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Neurochemical Research

, Volume 42, Issue 7, pp 1972–1982 | Cite as

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

  • David Bibi
  • Hafiz Mawasi
  • Alessio Nocentini
  • Claudiu T. Supuran
  • Bogdan Wlodarczyk
  • Richard H. Finnell
  • Meir BialerEmail author
Original Paper

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.

Keywords

New antiepileptic drugs Valproic acid 4-Aminobenzensulfonamides Teratogenicity Carbonic anhydrase inhibition 

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

Notes

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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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • David Bibi
    • 1
  • Hafiz Mawasi
    • 1
  • Alessio Nocentini
    • 3
  • Claudiu T. Supuran
    • 3
  • Bogdan Wlodarczyk
    • 4
  • Richard H. Finnell
    • 4
  • Meir Bialer
    • 1
    • 2
    Email author
  1. 1.Faculty of Medicine, School of Pharmacy, Institute of Drug ResearchThe Hebrew University of JerusalemJerusalemIsrael
  2. 2.Affiliated with the David R. Bloom Center for PharmacyThe Hebrew University of JerusalemJerusalemIsrael
  3. 3.NEUROFARBA Dept., Sezione di Scienze FarmaceuticheUniversità degli Studi di FirenzeFlorenceItaly
  4. 4.Department of PediatricsThe University of Texas at Austin Dell Medical SchoolAustinUSA

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