Synthesis and primary anticonvulsant activity evaluation of 6-alkyoxyl-tetrazolo[5,1-a]phthalazine derivatives

Abstract

A new series of 6-alkyoxyl-tetrazolo[5,l-a] phthalazine derivatives (4 a-4 o) were synthesized as potential anticonvulsant agents. Anticonvulsant activity was evaluated by the maximal electroshock (MES) test. Neurotoxicity was evaluated by the rotarod neurotoxicity test. The pharmacological results showed that 6-(4-chlorophenyoxyl) - tetrazolo [5,1-a] phthalazine (4 m) was the most potent agent, with a median effective dose (ED₅₀) of 6.8 mg/kg and a median neurotoxic dose (TD₅₀) of 456.4 mg/kg. The protective index (PI = TD50/ED50) for compound 4 m was 67.1, which was significantly higher than that for the reference drug carbamazepine (PI = 6.4).

Key words

Antiepileptic drugs - Maximal electroshock - Phthalazine derivatives, anticonvulsant activity - Tetrazole

• References

• 1 Loscher W. New visions in the pharmacology of anticonvulsion. Eur J Pharmacol. 1998; 342: 1-13
• 2 Leppik IE. Antiepileptic drugs in development: prospects for the near future. Epilepsia. 1994; 35 (S4) 29-40
• 3 Perucca E. The new generation of antiepileptic drugs: advantages and disadvantages. Br J Clin Pharmacol. 1996; 42: 531-43
• 4 Lin Z, Kadaba PK. Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents. Med Res Rev. 1997; 17: 537-72
• 5 Al-Soud YA, Al-Masoudi NA, Ferwanah A. Synthesis and properties of new substituted 1,2,4-triazoles: potential antitumor agents. Bioorg Med Chem. 2003; 1: 1701-8
• 6 Sivakumar R, Kishore Gnanasam S, Ramachandran S, Leonard JT. Pharmacological evaluation of some new 1-substituted-4-hydroxy-phthalazines. Eur J Med Chem. 2002; 37: 793-801
• 7 Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA. Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia. 1978; 19: 409-28
• 8 Porter RJ, Cereghino JJ, Gladding GD, Hessie BJ, Kupferberg HJ, Scoville B et al Antiepileptic Drug Development Program. Cleve Clin Q. 1984; 51: 293-305
• 9 Hamilton MA, Russo RC, Thurston RC. Trimmed Spear-man-Karber method for estimating median lethal concentrations in toxicity bioassays. Env Sci Technol. 1977; 7: 714-19
• 10 Sun XY, Jin YZ, Li FN, Li G, Chai KY, Quan ZS. Synthesis of 8-alkoxy-4,5-dihydro-[1,2,4] triazole[4,3-a]quinoline-l-ones and evaluation of their anticonvulsant properties. Arch Pharm Res. 2006; 29: 1080-5
• 11 John HMH, John HE. Nucleophilic Heteroaromatic Substitution. II. Phthalazines. J Org Chem. 1971; 36: 3248-51
• 12 Chimirri A, Zappala M, Gitto R, Quartarone S, Bevacqua F. Synthesis and structural features of lH-tetrazolo[l,5–c] [2,3]-benzodiazepines. Heterocycles. 1999; 51: 1303-9