Anticonvulsant and Neurotoxicity Evaluation of Some Novel Kojic Acids and Allomaltol Derivatives

Abstract

A series of new 3-hydroxy-6-hydroxymethyl/methyl-2-substituted 4H-pyran-4-ones were synthesized and prepared by the reaction of kojic acid or allomaltol with piperidine derivatives and formaline as potential anticonvulsant compounds. The structure of the synthesized compounds was confirmed using the elemental analysis results and the spectroscopic techniques such as IR, 1H-NMR, and ESI-MS. Anticonvulsant activities were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet)-induced seizure tests. Neurotoxicity was determined by the rotorod toxicity test. All these tests were performed in accordance with the procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies and at all doses, 3-hydroxy-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-6-methyl-4H-pyran-4-one (compound 1), 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]methyl}-3-hydroxy-6-methyl-4H-pyran-4-one (compound 6), 2-[(4-acetyl-4-phenylpiperidin-1-yl)methyl]-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one (compound 11), and 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl] methyl}-3-hydroxy-6-hydroxymethyl-4H-pyran-4-one (compound 12) were found to have anticonvulsant activity against MES-induced seizures at 4 h. Also, 2-{[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]methyl}-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one (compound 8) was determined to be the most active compound against scMet-induced seizures at all doses at 0.5 and 4 h. In the rotorod neurotoxicity screening, all compounds showed no toxicity at all doses.

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

“…In our laboratory, a large number of Mannich bases of kojic acid (route A), chlorokojic acid (route B), and allomaltol (route C) were prepared (Scheme 1) for their various types of biological activities 4,[6][7][8][9][10][11] . Most of these compounds seemed to be promising candidates for anticonvulsant, antimicrobial and antiviral agents.…”

“…Most of these compounds seemed to be promising candidates for anticonvulsant, antimicrobial and antiviral agents. Mannich bases of kojic acid and allomaltol which contain lipophilic aryl portions were synthesized by our research group in order to increase the penetration to the blood-brain barrier 4,[6][7][8][9] . These compounds demonstrated significant anticonvulsant activities in vivo against maximal electroshock (MES)-and subcutaneous pentylenetetrazole (scPTZ)-induced seizure tests.…”

“…Because of providing a promising skeleton for development of both new and more potent derivatives, it has been used by many researchers as a starting material in preparation of new compounds [1][2][3][4][5][6][7][8][9][10][11] . Chlorokojic acid (2-chloromethyl-5-hydroxy-4H-pyran-4-one), which is synthesized by chlorination of kojic acid exhibits distinct antibacterial and antifungal activities [3][4][5] .…”

“…Moreover, these hydroxypyrone derivatives are known as effective chelating agents forming complexes with metals 5,12,13 and this ability plays a significant role in antimicrobial activity 14 . Kojic acid and its derivatives also display a variety of biological activities, such as antiepileptic 4,[6][7][8][9] , modest anti-inflammatory agent 5 , food additive 15 , antioxidant or antibrowning agent 16 , skinlightening product in cosmetics as a result of inhibition of melanin production 17 , herbicidal 18 , anti-speck 19 , pesticide and insecticide 20 , antitumor activity 21 and anti-diabetic agent 22 . Epilepsy, one of the more common neurological disorders, affects a large section of people.…”

“…The lipid solubility of a drug is an important factor in connection with its transfer into the central nervous system. The increase of anticonvulsant effect in Mannich bases of kojic acid and allomaltol (5-hydroxy-2-methyl-4H-pyran-4-one) is attributed to increase of lipophilicity 4,8,9 . Tuberculosis (TB), one of the earliest recorded human diseases and a chronic bacterial infection, continues to be an important global one with mortality worldwide killing more than 2 million people a year 28,29 .…”