Elsevier

Bioorganic & Medicinal Chemistry

Volume 19, Issue 20, 15 October 2011, Pages 6149-6156
Bioorganic & Medicinal Chemistry

Synthesis and anticonvulsant activity of new N-Mannich bases derived from 5-cyclopropyl-5-phenyl- and 5-cyclopropyl-5-(4-chlorophenyl)-imidazolidine-2,4-diones

https://doi.org/10.1016/j.bmc.2011.08.017Get rights and content

Abstract

Synthesis, physicochemical and anticonvulsant properties of new N-Mannich bases derived from 5-cyclopropyl-5-phenyl- and 5-cyclopropyl-5-(4-chlorophenyl)-imidazolidine-2,4-diones have been described. Initial anticonvulsant screening was performed using intraperitoneal (ip.) maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The neurotoxicity was determined applying the rotarod test. The in vivo results in mice showed that all compounds were effective especially in the MES screen. The quantitative evaluation after oral administration in rats showed that the most active was 5-cyclopropyl-5-phenyl-imidazolidine-2,4-dione (1) with ED50 values of 5.76 mg/kg (MES) and 57.31 mg/kg (scPTZ). This molecule was more potent than phenytoin and ethosuximide which were used as reference antiepileptic drugs. Additionally compound 1 with ED50 of 26.06 mg/kg in psychomotor seizure test (6-Hz) in mice showed comparable activity to new generation anticonvulsant – levetiracetam.

Graphical abstract

The library of new N-Mannich bases derived from 5-cyclopropyl-5-phenyl- and 5-cyclopropyl-5-(4-chlorophenyl)-imidazolidine-2,4-diones have been synthesized. The in vivo results showed that all of compounds were effective in maximal electroshock test (MES).

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Introduction

During the last two decades several new antiepileptic drugs (AEDs) have been marked but still about one third of patients with epilepsy do not respond for the applied treatment. Furthermore many of those medications cause serious side effects from which more common are ataxia, nausea, mental dulling, and hepatotoxicity.1, 2, 3 The currently used AEDs can be classified into four categories on the basis of the main molecular mechanisms of action, as follow: (i) modulation of voltage-dependent Na+ and/or Ca2+ channels, (ii) enhancement of GABA-mediated inhibition or other effect on the GABA system, (iii) inhibition of synaptic excitation mediated by ionotropic glutamate receptors.4

Conceptually, there are two different methods of obtaining new anticonvulsants namely knowledge-based approaches and screening approaches. Knowledge-based approaches rely on the use of different pharmacophores that were established through the analysis of structural characteristics of clinically effective AEDs as well as other anticonvulsant active compounds. Serendipitous approaches involve screening of either diverse or focus compound libraries.5

It is well documented that the important core fragment of anticonvulsants is defined by nitrogen heteroatomic system, usually a cyclic imide, at least of one carbonyl group and phenyl or alkyl groups attached to the heterocyclic system.6, 7, 8 This common template is present in the structures of two old, however, well-established AEDs such as ethosuximide and phenytoin as well as among the newest drugs, for example, levetiracetam, brivaracetam, or seletracetam.9, 10, 11 Taking into consideration the above our researches are focused on systematic structural modifications in a group of pyrrolidine-2,5-dione and imidazolidine-2,4-dione derivatives.12, 13, 14, 15, 16, 17 The structure–activity relationships (SARs) studies performed among these molecules showed higher activity for differently substituted imidazolidine-2,4-diones in comparison to respective pyrrolidine-2,5-dione analogs.18 Therefore in our recent studies we have demonstrated the potent anticonvulsant activity among the N-Mannich bases derived from 5-cyclopropyl-5-phenyl-imidazolidine-2,4-diones.19 Several compounds showed activity in the MES test that was superior to phenytoin, used as a model substance (Fig. 1).

Following these findings, as part of our efforts to design new anticonvulsant agents in the present studies we have synthesized a new series of N-Mannich bases derived from 5-cyclopropyl-5-phenyl- (1) and 5-cyclopropyl-5-(4-chlorophenyl)-imidazolidine-2,4-diones (2). These molecules have been designed as analogs of compounds A and B (Fig. 1) in which an amine function have been modified. The main goal was to obtain compounds active both in maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scPTZ) screens. As basic fragments we have introduced different piperazines with alkyl, alkylene, ketone, or ester moieties at position-4. Finally, the piperazine fragment has been changed into tetrahydroisoquinoline or morpholine.

Section snippets

Chemistry

The synthesis of compounds 116 was accomplished as shown in Scheme 1. The starting 5-cyclopropyl-5-phenyl- (1) and 5-cyclopropyl-5-(4-chlorophenyl)-imidazolidine-2,4-dione (2) were obtained from the appropriately substituted ketones by means of the Bücherer–Berg reaction with modifications described by Goodson et al.20 In the next step the aminoalkylation of the acidic proton (N3H) of 1 and 2 carried out in the present of formaldehyde and appropriate amines enabled to obtain final compounds 3

Conclusion

The library of sixteen new N-Mannich bases derived from 5-cyclopropyl-5-phenyl- and 5-cyclopropyl-5-(4-chlorophenyl)-imidazolidine-2,4-dione derivatives has been synthesized and tested for anticonvulsant activity. The results of anticonvulsant screening revealed that some of derivatives were effective in the MES test. The quantitative studies in rats after oral administration showed that five compounds were more potent than phenytoin in the maximal electroshock test. The highest activity was

Chemistry

All chemicals and solvents were obtained from Merck (Darmstadt, Germany) and were used without purification. Melting points (mp) were determined in open capillaries on a Büchi 353 melting point apparatus (Büchi Labortechnik, Flawil, Switzerland) and are uncorrected. The purity and homogeneity of the compounds were assessed by the thin-layer chromatography (TLC) performed on Merck silica gel 60 F254 aluminum sheets (Merck, Darmstadt, Germany), using the developing system consisted of S1:

Acknowledgments

The authors wish to thank Dr. James Stables for providing them with pharmacological data through the Antiepileptic Drug Development Program (Epilepsy Branch, National Institute of Neurological Disorders and Stroke, National Institute of Health, Rockville, MD, USA).

We are pleased to acknowledge the generous financial support of this work by the Grant of the Minister Committee for Scientific Research, Poland (Grant No. N405 298536).

References and notes (31)

  • W. Löscher et al.

    Epilepsy Res.

    (2006)
  • M.A. Rogawski

    Epilepsy Res.

    (2006)
  • S.M. Tasso et al.

    J. Mol. Struct.

    (2000)
  • L. Bruno-Blanch et al.

    Bioorg. Med. Chem. Lett.

    (2003)
  • M. Bialer et al.

    Epilepsy Res.

    (2007)
  • J. Obniska et al.

    J. Fluorine Chem.

    (2006)
  • J. Obniska et al.

    Eur. J. Med. Chem.

    (2006)
  • K. Kamiński et al.

    Bioorg. Med. Chem.

    (2008)
  • J. Obniska et al.

    Eur. J. Med. Chem.

    (2009)
  • J. Obniska et al.

    Bioorg. Med. Chem.

    (2010)
  • M.A. Rogawski

    Epilepsy Res.

    (2006)
  • M.E. Barton et al.

    Epilepsy Res.

    (2001)
  • N.W. Dunham et al.

    J. Am. Pharm. Assoc. Sci.

    (1957)
  • R. Thirumurugan et al.

    Bioorg. Med. Chem.

    (2006)
  • J.A. Cramer et al.

    Expert Rev. Neurother.

    (2010)
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