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Design and Comparative Evaluation of the Anticonvulsant Profile, Carbonic-Anhydrate Inhibition and Teratogenicity of Novel Carbamate Derivatives of Branched Aliphatic Carboxylic Acids with 4-Aminobenzensulfonamide

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Abstract

Epilepsy is one of the most common neurological diseases, with between 34 and 76 per 100,000 people developing epilepsy annually. Epilepsy therapy for the past 100+ years is based on the use of antiepileptic drugs (AEDs). Despite the availability of more than twenty old and new AEDs, approximately 30% of patients with epilepsy are not seizure-free with the existing medications. In addition, the clinical use of the existing AEDs is restricted by their side-effects, including the teratogenicity associated with valproic acid that restricts its use in women of child-bearing age. Thus, there is an unmet clinical need to develop new, effective AEDs. In the present study, a novel class of carbamates incorporating phenethyl or branched aliphatic chains with 6–9 carbons in their side-chain, and 4-benzenesulfonamide-carbamate moieties were synthesized and evaluated for their anticonvulsant activity, teratogenicity and carbonic anhydrase (CA) inhibition. Three of the ten newly synthesized carbamates showed anticonvulsant activity in the maximal-electroshock (MES) and 6 Hz tests in rodents. In mice, 3-methyl-2-propylpentyl(4-sulfamoylphenyl)carbamate(1), 3-methyl-pentan-2-yl-(4-sulfamoylphenyl)carbamate (9) and 3-methylpentyl, (4-sulfamoylphenyl)carbamate (10) had ED50 values of 136, 31 and 14 mg/kg (MES) and 74, 53, and 80 mg/kg (6 Hz), respectively. Compound (10) had rat-MES-ED50 = 13 mg/kg and ED50 of 59 mg/kg at the mouse-corneal-kindling test. These potent carbamates (1,9,10) induced neural tube defects only at doses markedly exceeding their anticonvuslnat-ED50 values. None of these compounds were potent inhibitors of CA IV, but inhibited CA isoforms I, II and VII. The anticonvulsant properties of these compounds and particularly compound 10 make them potential candidates for further evaluation and development as new AEDs.

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Abbreviations

CMK:

Corneal kindled mouse

CNS:

Central nervous system

AED:

Antiepileptic drug

SAR:

Structure–activity relationship

MES:

Maximal electroshock seizure

scMet:

Subcutaneous metrazol

PI:

Protective index

VPA:

Valproic acid

SPD:

Sec-butylisopropylaceatmide

THF:

Tetrahydrofuran

DCM:

Dichlromethane

NTD:

Neural tube defects

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Acknowledgements

This work is abstracted from the Ph.D. thesis of David Bibi in partial fulfillment of the Ph.D. degree requirements for The Hebrew University of Jerusalem. The authors thank Drs. John Keane and Shamsi Raeissi, of the NIH-NINDS Epilepsy Therapy Screening Program (ETSP) for testing the compounds in the ETSP and Dvora Izgelov and Bella Shusterman from the Hebrew University for their skillfully assistance with the HPLC and in the syntheses, respectively.

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Authors and Affiliations

  1. Faculty of Medicine, School of Pharmacy, Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel

    David Bibi, Hafiz Mawasi & Meir Bialer

  2. Affiliated with the David R. Bloom Center for Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel

    Meir Bialer

  3. NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019, Florence, Italy

    Alessio Nocentini & Claudiu T. Supuran

  4. Department of Pediatrics, The University of Texas at Austin Dell Medical School, Austin, TX, USA

    Bogdan Wlodarczyk & Richard H. Finnell

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  1. David Bibi
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  2. Hafiz Mawasi
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Correspondence to Meir Bialer.

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Bibi, D., Mawasi, H., Nocentini, A. et al. Design and Comparative Evaluation of the Anticonvulsant Profile, Carbonic-Anhydrate Inhibition and Teratogenicity of Novel Carbamate Derivatives of Branched Aliphatic Carboxylic Acids with 4-Aminobenzensulfonamide. Neurochem Res 42, 1972–1982 (2017). https://doi.org/10.1007/s11064-017-2216-x

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  • DOI: https://doi.org/10.1007/s11064-017-2216-x

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