Synthesis and Anticonvulsant Activity of Novel and Potent 6,7-Methylenedioxyphthalazin-1(2H)-ones

Abstract

In this paper, we describe the synthesis of a series of novel substituted 4-aryl-6,7-methylenedioxyphthalazin-1(2H)-ones. The anticonvulsant activity of these compounds against audiogenic seizures was evaluated in DBA/2 mice after intraperitoneal (ip) injection. Most of these derivatives are more active than 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive AMPA receptor antagonist. As deduced by the rotarod test, all the compounds exhibit a toxicity lower than that of 1. Within the series of derivatives submitted to investigation, 4-(4-aminophenyl)-2-butylcarbamoyl-6,7-methylenedioxyphthalazin -1(2H)-one (21) proved to be the most active compound and is 11-fold more potent than 1 (i.e., ED50 3.25 micromol/kg for 21 versus ED50 35.8 micromol/kg for 1). When compared to 1, compound 21 as well as its analogue 4-(4-aminophenyl)-6,7-methylenedioxyphthalazin-1(2H)-one (16) show a longer lasting anticonvulsant activity. Compound 21 also effectively suppresses seizures induced in Swiss mice by maximal electroshock (MES) and pentylenetetrazole (PTZ). Furthermore, it antagonizes in vivo seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), 2-amino-3-(3-hydroxy-5-tert-butyl-isoxazol-4-yl)propionic acid (ATPA), and kainate (KA), and its anticonvulsant activity is reversed by pretreatment with aniracetam. Using the patch-clamp technique, the capability of derivatives 16 and 21 to antagonize KA-evoked currents in primary cultures of granule neurons was tested. They behaved as antagonists, but they proved to be less effective than 1 and 1-(4-aminophenyl)-3,4-dihydro-4-methyl-3-N-methylcarbamoyl-7,8-met hylenedioxy-5H-2,3-benzodiazepine (2, GYKI 53655) to reduce the KA-evoked currents.

An Efficient Three Component Synthesis of 1H-Indazolo[2, 1-b]phthalazine-triones Catalyzed by Orthophosphoric Acid in Water-Phenol System

“…Amongst, nitrogen heterocyclic containing a phthalazine moiety was reported to possess anticonvulsant 10 , cardiotonic 11 , vasorelaxant 12 antimicrobial 13 , anti-inflammatory 14 , antifungal 15 and anticancer 16,17 activities. Newly, three-RESEARCH ARTICLE component reactions of dimedone (5,5- 23 , N-halo sulphonamides 24 , silica supported poly phosphoric acid 25 , 26 Mg(HSO 4 ) 2 , phosphor sulfonic acids 27 , nano silica sulphuric acid 28 , sulfonated polyethylene glycol 29 and boron sulfonic acid 30 .…”

Heteropoly Acid in Ionic Liquid - An Efficient Catalyst for the Preparation of 2H-Indazolo[2,1-b]Phthalazine-Triones

“…Phthalazine derivatives were reported to possess vasorelaxant [2], cardiotonic [3], and anticonvulsant [4], activities. Therefore, a number of methods have been reported in the literature for the synthesis of phthalazine derivatives [4][5][6][7][8][9][10][11].…”

Synthesis of chiral N-(2-(1-oxophthalazin-2(1H)-yl) ethanoyl)-α-amino acid derivatives as antitumor agents

“…Among a large variety of heterocyclic nuclei is phthalazine (I, HAV3C II) which is interesting because its derivatives show various pharmacological and biological activities ( Figure 1). [1][2][3] Phthalazine derivatives were reported to possess anticonvulsant, 4 cardiotonic, 5 and vasorelaxant activities. 6 Therefore, a number of methods have been reported for the synthesis of phthalazine derivatives.…”

“…6 Therefore, a number of methods have been reported for the synthesis of phthalazine derivatives. 4,[7][8][9][10][11][12][13] On the other hand, several α-amino acids-conjugated heterocycles were reported as potential antitumor agents, for instance, 4-toluenesulfonylureido derivatives of amines, amino acids, dipeptides, 14 and 2-(4-This motivated us to synthesize 1-oxophthalazine moiety conjugated with flexible amino acids as side chain hoping that the produced compounds will have improved biological activity.…”