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Synthesis and studies on antidepressant and anticonvulsant activities of some 3-(2-thienyl)pyrazoline derivatives.

In this study, the synthesis of twelve 3‐(2‐thienyl)pyrazoline derivatives are described. The structures of all compounds were confirmed by UV, IR, 1H‐NMR, mass spectral data, and microanalyses. In the pharmacological studies, antidepressant and anticonvulsant activities of these compounds have been screened. The antidepressant activities of the compounds were investigated by Porsolts behavioral despair test (forced swimming) on albino mice and compared with tranylcypromine. Among the compounds examined, the compounds 9 and 12 showed significant antidepressant activity. Anticonvulsant activities of the compounds were determined by maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (metrazol) (scMet.) tests, neurotoxicities were determined by rotarod toxicity test on albino mice. Compound 8 was found to be protective against MES in the range of 30–300 mg/kg dose levels at four hours. None of the synthesized compounds showed neurotoxicity at 30–300 mg/kg dose levels.

Synthesis of some novel 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone oxime ester derivatives and evaluation of their anticonvulsant activity

Twenty-three new oxime ester derivatives of nafimidone were synthesized with the prospect of potential anticonvulsant activities. MES and ScM tests were employed for their anticonvulsant activities and rotorod test for neurological deficits. Eighteen compounds were found to be protective against MES seizures. Alkyl (1-8) and arylalkyl (9, 10) oxime ester derivatives were found to be more active than aryl oxime ester derivatives (11-23). Five compounds (2, 3, 7, 9, 10), which were protective at 0.5 h at the doses of 30 mg/kg and higher in MES test, showed the highest activity. Compound 17 was the most active one in ScM test at all dose levels at 4 h.

Synthesis, Anticonvulsant and Antimicrobial Activities of Some New [1-(2-Naphthyl)-2-(pyrazol-1-yl)ethanone]oxime Ethers

In this study, 12 new oxime ether derivatives, which were expected to show anticonvulsant and antimicrobial activities, were synthesized. Oxime ether derivatives were synthesized by the reaction of various alkyl halides with 1-(2- naphthyl)-2-(pyrazol-1-yl)ethanone oxime. Anticonvulsant activity of the compounds was determined by maximal electroshock (MES) and subcutaneous metrazol (ScM) seizure tests, while neurological disorders were evaluated using rotorod toxicity test according to the ASP of NIH. Compound 1, 6 and 7 showed anticonvulsant activity at 300 mg/kg dose at 4 h, but compounds 1 and 7 showed toxicity at 300 mg/kg dose at half an hour. Antimicrobial activities of the compounds were also determined using agar microdilution method. Compound 1 and 5 were found to have the highest antifungal activity among the other compounds.

Design, synthesis and in vivo/in vitro screening of novel chlorokojic acid derivatives

A series of novel Mannich bases of chlorokojic acid (2-chloromethyl-5-hydroxy-4H-pyran-4-one) were synthesized and their biological activities were investigated. Anticonvulsant activity results according to phase-I tests of Antiepileptic Drug Development (ADD) Program revealed that compound 13 was the most effective one at 4 h against subcutaneous pentylenetetrazole (scPTZ)-induced seizure test. Antimicrobial activities were evaluated in vitro against bacteria and fungi by using broth microdilution method. The antitubercular activities against Mycobacterium tuberculosis and M. avium were discussed with Resazurin microplate assay (REMA). The antimicrobial activity results indicated that compounds 1 and 12 (MIC: 8–16 µg/mL) showed higher activity against Gram negative bacteria while compound 12 had MIC: 4–16 µg/mL against Gram positive bacteria. Compound 1 was the most active one with MIC values of 8–32 µg/mL against fungi. Mannich bases also exhibit significant antitubercular activity in a MIC range of 4 to 32 µg/mL, especially compound 18 against M. avium.

Synthesis of some novel 3-methyl-6-(2-substituted propanoyl/propyl)-2-benzoxazolinone derivatives and anti-nociceptive activity.

In this study, 12 new 3-methyl-6-(2-substituted aminopropanoyl)-2-benzoxazolinone and 3-methyl-6-(1-hydroxy-2-substituted aminopropyl)-2-benzoxazolinone derivatives have been prepared. Their structures have been elucidated by IR, 1H NMR spectra and by elementary analysis. The anti-nociceptive activity of these compounds has been investigated by using a modified Koster test. It was found that most compounds are capable of inducing anti-nociception in animals.

New (arylalkyl)azole derivatives showing anticonvulsant effects could have VGSC and/or GABAAR affinity according to molecular modeling studies.

(Arylalkyl)azoles (AAAs) emerged as a novel class of antiepileptic agents with the invention of nafimidone and denzimol. Several AAA derivatives with potent anticonvulsant activities have been reported so far, however neurotoxicity was usually an issue. We prepared a set of ester derivatives of 1-(2-naphthyl)-2-(1H-1,2,4-triazol-1-yl)ethanone oxime and evaluated their anticonvulsant and neurotoxic effects in mice. Most of our compounds were protective against maximal electroshock (MES)- and/or subcutaneous metrazol (s.c. MET)-induced seizures whereas none of them showed neurotoxicity. Nafimidone and denzimol have an activity profile similar to that of phenytoin or carbamazepine, both of which are known to inhibit voltage-gated sodium channels (VGSCs) as well as to enhance γ-aminobutiric acid (GABA)-mediated response. In order to get insights into the effects of our compounds on VGSCs and A-type GABA receptors (GABAARs) we performed docking studies using homology model of Na+ channel inner pore and GABAAR as docking scaffolds. We found that our compounds bind VGSCs in similar ways as phenytoin, carbamazepine, and lamotrigine. They showed strong affinity to benzodiazepine (BZD) binding site and their binding interactions were mainly complied with the experimental data and the reported BZD binding model.

Synthesis and anticonvulsant activity of some 2/3-benzoylaminopropionanilide derivatives.

In this study, the synthesis and anticonvulsant properties of sixteen 2/3-benzoylaminopropionanilide derivatives were described. Molecular design of the compounds has been based on the modification of lacosamide which is a functionalized amino acid with a novel anticonvulsant activity. The structural confirmation of the title compounds was achieved by spectral and analytical data. The anticonvulsant activity profile of synthesized compounds was determined by maximal electroshock (MES) and subcutaneous metrazole (scMet) seizure tests, whereas their neurotoxicity was examined using rotarod test. All these tests were performed in accordance with the procedures of the Antiepileptic Drug Development (ADD) program. The majority of the compounds were effective in the MES or scMet screening tests. None of the compounds showed neurotoxicity according to the rotarod test at studied doses. Most active compounds in the series were 3, 12 and 13, which bearing 2-methyl, 2-ethyl and 2-isopropyl substituent on the N-phenyl ring, respectively.

X-ray and DFT calculated structures of 2-(1H-imidazol-1-yl)-1-(2-naphthyl)ethan-1-one N-phenylthiosemicarbazone and 2-(1H-imidazol-1-yl)-1-(2-naphthyl)ethan-1-one N-(4-chlorophenyl)thiosemicarbazone

Crystal and molecular structures of two new compounds 2-(1H-imidazol-1-yl)-1-(2-naphthyl)ethan-1-one N-phenylthiosemicarbazone, C22H19N5S, (I) and 2-(1H-imidazol-1-yl)-1-(2-naphthyl)ethan-1-one N-(4-chlorophenyl)thiosemicarbazone, C22H18ClN5S, (II) have been determined by single-crystal X-ray diffraction. Molecular geometries from X-ray experiment of I and II have been compared with those calculated using the Density Functional Theory (DFT) with B3LYP/6-31G(d,p) basis set. Both compounds crystallize in the monoclinic space group P21/c with Z = 4: a = 13.2880(5), 14.2648(3) Å, b = 9.4122(2), 9.3892(3) Å, c = 15.6341(6), 15.6268(4) Å, β = 101.779(3)°, 104.926(2)°, for I and II, respectively. An extensive two-dimensional network of N-H⋯N hydrogen bonds and π-ring interactions are responsible for crystal stabilization in both structures.

Synthesis and anticonvulsant activity of some N-(benzoyl)glycinanilide derivatives

Glycine is a major inhibitory neurotransmitter and recent studies have shown that certain lipophilic glycine derivatives demonstrate anticonvulsant activity in animal epilepsy models. On the other hand, anilide is another fruitful structure for designing potential anticonvulsant agents. Ameltolide, ralitoline and some phthalimide derivatives are the examples of anilide analogs with potent anticonvulsant activity. In this study, two key structural pharmacophores were combined and a series of N-benzoylglycinanilide derivatives were designed. Their anticonvulsant activities evaluated against maximal electroshock (MES) and subcutaneous metrazole seizure tests, whereas their neurotoxicity was examined by rotarod test. The preliminary screening results indicated that majority of the compounds were effective in the MES test. None of the compounds showed neurotoxicity according to the rotarod test at studied doses. The most active compound in the series is N-(2-((4-methoxyphenyl)amino)-2-oxoethyl)benzamide (compound 8) which bearing 4-methoxy substituent on the N-phenyl ring.