Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 22, Pages -Publisher
MDPI
DOI: 10.3390/ijms232214401
Keywords
quinoxaline; anxiolytic; pharmacophore; diazepam; ADMET
Funding
- Ministry of Science and Higher Education of the Russian Federation [FENW-2020-0031 (0852-2020-0031)]
- Program for Basic Scientific Research of the Russian Academy of Sciences [0710-20190044]
- RFBR [20-015-00164]
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A new series of quinoxaline derivatives were synthesized and evaluated for their anxiolytic potential in vivo. Four active compounds were found, with compound 2b showing the best anxiolytic properties. Pharmacophore analysis revealed the contribution of different features to the observed activity. Compound 2b exhibited high anxiolytic effects and low toxicity.
A new series of quinoxaline derivatives, 2a-4b, were synthesized and their anxiolytic potential was evaluated in vivo using elevated plus maze (EPM), open field (OF) and light-dark box (LDB) techniques. According to the results of the EPM, four active compounds were found in 2a, 2b, 2c, 4b. Their anxiolytic properties were confirmed in terms of LDB and the most active was compound 2b. In the OF, only 2c had an influence on the locomotor activity of the rodents. Thus, the most promising substance was determined; this was 2b, which has the structure of 2-(2-{[3-(4-tert-butylphenyl)quinoxaline-2-yl]methyl}-4,5-dimethoxyphenyl)-N-methylethan-1-amine hydrochloride. The obtained data were analyzed with the pharmacophore feature prediction approach, which made it possible to compare the structures of the studied compounds with the reference drug diazepam, and to determine the contribution of pharmacophores to the manifestation of the activity under study. ADMET analysis was carried out for compound 2b and the acute oral toxicity of this substance was also tested in vivo. As a result of the study, a promising compound with a high anxiolytic effect and low level of toxicity 2b was found, which is of interest for further preclinical study of its properties.
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