Similar Safety Profile of the Enantiomeric N-Aminoalkyl Derivatives of Trans-2-Aminocyclohexan-1-ol Demonstrating Anticonvulsant Activity.

Epilepsy is one of the most common neurological disorder in the world. Many antiepileptic drugs cause multiple adverse effects. Moreover, multidrug resistance is a serious problem in epilepsy treatment. In the present study we evaluated the safety profile of three (1-3) new chiral N-aminoalkyl derivatives of trans-2-aminocyclohexan-1-ol demonstrating anticonvulsant activity. Our aim was also to determine differences between the enantiomeric compounds with respect to their safety profile. The results of the study indicated that compounds 1-3 are non-cytotoxic for astrocytes, although they exhibit cytotoxic activity against human glioblastoma cells. Moreover, 1-3 did not affect the viability of HepG2 cells and did not produce adducts with glutathione. Compounds 1-3 demonstrated no mutagenic activity either in the Salmonella typhimurium or in Vibrio harveyi tests. Additionally, the compounds displayed a strong or moderate antimutagenic effect. Finally, the P-glycoprotein (P-gp) ATPase assay demonstrated that both enantiomers are potent P-gp inhibitors. To sum up, our results indicate that the newly synthesized derivatives may be considered promising candidates for further research on anticonvulsant drug discovery and development. Our study indicated the similar safety profile of the enantiomeric N-aminoalkyl derivatives of trans-2-aminocyclohexan-1-ol, although in the previous studies both enantiomers differ in their biotransformation pathways and pharmacological activity.

Preliminary Safety Assessment of New Azinesulfonamide Analogs of Aripiprazole using Prokaryotic Models.

Purpose: Determination of the mutagenic potential of new biologically active compounds is of great concern for preliminary toxicity testing and drug development. Methods: The mutagenic and antimutagenic effects of some quinoline- and isoquinolinesulfonamide analogs of aripiprazole (1-8), which display potent antidepressant, anxiolytic, and antipsychotic properties, were evaluated using the Vibrio harveyi assay and OSIRIS Property Explorer software. Additionally, the Ames test was used as the reference. Results: In silico prediction showed that compounds 5 (N-(3-(4-(2,3- dichlorophenyl)piperazin-1-yl)propyl)quinoline-7-sulfonamide) and 6 (N-(4-(4-(2,3- Dichlorophenyl)piperazin-1-yl)butyl)quinoline-7-sulfonamide) trigger a mutagenic structural alert. However, this was not confirmed by in vitro assays, as none of the tested compounds displayed mutagenic activity against all tested strains of bacteria. Moreover, compounds 1-8 displayed a protective effect against the mutagenicity induced by a direct acting mutagen NQNO. The most beneficial antimutagenic properties showed compound 5 which exhibited strong antimutagenic properties in all tested V. harveyi strains. High antimutagenic potency of this compound was confirmed in the Ames TA100 assay system. Conclusion: Newly synthesized azinesulfonamide analogs of aripiprazole may be considered as genotoxically safe as they do not display mutagenic activity on the tester strains. Moreover, the tested compounds demonstrated significant antimutagenic properties that can be valuable for prevention of the NQNO genotoxicity. Additionally, it appears that the Vibrio harveyi assay can be applied for primary mutagenicity and antimutagenicity assessment of chemical substances, thus, representing a useful alternative tool for compounds safety evaluation.

Preliminary mutagenicity and genotoxicity evaluation of selected arylsulfonamide derivatives of (aryloxy)alkylamines with potential psychotropic properties.

Determination of the mutagenic and genotoxic liability of biologically active compounds is of great concern for preliminary toxicity testing and drug development. In this study, we focused on the evaluation of the mutagenic and genotoxic effects of selected arylsulfonamide derivatives of aryloxyethyl piperidines and pyrrolidines (1-8), classified as 5-HT7 receptor antagonist with antidepressant and procognitive properties, using in silico and in vitro methods: the Vibrio harveyi assay and the SOS/umu-test (umuC Easy CS test). Finally, the antimutagenic potential of tested compounds was evaluated with the V. harveyi assay. It was demonstrated that none of the examined compounds produced a positive response in in vitro assays and these results were in line with in silico prediction. Additionally, all the tested compounds demonstrated various antimutagenic potential, with compound 1 (5-chloro-N-((1-(2-phenoxyethyl)piperidin-4-yl)methyl)thiophene-2-sulfonamide) being the most active against NQNO-induced mutagenicity.

Evaluation of anticonvulsant and antinociceptive properties of new N-Mannich bases derived from pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione.

The aim of the present experiments was to examine anticonvulsant activity of new pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione derivatives in animal models of epilepsy. In addition, the possible collateral antinociceptive activity was assessed. Anticonvulsant activity was investigated in the electroconvulsive threshold (MEST) test and the pilocarpine-induced seizure models in mice. Antinociceptive activity was examined in the hot plate and the formalin tests in mice. Considering the drug safety evaluation, the Vibrio harveyi test was used to estimate anti/mutagenic activity. To determine the plausible mechanism of anticonvulsant action, for two chosen compounds (12 and 23), in vitro binding assays were carried out. All of the tested compounds revealed significant anticonvulsant activity in the MEST test. Compounds 12 and 23 displayed anticonvulsant effect also in pilocarpine-induced seizures. Four of the tested compounds (12, 13, 15, and 24) revealed analgesic activity in the hot plate test as well as in the first phase of the formalin test, and all of them were active in the second phase of the formalin test. The possible mechanism of action of compounds 12 and 23 is the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. The obtained results indicate that in the group of pyrrolidine-2,5-diones, new anticonvulsants with collateral analgesic properties can be found.

Design, synthesis and biological activity of new amides derived from 3-methyl-3-phenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid.

A series of new 3-methyl-3-phenyl-2,5-dioxo-pyrrolidin-1-yl-acetamides (6-23) has been synthesized and evaluated for their anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection in mice. The acute neurological toxicity was determined using the rotarod test. The in vivo preliminary pharmacological results showed that in the whole series only two compounds (15, 21) were devoid of activity, whereas other molecules revealed protection in at least one animal model of epilepsy (MES or/and scPTZ). The in vivo quantitative studies in mice showed that in the MES test the most active were 1-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-3-phenyl-pyrrolidine-2,5-dione (17), 1-{2-[4-(4-fluorophenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-3-phenyl-pyrrolidine-2,5-dione (8), and its 2-fluorophenyl analog (7) with ED50 values of 97.51 mg/kg (17), 104.11 mg/kg (8), and 114.68 mg/kg (7), respectively. In the scPTZ screen the most potent were compound 6 with an ED50 = 40.87 mg/kg, and 4-benzylpiperidine derivative 22 - ED50 = 60.00 mg/kg. Furthermore, selected compounds 8, 14, 17, and 23 were tested in the psychomotor seizure 6-Hz test. Compounds 7, 8, and 17 revealed significant analgesic activity in the formalin model of tonic pain in mice, without impairment of the motor coordination in the chimney test. The in vitro binding studies showed that the mechanism of anticonvulsant activity may be partially related with the influence on the voltage-gated sodium and calcium channels. The mutagenic and antimutagenic effects of 13, 17, and 22 were evaluated using the novel Vibrio harveyi assay.

Antimutagenic compounds and their possible mechanisms of action.

Mutagenicity refers to the induction of permanent changes in the DNA sequence of an organism, which may result in a heritable change in the characteristics of living systems. Antimutagenic agents are able to counteract the effects of mutagens. This group of agents includes both natural and synthetic compounds. Based on their mechanism of action among antimutagens, several classes of compounds may be distinguished. These are compounds with antioxidant activity; compounds that inhibit the activation of mutagens; blocking agents; as well as compounds characterized with several modes of action. It was reported previously that several antitumor compounds act through the antimutagenic mechanism. Hence, searching for antimutagenic compounds represents a rapidly expanding field of cancer research. It may be observed that, in recent years, many publications were focused on the screening of both natural and synthetic compounds for their beneficial muta/antimutagenicity profile. Thus, the present review attempts to give a brief outline on substances presenting antimutagenic potency and their possible mechanism of action. Additionally, in the present paper, a screening strategy for mutagenicity testing was presented and the characteristics of the most widely used antimutagenicity assays were described.

Evaluation of mutagenic and antimutagenic properties of new derivatives of pyrrolidine-2,5-dione with anti-epileptic activity, by use of the Vibrio harveyi mutagenicity test.

The Vibrio harveyi test was used to evaluate mutagenic and antimutagenic properties of nineteen new derivatives of pyrrolidine-2,5-dione (compounds 1-19) with antiepileptic activity. Four V. harveyi strains were used: BB7 (wild type) and the genetically modified strains BB7M, BB7X and BB7XM (i.e. strains with additional mucA and mucB genes, UV hypersensitivity, and UV hypersensitivity with plasmid pAB91273, respectively). None of the derivatives of 2-ethyl-2-methylsuccinic acid (compounds 1-7) had mutagenic activity against the tester strains of V. harveyi, but this set had strong or moderate antimutagenic activity against 4-nitroquinoline-N-oxide (NQNO) in the tester strains BB7, BB7X, and BB7M. This antimutagenic activity ranged from 51% to 67%, through 51-66% to 71-83% for V. harveyi BB7, BB7X and BB7M strains, respectively. Mutagenic activities in the group of 2,2-diphenyl-succinic acid derivatives (compounds 8-19) were variable and depended on the tester strain used. Compounds 8-19 were devoid of mutagenic properties against BB7 (wild-type strain). Among this group only compound 9, with the fluorine substituent in position 2 of the aromatic system, was devoid of mutagenic potential against all tester strains. The compounds in this group (8-19) demonstrated strong antimutagenic activity only against strain BB7 (inhibition ranging from 51% to 71%). We conclude that there are various mutagenic and antimutagenic activities of derivatives of pyrrolidine-2,5-dione. Moreover, our studies have proven that the V. harveyi test can be applied for primary mutagenicity and antimutagenicity assessment of these new compounds.

Monoclonal antibodies in targeted therapy.

Targeted therapy is a new therapeutic method consisting in the inhibition of specific molecular pathways. In modern therapy, the key role is played by monoclonal antibodies, included in the group of biological agents. The success of molecularly targeted therapy is to define the proper "molecular target", selecting the right drug active against a specific "target" and selecting a group of patients who benefit from treatment. Introduction of targeted therapy resulted in improved results of the treatment of many serious and chronic diseases. In general, targeted molecular therapies have good toxicity profiles, but some patients are exquisitely sensitive to these drugs and can develop particular and severe toxicities. Patient selection and proper monitoring significantly decrease the risk of life-threatening adverse events. Data concerning late side effects are still unavailable because of the short follow-up of molecularly targeted therapy. Currently in the U.S. and Europe there are approximately 31 registered therapeutic monoclonal antibodies, while 160 are subjected to clinical trials. This paper presents an overview of therapeutic monoclonal antibodies currently used in therapy and the present state of knowledge about them.