DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NEW SUCCINIMIDE, 2-IMINOTHIAZOLINE AND OXAZINE DERIVATIVES BASED BENZOPYRONE AS ANTICONVULSANT AGENTS
Keywords:Benzopyrone, Succinimide, 2-Iminothiazoline, Oxazine, Anticonvulsant
Objective: The objective of the present study was to synthesize novel benzopyrone derivatives with potential and safer anticonvulsant activity.
Methods: New benzopyrone derivatives have been synthesized and characterized by spectral and elemental analysis. These compounds tested for anticonvulsant activity using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens (phase 1), which are the most widely employed seizure models for early identification of new anticonvulsant agents. Phase 2 including, neurotoxicity screening and quantitative determination of the median effective dose (ED50), median lethal dose (LD50) and protective index (PI) for the active compounds from phase 1.
Results: Compound 12b possessed potent anticonvulsant activity with ED50 values of 94.75 and 70.7 mg/kg in the MES and scPTZ screens respectively, and had LD50 value of 2546 mg/kg after intraperitoneal injection to mice, which provide compound 12b with a wide protective index of 26.87 and 36.01 for MES and scPTZ screens respectively compared to the reference drug Phenobarbital with PI of 12.16 and 20.08, respectively. In addition, compound 12b exhibited mild neurotoxicity at the maximum administrated dose (200 mg/kg).
Conclusion: Compound 12b possessed broad spectrum activity for the treatment of all types of seizures, with a wide protective index compared to Phenobarbital. Consequently, compound 12b can be selected as a new bio candidate lead for further study.
Keywords: Benzopyrone, Succinimide, 2-Iminothiazoline, Oxazine; Anticonvulsant.
Fisher RS, Van Emde Boas W, Blume W, Elger C, Genton P, Lee P, et al. Epileptic seizures and epilepsy: definitions proposed by the international league against epilepsy (ILAE) and the international bureau for epilepsy (IBE). Epilepsia 2005;46:470-2.
World Health Organisation. Epilepsy: epidemiology, etiology, and prognosis WHO Fact sheet; 2015. p. No999.
Singh DMR, Garg G, Saraf SW, Saraf S. Artemisia scoparia: a review. Pharmacogn Mag 2006;2:25-8.
Luszczki JJ, Wojdaa E, Andres-Machb M, Cisowskic W, Glenskc M, Glowniakd K, et al. Anticonvulsant and acute neurotoxic effects of imperatorin, osthole and valproate in the maximal electroshock seizure and chimney tests in mice: a comparative study. Epilepsy Res 2009;85:293-9.
Loscher W, Lehmann H, Teschendorf HJ, Traut M, Gross G. Inhibition of monoamine oxidase type A, but not type B, is an effective means of inducing anticonvulsant activity in the kindling model of epilepsy. J Pharmacol Exp Ther 1999;288:984-92.
Genovese S, Epifano F, Curini M, Dudra-Jastrzebska M, Luszczki JJ. Prenyloxyphenylpropanoids as a novel class of anticonvulsive agents. Bioorg Med Chem Lett 2009;19:5419-22.
Leduc B. ''Antiseizure drugs'' in ''Foye's principles of medicinal chemistry''. 7th ed. Williams DA, Lemke TL. Ed. Lippincott Williams and Wilkins; 2013. p. 540-69.
Gursoy A, Terzioglu N. Synthesis, and isolation of new regioisomerio 4-thiazolidinones and their anticonvulsant activity. Turk J Chem 2005;29:247-54.
Ergenc N, Capan G. Synthesis and anticonvulsant activity of new 4-thiazolidone and 4-thiazoline derivatives. Farmaco 1994;49:449-51.
El-Ansary SL, Hussein MM, Said MM. Synthesis and biological evaluation of some new 2H-1-benzopyranes. Bull Fac Pharm (Cairo Univ) 1994;32:369-73.
Abu Shady HA, El-Ansary SL, Abou El-Ella DA, Farag NAH. Benzopyranone derivatives (part I): synthesis of various benzopyranyl imidazolidinetriones, arylpyrano benzoxazinone, pyrano benzoxazinetriones and benzopyranoyl-triazinetrione derivatives of potential CNS depressant activity. Bull Fac Pharm (Cairo Univ) 2004;42:31-42.
Santana L, lez-DÄ±az HG, Quezada E, Uriarte E, Yanez M, Vin D, et al. Quantitative structure-activity relationship and complex network approach to monoamine oxidase a and b inhibitors. J Med Chem 2008;51:6740-51.
Dubovik IP, Garazd MM, Vinogradova VI, Khilya VP. Modified coumarins. 22. synthesis of N-coumarinyl oxyacetyl derivatives of cytisine. Chem Nat Compd 2006;42:133-7.
Loscher W, H_nack D, Fassbender PC, Naolting B. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models. Epilepsy Res 1991;8:171-89.
Swinyard EA. ''Assay of antiepileptic drug activity in experimental animals: Standard tests'' In: Mercier J. Eds. ''Anticonvulsant Drugs, International Encyclopedia of pharmacology and therapeutic''. Vol. I. Pergamon Press; 1972. p. 47-65.
Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA. Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia 1978;19:409-28.
Kitano Y, Usui C, Takasuna K, Hirohashi M, Nomura M. Increasing current electroshock seizure test: a new method for assessment of anti-and pro-convulsant activities of drugs in mice. J Pharmacol Toxicol Methods 1996;35:25-9.
Loscher W, Nau H, Marescaux C, Vergnes M. Comparative evaluation of anticonvulsant and toxic potencies of valproic acid and 2-ene-valproic acid in different models of epilepsy. Eur J Pharmacol 1984;99:211-8.
Litchfield JT, Wilcoxon FA. A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 1949;96:99-113.
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-1-ones and evaluation of their anticonvulsant properties. Arch Pharmacal Res 2006;29:1080-5.
Kerber G. ''Pharmacologiche methoden auffindung von arzneimtteln und gifter and analysis rhnerwirkung swiservor'' Dr. Med. Leopold Ther. Wissenschaftjihe Verlage Geese Gasellschaft, MBH; 1941.
Finney JD. ''Statistical method in biological assay'', Charles Griffen and Company Limit. London; 1946. p. 528.
Amin KM, Abdel-Rahman DE, Al-Eryani YA. Synthesis and preliminary evaluation of some substituted coumarins as anticonvulsant agents. Bioorg Med Chem 2008;16:5377-88.
Loscher W, Schmidt D. Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations. Epilepsy Res 1988;2:145-81.
Hassan MZ, Khan SA, Amir M. Design, synthesis and evaluation of N-(substituted benzothiazol-2-yl)amides as anticonvulsant and neuroprotective. Eur J Med Chem 2012;58:206-13.
Ucar VD, Kim VD, Cacciaguerra S, Spampinato S, Stables JP, Depovere P, et al. Synthesis and anticonvulsant activity of 2 (3H)-benzoxazolone and 2 (3H)-benzothiazolone derivatives. J Med Chem 1998;41:1138-45.