity: they exhibited significant cytotoxicity towards all the evaluated cell lines, including MCF-7 breast cancer, and hindered migration-motility activity of cancer cells demonstrating more potent activity than α-mangostin which served as a reference xanthone. Conclusion: These results suggest that our xanthone derivatives may be further analyzed in order to include them in cancer treatment protocols.

We investigated the therapeutic effect of MH-76 and MH-79, which are non-quinazoline α1-adrenoceptor antagonists with an additional ability to stimulate the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/K + pathway, on deoxycorticosterone acetate (DOCA)-salt induced hypertension in rats. Prazosin was used as a reference compound, as quinazoline-based α1-adrenolytics may potentially exert unfavorable proapoptotic and necrotic effects. DOCA-salt hypertension was induced by DOCA (20 mg/kg s.c., twice weekly) administration plus 1% NaCl and 0.2% KCl solutions in drinking water for 12 weeks. The studied compounds MH-76, MH-79 (10 mg/kg i.p.) or prazosin (0.4 mg/kg i.p.) were administered to the DOCA-salt-treated rats, starting from the 6th week of DOCA-salt treatment and continuing for 6 weeks. This study showed that the administration of MH-79 and, to a lesser extent, MH-76 decreased elevated systolic blood pressure and heart rate, reduced heart and kidney hypertrophy, and reversed the histopathological alterations of the heart, kidney, and vessels in DOCA-salt hypertensive rats. MH-79 reversed endothelial dysfunction, which reduced inflammatory cell infiltration, arteriosclerotic alterations in renal and coronary arteries, and tubulointerstitial fibrosis. Prazosin showed a potent hemodynamic effect and reduced cardiac and renal fibrosis but exerted detrimental effects on blood vessels, potentiating fibroplasia of the media of the intrarenal artery and causing calcification of coronary arteries. Prazosin did not reverse endothelial dysfunction. Our results show the beneficial effect of non-quinazoline α1-adrenolytics on cardiac, vascular, and renal dysfunction in DOCA-salt hypertensive rats. Our findings also support the idea that targeting endothelial protection and endothelial integrity would yield beneficial effects against cardiac, blood vessel and renal injury related to hypertension.

Background: Quinazoline α1-adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first line therapy of hypertension. Recent studies have shown that quinazoline-based α1-adrenoceptors antagonists (prazosin, doxazosin) induce the apoptosis and necrosis, which may be responsible for ALLHAT outcomes, however, these effects were proven to be independent of α1-adrenoceptor blockade and were associated with the presence of quinazoline moiety. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1-adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity. In this study we aimed to further investigate and compare the effects of MH-76 and prazosin on inflammation in adipose tissue of fructose-fed rats. Methods: Abdominal adipose tissue was collected from four groups of fructose-fed rats (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical, histopathological and immunohistochemical studies. Moreover, selected tissue distribution studies were performed. Results: Treatment with MH-76 but not with prazosin improved endothelial integrity, reduced adipose tissue inflammation and infiltration by immune cells, resulting in lowering leptin, MCP-1, IL-6, TNF-α and PAI-1 levels. In adipose tissue from Fructose + MH-76 animals, a higher amount of eosinophils accompanied with higher IL-4 concentration was observed. Treatment with MH-76 but not with prazosin markedly reduced phosphorylation of IRS-1 at Ser307. Conclusion: MH-76 may improve insulin signaling in adipose tissue by reducing the pro-inflammatory cytokine production and inhibiting the inflammatory cells recruitment. In contrast, in adipose tissue from animals treated with prazosin, the inflammatory effect was clearly enhanced.

In vitro mutagenic, antimutagenic, and antioxidant potency evaluation and biotransformation of six novel 4-substituted 1-(2-methoxyphenyl)piperazine derivatives demonstrating antidepressant-like activity were investigated. Mutagenic and antimutagenic properties were assessed using the Ames test; free radical scavenging activity was evaluated with 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay and biotransformation was performed with liver microsomes. It was found that all tested compounds are not mutagenic in bacterial strains TA100 and TA1535 and exhibit antimutagenic effects in the Ames test. Noteworthy, compounds possessing propyl linker between phenoxyl and N-(2-methoxyphenyl)piperazine displayed more pronounced antimutagenic properties than derivatives with ethoxyethyl linker. Additionally, compounds 2 and 6 in vitro biotransformation showed that primarily their hydroxylated or O-dealkylated metabolites are formed. Some of the compounds exhibited intrinsic clearance values lower than those reported previously for antidepressant imipramine. To sum up, the results of the present study might represent a valuable step in designing and planning future studies with piperazine derivatives.

Epilepsy, one of the most frequent neurological disorders, is still insufficiently treated in about 30% of patients. As a consequence, identification of novel anticonvulsant agents is an important issue in medicinal chemistry. In the present article we report synthesis, physicochemical, and pharmacological evaluation of N-trans-cinnamoyl derivatives of R and S-2-aminopropan-1-ol, as well as R and S-2-aminobutan-1-ol. The structures were confirmed by spectroscopy and for derivatives of 2-aminopropan-1-ols the configuration was evaluated by means of crystallography. The investigated compounds were tested in rodent models of seizures: maximal electroshock (MES) and subcutaneous pentetrazol test (scPTZ), and also in a rodent model of epileptogenesis: pilocarpine-induced status prevention. Additionally, derivatives of 2-aminopropan-1-ols were tested in benzodiazepine-resistant electrographic status epilepticus rat model as well as in vitro for inhibition of isoenzymes of cytochrome P450. All of the tested compounds showed promising anticonvulsant activity in MES. For R(-)-(2E)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide pharmacological parameters were found as follows: ED50 = 76.7 (68.2-81.3) mg/kg (MES, mice i.p., time = 0.5 h), ED50 = 127.2 (102.1-157.9) mg/kg (scPTZ, mice i.p., time = 0.25 h), TD50 = 208.3 (151.4-230.6) mg/kg (rotarod, mice i.p., time = 0.25 h). Evaluation in pilocarpine status prevention proved that all of the reported compounds reduced spontaneous seizure activity and act as antiepileptogenic agents. Both enantiomers of 2-aminopropan-1-ols did not influence cytochrome P450 isoenzymes activity in vitro and are likely not to interact with CYP substrates in vivo. Chirality 28:482-488, 2016. © 2016 Wiley Periodicals, Inc.

A series of thirty N-(phenoxy)alkyl or N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols has been designed, synthesized and evaluated for anticonvulsant activity in MES, 6 Hz test, and pilocarpine-induced status epilepticus. Among the title compounds, the most promising seems R-(−)-2N-{2-[2-(2,6-dimethylphenoxy)ethoxy]ethyl}aminopropan-1-ol hydrochloride (22a) with proved absolute configuration with X-ray analysis and enantiomeric purity. The compound is effective in MES test with ED50 = 12.92 mg/kg b.w. and its rotarod TD50 = 33.26 mg/kg b.w. The activity dose is also effective in a neurogenic pain model—the formalin test. Within high throughput profile assay, among eighty one targets, the strongest affinity of the compound is observed towards σ receptors and 5-HT transporter and the compound does not bind to hERG. It also does not exhibit mutagenic properties in the Vibrio harveyi test. Moreover, murine liver microsomal assay and pharmacokinetics profile (mice, iv, p.o., ip) indicate that the liver is the primary site of biotransformation of the compound, suggesting that both 22a and its metabolite(s) are active, compensating probably low bioavailability of the parent molecule.

Doxorubicin (DOX) therapy is limited by both cancer cells resistance and cardiotoxicity. DOX biotransformation to doxorubicinol (DOXol) by reductases enzymes (mainly by CBR1; carbonyl reductase 1) is a key process responsible for DOX adverse effects development. Thus, inhibition of CBR1 can increase the therapeutic effect of DOX. In the present study, we used a group of new synthetized cinnamic acid (CA) derivatives to improve the effectiveness and safety profile of DOX therapy against cancer cells in vitro. The possible mechanism of CBR1 inhibition was simulated by molecular modelling studies. The kinetics of DOX reduction in the presence of active CA derivatives were measured in cytosols. The chemosensitising activity of CA derivatives including proapoptotic, anti-invasiveness activity were investigated in A549 lung cancer cell line. In our research 7 from 16 tested CA derivatives binded to the active site of CBR1 enzyme and improved DOX stability by inhibition of DOXol formation. Co-treatment of A549 cells with active CA derivatives and DOX induced cells apoptosis by activation of caspase cascade. At the same time we observed decrease of invasive properties (cell migration and transmigration assays) and the rearangments of F-actin cytoskeleton in CA derivatves + DOX treated cells. Meanwhile, control, human lung fibroblasts stay realtivelly unvulnerable and viable. New synthetized CA derivatives may inhibit the activity of CBR1 leading to the stabilization of DOX therapeutic levels in cancer cells and to protect the myocardium against DOXol cytotoxic effect. Favourable physicochemical properties supported by a safety profile and multidirectional chemosensitising activity render CA derivatives a promising group for the development of agent useful in combined therapy.

Epilepsy is one of the most frequent neurological disorders affecting about 1% of the world&rsquo, 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 &micro, M. 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.

Metabolic syndrome associated with insulin resistance and hypertension is often caused by excessive fructose consumption. Treatment of hypertension in patients with metabolic syndrome is a difficult task as many antihypertensive drugs have adverse effects on the metabolic profile. We investigated if MH-76 and MH-79, non-quinazoline αMale rats were divided into 5 groups (n = 8) and studied for 18 weeks: group control: standard diet and drinking water; group Fructose: high-fructose diet (20% fructose in drinking water); groups Fructose + MH-76, Fructose + MH-79, Fructose + prazosin: high-fructose diet with subsequent MH-76, MH-79 (5 mg/kg/day ip) or prazosin (0.2 mg/kg/day ip) treatment 12 weeks later. In addition to their antihypertensive effect, the studied compounds reversed endothelial dysfunction, decreased hyperglycemia and hypertriglyceridemia, as well as prevented abdominal adiposity. Moreover, MH-76 reduced insulin resistance and decreased TNF-α concentration and lipid peroxidation in adipose tissue. Prazosin treatment exerted an antihypertensive effect, reduced hyperglycemia but did not improve endothelial dysfunction, insulin resistance, and abdominal adiposity. The lower efficacy of prazosin may be the result of its short half-time and the lack of described pleiotropic effects.α

The aim of this study was to evaluate antifungal activity in a diverse group of chlorine-containing xanthone and phenoxyethyl amine derivatives - and to select the most promising compounds for further studies. The antifungal efficacy of 16 compounds was tested with qualitative and quantitative methods against both reference and clinical strains of dermatophytes, moulds and yeasts. The disc-diffusion method has demonstrated that from 16 tested compounds, 7 possess good antifungal activity against dermatophytes and/or moulds while none of them has shown good efficacy against yeasts or bacterial strains. The most active compounds (2, 4, 10, 11, 12, 15, 16) were tested quantitatively by broth dilution method to obtain MIC values. The MIC values against dermatophytes ranged from 8 to 64 μg/ml. Compound 2 was the most active one against dermatophytes (MIC 50 and MIC 90 were 8 μg/ml). The MIC values for moulds ranged from 16 to 256 μg/ml. Compound 4 was the most active one against moulds, with MIC 50 and MIC 90 values amounting to 32 μg/ml. Among the tested compounds, compound 4 (derivative of xanthone) was the most active one and expressed good antifungal efficacy against clinical strains of dermatophytes and moulds. However, another xanthone derivative (compound 2) was the most active and selective against dermatophytes.

Numerous studies have proven that both stimulation and blockade of 5-HT1A and the blockade of 5-HT7 receptors might cause the anxiolytic-like effects. Biased agonists selectively activate specific signaling pathways. Therefore, they might offer novel treatment strategies. In this study, we investigated the anxiolytic-like activity, as well as the possible mechanism of action of 1-[(2,5-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-17). In our previous experiments, HBK-17 showed high affinity for 5-HT1A and 5-HT7 receptors and antidepressant-like properties. We performed the four plate test and the elevated plus maze test to determine anxiolytic-like activity. Toward a better understanding of the pharmacological properties of HBK-17 we used various functional assays to determine its intrinsic activity at 5-HT1A, 5-HT2A, 5-HT7, and D2 receptors and UHPLC-MS/MS method to evaluate its pharmacokinetic profile. We observed the anxiolytic-like activity of HBK-17 in both behavioral tests and the effect was reversed by the pretreatment with WAY-100635, which proves that 5-HT1A receptor activation was essential for the anxiolytic-like effect. Moreover, the compound moderately antagonized D2, weakly 5-HT7 and very weakly 5-HT2A receptors. We demonstrated that HBK-17 preferentially activated s-arrestin signaling after binding to the 5-HT1A receptor. HBK-17 was rapidly absorbed after intraperitoneal administration and had a half-life of about 150 min. HBK-17 slightly penetrated the peripheral compartment and showed bioavailability of approximately 45%. The unique pharmacological profile of HBK-17 encourages further experiments to understand its mechanism of action fully.

A number of cinnamamide derivatives possess anticonvulsant activity due to the presence of a number of important pharmacophore elements in their structures. In order to study the correlations between anticonvulsant activity and molecular structure, the crystal structures of three new cinnamamide derivatives with proven anticonvulsant activity were determined by X-ray diffraction, namely (R,S)-(2E)-N-(2-hydroxybutyl)-3-phenylprop-2-enamide–water (3/1), C13H17NO2·0.33H2O, (1), (2E)-N-(1-hydroxy-2-methylpropan-2-yl)-3-phenylprop-2-enamide, C13H17NO2, (2), and (R,S)-(2E)-N-(1-hydroxy-3-methyl-butan-2-yl)-3-phenylprop-2-enamide, C14H19NO2, (3). Compound (1) crystallizes in the space group P\overline{1} with three molecules in the asymmetric unit, whereas compounds (2) and (3) crystallize in the space group P21/c with one and two molecules, respectively, in their asymmetric units. The carbonyl group of (2) is engaged in an intramolecular hydrogen bond with the hydroxy group. This type of interaction is observed for the first time in these kinds of derivatives. A disorder of the substituent at the N atom occurs in the crystal structures of (2) and (3). The crystal packing of all three structures is dominated by a network of O—H...O and N—H...O hydrogen bonds, and leads to the formation of chains and/or rings. Furthermore, the crystal structures are stabilized by numerous C—H...O contacts. We analyzed the molecular structures and intermolecular interactions in order to propose a pharmacophore model for cinnamamide derivatives.

Xanthone derivatives of acetic, propionic and 2-methylpropionic acids were synthesized and assayed for their anti-inflammatory, analgesic and ulcerogenic activities. Compound 8 causes a dose-dependent diminution of paw edema (up to 61%) in the carrageenan model and at the highest tested dose reduces mechanical hyperalgesia in the Randall-Selitto test more effectively than the reference compound (~75% and ~32%, respectively). It shows high in vitro metabolic stability (Clint=12.5 μL/mg/min, t1/2=138.6 min) in the rat liver microsomes. None of the studied xanthone derivatives are ulcerogenic. The results of the present study suggest that compound 8 can be of interest in the future for the search for antinociceptive and antiedematous agents devoid of ulcerogenic effect.

Cinnamic acid derivatives are widely used in cosmetics and possess various functions. This group of compounds includes both naturally occurring and synthetic substances. On the basis of the Cosmetic Ingredient Database (CosIng) and available literature, this review summarizes their functions in cosmetics, including their physicochemical and biological properties as well as reported adverse effects. A perfuming function is typical of many derivatives of cinnamaldehyde, cinnamyl alcohol, dihydrocinnamyl alcohol and cinnamic acid itself; these substances are commonly used in cosmetics all over the world. Some of them show allergic and photoallergic potential, resulting in restrictions in maximum concentrations and/or a requirement to indicate the presence of some substances in the list of ingredients when their concentrations exceed certain fixed values in a cosmetic product. Another important function of cinnamic acid derivatives in cosmetics is UV protection. Ester derivatives such as ethylhexyl methoxycinnamate (octinoxate), isoamyl p-methoxycinnamte (amiloxiate), octocrylene and cinoxate are used in cosmetics all over the world as UV filters. However, their maximum concentrations in cosmetic products are restricted due to their adverse effects, which include contact and a photocontact allergies, phototoxic contact dermatitis, contact dermatitis, estrogenic modulation and generation of reactive oxygen species. Other rarely utilized functions of cinnamic acid derivatives are as an antioxidant, in skin conditioning, hair conditioning, as a tonic and in antimicrobial activities. Moreover, some currently investigated natural and synthetic derivatives of cinnamic acid have shown skin lightening and anti-ageing properties. Some of them may become new cosmetic ingredients in the future. In particular, 4-hydroxycinnamic acid, which is currently indexed as a skin-conditioning cosmetics ingredient, has been widely tested in vitro and in vivo as a new drug candidate for the treatment of hyperpigmentation.

A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α1-(compound 2 and 8), β-(compounds 1, 3, 4, 7), α1/β-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives.

The aim of this study was to explore the α1-adrenoceptor-independent mechanisms involved in the vasorelaxant properties of two non-quinazoline α1-adrenoceptors antagonists (MH-76 and MH-79). Endothelium intact and endothelium denuded rat aorta was contracted with 1 μM phenylephrine to plateau, and the vasodilatory effect of MH-76 and MH-79 was examined in the absence or presence of inhibitors of the different signal transduction pathways. cGMP concetration was measured in rat aorta (enzyme immunoassay kit). In human aortic endothelial cells (HAEC) NO production was examined using a DAF-FM DA fluorescent indicator, whereas in human aortic smooth muscle cells the influence of the title compounds on K+ efflux was evaluated. The vasorelaxant effect of MH-76 and MH-79 was attenuated by endothelium removal, Nω-Nitro- l -arginine methyl ester (L-NAME) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) pretreatment to the level characteristic for α1-adrenoreceptor blocking activity. In addition, the MH-76 and MH-79 induced relaxation was reduced by K+ channels blockers. In endothelium intact rat aorta, MH-76 and MH-79 caused an increase in cGMP level, whereas in HAEC they increased NO generation. In contrast, the reference, quinazoline based α1-antagonist prazosin, did not influence NO production. Our findings suggest that the mechanisms underlying the vasodilatory properties of non-quinazoline based α1-adrenoceptors antagonists MH-76 and MH-79 involve not only α1-adrenoceptor blocking activity but also the activation of the endothelial NO–cGMP signalling pathway and the subsequent opening of K+ channels. Our studies show that such double mechanism of action is superior to pure α1-adrenoceptor blockade, and may be considered as a promising alternative for the prevention and treatment of cardiovascular diseases.

Aim of the study was evaluation of anxiolytic, antidepressant, anticonvulsant and analgesic activity in a series of a consistent group of compounds. A series of eleven new N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives has been obtained. Their affinity towards 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, D2 and α1 receptors has been assessed, and then functional assays were performed. The compounds were evaluated in mice, i.p. for their antidepressant-like (forced swim test), locomotor, anxiolytic-like (four-plate test) activities as well as – at higher doses – for anticonvulsant potential (MES) and neurotoxicity (rotarod). Two compounds (3, 6) were also evaluated for their analgesic activity in neuropathic pain models (streptozocin test, oxaliplatin test) and they were found active against allodynia in diabetic neuropathic pain at 30 mg/kg. Among the compounds, anxiolytic-like, anticonvulsant or analgesic activity was observed but antidepressant-like activity was not. One of the two most interesting compounds is 1-{2-[2-(2,4,6-trimethylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine dihydrochloride (9), exhibiting anxiolytic and anticonvulsant activity in mice, i.p. 30 min after administration (at 2.5 mg/kg and ED50 = 26.33 mg/kg, respectively), which can be justified by the receptor profile: 5-HT1A Ki = 5 nM (antagonist), 5-HT7 Ki = 70 nM, α1 Ki = 15 nM, D2 Ki = 189 nM (antagonist). Another interesting compound is 1-[3-(2,4,6-trimethylphenoxy)propyl]-4-(4-methoxyphenyl)piperazine dihydrochloride (3), exhibiting anxiolytic, anticonvulsant and antiallodynic activity in mice, i.p., 30 min after administration (at 10 mg/kg, ED50 = 23.50 mg/kg, at 30 mg/kg, respectively), which can be related with 5-HT1A weak antagonism (Ki = 146 nM), or other possible mechanism of action, not evaluated within presented study. Additionally, for the most active compound in the four-plate test (7), molecular modeling was performed (docking to receptors 5-HT1A, 5-HT2A, 5-HT7, D2 and α1A).

Summary Reactive oxygen species (ROS) are critically involved in the action of anticancer agents. In this study, we investigated the role of ROS in the anticancer mechanism of new aminoalkanol derivatives of xanthone. Most xanthones used in the study displayed significant pro-oxidant effects similar to those of gambogic acid, one of the most active anticancer xanthones. The pro-oxidant activity of our xanthones was shown both directly (by determination of ROS induction, effects on the levels of intracellular antioxidants, and expression of antioxidant enzymes) and indirectly by demonstrating that the overexpression of manganese superoxide dismutase decreases ROS-mediated cell senescence. We also observed that mitochondrial dysfunction and cellular apoptosis enhancement correlated with xanthone-induced oxidative stress. Finally, we showed that the use of the antioxidant N-acetyl-L-cysteine partly reversed these effects of aminoalkanol xanthones. Our results demonstrated that novel aminoalkanol xanthones mediated their anticancer activity primarily through ROS elevation and enhanced oxidative stress, which led to mitochondrial cell death stimulation; this mechanism was similar to the activity of gambogic acid.

A series of 17 new phenoxyacetamides has been prepared via multistep chemical synthesis as a continuation of the research carried out by our group on di- and tri-substituted phenoxyalkyl and phenoxyacetyl derivatives of amines. The obtained compounds vary in an amide component, for example aminoalkanol or (un)modified amino acid moieties were introduced. The structures of selected products were confirmed by means of crystallographic methods. All 17 compounds were the subject of preliminary screening for potential anticonvulsant activity (MES, 6 Hz and/or scMET tests) and neurotoxicity (rotarod) in mice after intraperitoneal administration, while several active compounds were subsequently examined in additional models (e.g. MES and rotarod – rats, p.o. or i.p., hippocampal kindling – rats, i.p.). Finally, safety studies (cytotoxicity and cell proliferation assays on astrocytes, metabolic stability assessment, mutagenicity evaluation) were performed for several active compounds, including the most promising one (R-(–)-2-(2,6-dimethylphenoxy)-N-(1-hydroxypropan-2-yl)acetamide, MES ED(50) = 12.00 mg per kg b.w., rats, p.o.).

The aim of this study was to explore the α

In this study, we report the synthesis, spectral characterization, antiepileptic activity and biotransformation of three new, chiral, N-aminoalkyl derivatives of trans – 2 aminocyclohexan-1-ol: 1 (R enantiomer), 2 (S enantiomer) and 3 (racemate). Antiepileptic activity of the titled compounds was studied using MES and scMet. Moreover, in this study, the biotransformation of 1, 2 and 3 in microbial model (Cunninghamella), liver microsomal assay as well as in silico studies (MetaSite) was evaluated. Studies have indicated that 1, 2 and 3 have good antiepileptic activity in vivo, comparable to valproate. Biotransformation assays showed that the most probable metabolite (indicated in every tested assays) was M1. The microbial model as well as in silico study showed no difference in biotransformation between tested enantiomers. However, in a rat liver microsomal study compound 1 and 2 (R and S enantiomer) had different main metabolite – M2 for 1 and M1 for 2. MS/MS fragmentation allowed us to predict the structures of obtained metabolites, which were in agreement with 1°alcohol (M1) and carboxylic acid (M2). Our research has shown that microbial model, microsomal assay, and computational methods can be included as useful and reliable tools in early ADME-Tox assays in the process of developing new drug candidates. Chirality 27:163–169, 2015. © 2014 Wiley Periodicals, Inc.

In this study, thirty-five N-substituted derivatives of cinnamic acid amide (cinnamamide) were evaluated for anti-Helicobacter pylori activity using an agar disc-diffusion method. Qualitative screening was performed on a reference H. pylori strain (ATCC 43504), resulting in the identification of the three most active compounds, 8 (R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide, minimal inhibitory concentration, MIC = 7.5 µg/mL), 23 ((2E)-3-(4-chlorophenyl)-N-(2-hydroxycyclohexyl)prop-2-enamide, MIC = 10 µg/mL), and 28 ((2E)-3-(4-chlorophenyl)-N-(4-oxocyclohexyl)prop-2-enamide, MIC = 10 µg/mL). These compounds were further tested on twelve well-characterized clinical strains, yielding MIC values that ranged from 10 to 1000 µg/mL. Preliminary safety assessments of the compounds were made using the MTT viability test for cytotoxicity and Ames test for mutagenicity, which showed them to be generally safe, although compounds 8 and 28 showed mutagenic activity at some of the tested concentrations. The results of this study showed the anti-H. pylori potential of cinnamamide derivatives.