Discovery of (E)-3-(4-chlorophenyl)-N-(5-hydroxypentyl)acrylamide among N-substituted cinnamamide derivatives as a novel cosmetic ingredient for hyperpigmentation.

Hyperpigmentation disorders may result from inappropriate melanin deposition and/or excessive melanin synthesis. They are classified mainly as aesthetic problems, but they can significantly affect human health by decreasing self-esteem. There are available only limited treatment options for hyperpigmentation disorder, among others, cosmetic products applied topically. Depigmenting ingredients were found to be ineffective and characterized by various side effects. As a result, many efforts are made to discover novel, potent, and safe melanogenesis inhibitors for possible use in topical cosmetic depigmenting formulations. Cinnamic acid derivatives constitute a widely tested group for that purpose. This article reports research in the group of N-alkyl cinnamamide derivatives (un)substituted in phenyl ring. Among tested series, (E)-3-(4-chlorophenyl)-N-(5-hydroxypentyl)acrylamide (compound 21) showed the most promising inhibitory properties in mushroom tyrosinase assay (IC50 = 36.98 ± 1.07 µM for monophenolase activity, IC50 = 146.71 ± 16.82 µM for diphenolase activity) and melanin production inhibition in B16F10 mouse melanoma cell line at concentration 6.25 µM resulting probably from decreasing of Tyr, Mitf, Tyrp-1, and Tyrp-2 genes expression. This compound also showed melanin production inhibitory properties in pigmented reconstructed human epidermis when used in 1 % and 2 % solutions in 50 % PEG400. In vitro evaluation of its safety profile showed no cytotoxicity to human keratinocytes HaCaT, human skin fibroblasts BJ, and human primary epidermal melanocytes HEMa, no mutagenicity in the Ames test, no genotoxicity in micronucleus test, no phototoxicity, as well as no skin irritation potential tested in PEG400 solution. This compound was also shown to penetrate across the epidermis to reach the possible site of action. The performed research led to classify (E)-3-(4-chlorophenyl)-N-(5-hydroxypentyl)acrylamide as a novel potential depigmenting cosmetic ingredient.

In vitro safety evaluation of (6-methoxy-9-oxo-9H-xanthen-2-yl)methyl (E)-3-(2,4-dimethoxyphenyl)acrylate (K-116) - the novel potential UV filter designed by means of a double chromophore strategy.

The use of topical photoprotection is necessary to reduce adverse effects caused by excessive exposure to ultraviolet radiation. Despite the high standards set for UV filters, many of them may contribute to the occurrence of adverse effects. The newly synthesised compound K-116, the (E)-cinnamoyl xanthone derivative, could be an alternative. We conducted extended in vitro safety evaluation of compound K-116. The research included assessment of irritation potential on skin tissue, evaluation of penetration through the epidermis, and assessment of phototoxicity, and mutagenicity. Additionally, the eco-safety of compound K-116 was evaluated, including an examination of its degradation pathway in the Cunninghamella echinulata model, as well as in silico simulation of the toxicity of both the parent compound and its degradation products. The research showed that compound K-116 tested in future application conditions is deprived of skin irritant potential additionally it does not penetrate through the epidermis. Results showed that K-116 concentrate is not phototoxic and not mutagenic. The eco-safety studies showed that it undergoes biodegradation in 27% in Cunninghamella echinulata model. The parent compound and formed metabolite are less toxic than reference UV filters (octinoxate and octocrylene).

Hyperthermia Intensifies α-Mangostin and Synthetic Xanthones' Antimalignancy Properties.

In order to improve naturally occurring xanthones' anticancer properties, chemical synthesis is proposed. In this study, from eight novel xanthone derivatives coupled to morpholine or aminoalkyl morpholine, only the two most active ones were chosen. For additional enhancement of the anticancer activity of our tested compounds, we combined chemotherapy with hyperthermia in the range of 39-41 °C, from which the mild conditions of 39 °C were the most influencing. This approach had a profound impact on the anticancer properties of the tested compounds. TOV-21G and SC-OV-3 ovarian cell line motility and metastasis behavior were tested in native and hyperthermia conditions, indicating decreased wound healing properties and clonogenic activity. Similarly, the expression of genes involved in metastasis was hampered. The expression of heat shock proteins involved in cancer progression (Hsc70, HSP90A, and HSP90B) was significantly influenced by xanthone derivatives. Chemotherapy in mild hyperthermia conditions had also an impact on decreasing mitochondria potential, visualized with JC-1. Synthetic xanthone ring modifications may increase the anticancer activity of the obtained substances. Additional improvement of their activity can be achieved by applying mild hyperthermia conditions. Further development of a combined anticancer therapy approach may result in increasing currently known chemotherapeutics, resulting in a greater recovery rate and diminishment of the cytotoxicity of drugs.

HBK-15, a Multimodal Compound, Showed an Anxiolytic-Like Effect in Rats.

Anxiety is a common mental disorder, and its prevalence has lately increased because of the COVID-19 pandemic. Unfortunately, the available anxiolytics are often ineffective, and most possess addictive potential. Thus, searching for novel compounds is essential. In our previous studies, we selected a multimodal compound, HBK-15, which showed a fast antidepressant-like effect in animal models of depression. HBK-15 demonstrated a high affinity for serotonin 5-HT1A receptors and moderate for 5-HT7, dopamine D2, and α1-adrenoceptors. Based on the receptor profile and preliminary studies, we aimed to investigate the anxiolytic potential of HBK-15 using the conditioned-response rat model of anxiety, i.e., the Vogel drinking test. We performed hot plate and free-drinking tests to exclude false positive results in the Vogel test. Using radioligand binding studies, we also investigated the affinity of the compound for the selected biological targets, which play a role in anxiety. Our experiments revealed that HBK-15 showed an anxiolytic-like effect in rats (5 mg/kg) without influencing the pain threshold or the amount of water consumed in the free-drinking test. Furthermore, the tested compound did not show a significant affinity for the selected biological targets, which suggests that its anxiolytic-like mechanism of action could be connected with the interaction with other receptors. This study indicates that multimodal compounds with a receptor profile similar to HBK-15 could be an attractive therapeutic option for patients with a generalized anxiety disorder. However, more studies are required to determine the exact mechanism of action of HBK-15 and its safety profile.

Anticonvulsant and analgesic in neuropathic pain activity in a group of new aminoalkanol derivatives.

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).

The Involvement of Xanthone and (E)-Cinnamoyl Chromophores for the Design and Synthesis of Novel Sunscreening Agents.

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.

S(+)-(2E)-N-(2-Hydroxypropyl)-3-Phenylprop-2-Enamide (KM-568): A Novel Cinnamamide Derivative with Anticonvulsant Activity in Animal Models 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.

Four N-(E)-cinnamoyl (cinnamamide) derivatives of aminoalkanols with promising anticonvulsant and analgesic activity.

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.

Design, synthesis and evaluation of activity and pharmacokinetic profile of new derivatives of xanthone and piperazine in the central nervous system.

Searching for CNS active cyclic amines derivatives containing heterocyclic xanthone core we designed and synthesized a set of fourteen novel 2- or 4-methylxanthone substituted by alkyl- or aryl-piperazine moieties. The compounds were evaluated in vivo for their potential antidepressant-like activity (in the forced swim test) and anxiolytic-like activity (four-plate test) and their inhibitory effect against rat 5-HT2 receptor was checked. The pharmacokinetic analysis of active compounds done by a non-compartmental approach have shown a rapid absorption of all studied molecules from intraperitoneal cavity and good penetration the blood-brain barrier after i.p. administration with brain to plasma ratios varied from 2.8 to 31.6. Genotoxicity and biotransformation of active compounds were studied. Compound 19 interactions with major classes of GPCRs, uptake systems and ion channels were tested and results indicated that it binds to 5-HT2A, 5-HT2B receptors and sodium channels.

Beneficial effects of non-quinazoline α1-adrenolytics on hypertension and altered metabolism in fructose-fed rats. A comparison with prazosin.

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.

Discovery of Novel UV-Filters with Favorable Safety Profiles in the 5-Arylideneimidazolidine-2,4-dione Derivatives Group.

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'-((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 ± 0.05 and favorable photostability. Diethyl 2,2'-((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 ± 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 µM 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.

Contribution of reactive oxygen species to the anticancer activity of aminoalkanol derivatives of xanthone.

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.

Synthesis and activity of di- or trisubstituted N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives on the central nervous system.

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).

Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3.

A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3 was designed, synthesized and evaluated for anticonvulsant activity in rodent models of seizures: maximal electroshock (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and 6-Hz test. There were identified three most active compounds: S-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (5) (ED50 MES=42.56, ED50 scPTZ=58.38, ED50 6-Hz 44mA=42.27mg/kg tested in mice after intraperitoneal (i.p.) administration); R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide (6) (ED50 MES=53.76, ED50 scPTZ=90.31, ED50 6-Hz 44mA=92.86mg/kg mice, i.p.); and R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide (11) (ED50 MES=55.58, ED50 scPTZ=102.15, ED50 6-Hz 44mA=51.27mg/kg mice, i.p.). Their structures and configurations were confirmed by crystal X-ray diffraction method. The structure-activity studies among the tested series showed that chlorine atom in position para or methyl group in position ortho of phenyl ring were beneficial for anticonvulsant activity. Methyl group in position para of phenyl ring decreased anticonvulsant activity in reported series of cinnamamide derivatives.

Evaluation of anti-inflammatory and ulcerogenic potential of zinc-ibuprofen and zinc-naproxen complexes in rats.

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.

In vitro mutagenic, antimutagenic, and antioxidant activities evaluation and biotransformation of some bioactive 4-substituted 1-(2-methoxyphenyl)piperazine derivatives.

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.

Anticonvulsant Activity of Enantiomeric N-trans-Cinnamoyl Derivatives of 2-Aminopropan-1-ols and 2-Aminobutan-1-ols.

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.

ANTIOXIDANT ACTIVITY OF XANTHONE DERIVATIVES.

Certain xanthone derivatives, such as these present in mangosteen fruits, show strong antioxidant activity. On the other hand, evidences accumulated that oxidative stress is involved in epileptogenesis. Therefore, the aim of the present study was to estimate total antioxidant capacity (expressed as a ferric reducing antioxidant power - FRAP) and evaluate ability to scavenge free radicals (DPPH methods) by xanthone derivatives showing antiepileptic activity. Selected 2-(aminomethyl)-9H-xanthen-9-one derivatives shared structural features, such as chlorine substituent in xanthone ring and different chiral (or not) alkanol groups at the nitrogen atom. The results of antioxidant activities among racemates revealed the highest activity for compound (RIS)-3 (31.7% in diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and (0.184 ± 0.003 mM Fe²âº/L) in FRAP assay. Among tested pair of enantiomers we observed that (R)-1 and (R)-2 showed higher reduction capacity ((R)-1: 0.096 ± 0.007 mM F²âº/L; (R)-2: 0.048 ± 0.005 mM Fe²âº/L, respectively) and stronger DPPH scavenging activity ((R)-1: 31 ± 3.0%; (R)-2: 29 ± 2.5%, respectively) comparing to their (S)-enantiomers and racemates.

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.

N-[(2,6-Dimethylphenoxy)alkyl]aminoalkanols-their physicochemical and anticonvulsant properties.

Twenty four new N-[(dimethylphenoxy)alkyl]aminoalkanols have been synthesized and evaluated for anticonvulsant activity in a series of in vivo tests: the maximum electroshock (MES), 6 Hz, and subcutaneous metrazole (ScMet). The compounds were also evaluated for possible neurotoxicity in the rotarod test. The majority of the achieved compounds exhibit quantified anticonvulsant activity. The most active compound 4: R-(-)-2N-[(2,6-dimethylphenoxy)ethyl]aminopropan-1-ol is active in MES with ED50=5.34 (male mice, ip), 22.28 (female mice, ip), 51.19 (male mice, po), 7.43 (rats, ip), and 28.60 (rats, po). Thermal analysis proved that its hydrochloride (4a) can exist in polymorphic forms. The compound binds to σ, 5-HT1A, and α2 receptors as well as 5-HT transporter and it does not exhibit mutagenic properties.