Original article
Design, synthesis and anticonvulsant evaluation of N-(benzo[d]thiazol-2-ylcarbamoyl)-2-methyl-4-oxoquinazoline-3(4H)-carbothioamide derivatives: A hybrid pharmacophore approach

https://doi.org/10.1016/j.ejmech.2013.06.026Get rights and content

Highlights

  • Hybrid benzothiazole-quinazoline carbothioamide derivatives were synthesized.

  • Initial screening of compounds showed significant to good anticonvulsant activity.

  • Further mechanism study indicates involvement of GABA and AMPA receptors.

  • SA 22 and SA 24 can be used as a template for designing potential anticonvulsant agents.

Abstract

Novel N-(benzo[d]thiazol-2-ylcarbamoyl)-2-methyl-4-oxoquinazoline-3(4H)-carbothioamide derivatives were synthesized and evaluation of their anticonvulsant effects was done using various models of experimental epilepsy. Initial anticonvulsant activities of the compounds were investigated using intraperitoneal (i.p.) maximal electroshock shock (MES), subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. The quantitative assessment after oral administration in rats showed that the most active was 2-methyl-4-oxo-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-ylcarbamoyl)quinazoline-3(4H)-carbothioamide (SA 24) with ED50 values of 82.5 μmol/kg (MES) and 510.5 μmol/kg (scPTZ). This molecule was more potent than phenytoin and ethosuximide which were used as reference antiepileptic drugs. To explain the possible mechanism for anticonvulsant action, some of the selected active compounds were subjected to GABA (γ-amino butyric acid) assay and AMPA ((S)-2-amino-3-(3-hydroxyl-5-methyl-4-isoxazolyl) propionic acid) induced seizure test.

Graphical abstract

In present study, synthesis and anticonvulsant activity of N-(benzo[d]thiazol-2-ylcarbamoyl)-2-methyl-4-oxoquinazoline-3(4H)-carbothioamide derivatives were evaluated.

  1. Download : Download full-size image

Introduction

Epilepsy is a heterogeneous group of disorders characterized by neuronal hyperexcitability and hypersynchronous neuronal firing presented with episodes of sensory, motor or autonomic phenomenon with or without loss of consciousness [1]. Epilepsy is one of the most common disorders of the brain, affecting more than 50 million individuals worldwide [2], [3]. Lamotrigine, tiagabine, felbamate, pregabalin, stiripentol and topiramate are recent antiepileptic drugs (AEDs) which are effective toward only 60–80% of patients companioned with undesirable side effects, such as headache, nausea, anorexia, ataxia, hepatotoxicity, drowsiness, gastrointestinal disturbance, gingival hyperplasia, and hirsutism [4], [5], [6], [7], [8]. In many cases the clinical use of AEDs is restricted by their side effect. Therefore, a substantial need remains to discover novel chemical entities for the development of new effective and safer AEDs. Quinazolin-4(3H)-one 1 and their derivatives constitute a significant class of heterocyclic compounds and are shown to have potent central nervous system (CNS) activities such as anticonvulsant and CNS depressant [9], [10], [11], [12], [13], [14]. 2-Aminobenzothiazoles and derivatives like 2-benzothiazolamines, benzothiazoles containing sulphonamide and guanidines emerged as new classes of anticonvulsant agents and one of its derivatives, riluzole (2-amino-6-trifluoromethoxy benzothiazole) 4 is clinically available drug reported to diminish sensitivity of one of the sub types from the family of ionotropic glutamate receptors (iGluRs) (S)-2-amino-3-(3-hydroxyl-5-methyl-4-isoxazolyl)propionic acid (AMPA) and also reported to show no effect on pentylenetetrazole (PTZ) induced convulsions in moderate doses [15], [16], [17]. Over activities of iGluRs are linked to mediate excitatory synaptic transmission. In particular AMPA antagonists have shown anticonvulsant and neuroprotective activity in various animal models [18]. They also offer therapeutic innervations without side effects associated with inhibition of N-methyl-d-aspartate (NMDA) receptors [19].

A literature survey revealed that the presence of a substituted aromatic ring at position 3 and a methyl group at position 2 on quinazolin-4(3H)-one nucleus is a necessary requirement for CNS depression and anticonvulsant activities [20]. Methaqualone 2a (2-methyl-3-o-tolyl-4(3H)-quinazolinone) is a well known anticonvulsant and sedative-hypnotic containing quinazolin-4(3H)-one nucleus responsible for its activity and its 3-(2-chlorophenyl)-2-methyl-4(3H)-quinazolinone analog (Mecloqualone) 2c was found to be 1.5 times more potent than phenytoin in maximal electroshock (MES) induced convulsions and 10 times more potent than troxidone against PTZ induced seizure [21], [22], [23]. It has been reported that convulsant induced seizure by inhibiting γ-amino butyric acid (GABA) neurotransmission (such as PTZ) and GABAA antagonist [24]. GABAA agonist shows therapeutic effects by increasing chloride influx via brain chloride channel or directly antagonizes the inhibitory spinal reflex of glycine. Quinazolin-4(3H)-one derivatives reported to control seizure induced by MES and PTZ i.e. exhibited broad spectrum of activity in animal models possibly via GABA activation [25], [26], [27].

In view of the above mentioned knowledge based facts of different pharmacophores and in continuation of our research program we have synthesized benzothiazole moiety, quinazolinone nucleus along with incorporated urea and electronic environment to get single molecular framework in the form of titled compounds 5 comprising the four pharmacophoric elements that are necessary for good anticonvulsant activity as suggested by Pandeya et al. (Fig. 1) [28]. These elements are present in many currently used antiepileptic drugs. These are hydrophobic domain (A), hydrogen bonding domain (HBD), electron donor moiety (D), and distal hydrophobic domain (R). The attachment of a second aryl ring designated as the distal ring to the proximal aryl ring to increase the van der waal's bonding at the binding site and to increase potency have also been reported [28], [29].

Intrigued by the above observations, and in an attempt to design and develop new potential anticonvulsant agents, a hybrid pharmacophoric approach was adopted in which the quinazolin-4(3H)-one and benzothiazole nuclei were hybridized in one structure hoping to synergize the anticonvulsant potential of both groups. The validity of this design was assessed through anticonvulsant screening of the target compounds.

Section snippets

Chemistry

The titled compounds (SA 130) described in this study were prepared as outlined in Scheme 1. Synthesis of substituted-benzothiazol-2yl-amines (1aj) and substituted benzothiazol-2yl-urea-(2aj) was carried out according to procedure mentioned in literature [30], [31] except o-benzothiazol-2yl-amines that were synthesized using o-substituted aniline in dry methanol and purified over silica gel using chloroform (CHCl3):ethyl acetate (EtOAc) (7:3) as eluent. The resulting thiourea was dissolved

Conclusion

The series of 30 new N-(benzo[d]thiazol-2-ylcarbamoyl)-2-methyl-4-oxoquinazoline-3(4H)-carbothioamide derivatives were designed, synthesized and their anticonvulsant activity were evaluated in three seizure models namely MES, scPTZ and 6-Hz model. The compounds (6-chlorobenzo[d]thiazol-2-ylcarbamoyl)-2-methyl-4-oxoquinazoline-3(4H)-carbothioamide (SA 22: PI = >3.4; scPTZ) and 2-methyl-4-oxo-(6-(trifluoromethoxy)benzo[d]thiazol-2ylcarbamoyl)quinazoline-3(4H)-carbothioamide (SA 24: PI = >26; MES,

Chemistry

All reagents were used as purchased from commercial suppliers like Merck India Ltd., S.D Fine Chemicals, Sigma Aldrich and Qualigens and were used without purification. The purity and homogeneity of the compounds were assessed by the TLC performed on Merck silica gel 60 F254 aluminum sheets using toluene:methanol (8:2) as eluents. Iodine chamber and Schimadzu (UV-160) spectrometer were used for visualization of TLC spots. Ashless Whatmann No. 1 filter paper was used for vacuum filtration.

Acknowledgments

The authors are thankful to Jamia Hamdard New Delhi, India for providing facility for research work. The author is thankful to IIT Delhi and CDRI Lucknow for spectral and elemental data along with Fortis Hospital for Liver toxicity studies. One of the authors (Sachin Malik) expresses thanks to Central Scientific Industrial Research (CSIR) New Delhi, India for the award of Senior Research Fellowship (SRF) as financial assistance.

References (51)

  • P. Yogeeswari et al.

    Anticonvulsant and neurotoxicity evaluation of some 6-chlorobenzothiazolyl-2-thiosemicarbazones

    Eur. J. Med. Chem.

    (2002)
  • X. Dai et al.

    Synthesis of 2-heterosubstituted quinazolinone atropisomeric phosphine ligands by direct lithiation of a 2-unsubstituted quinazolinone system

    Tetrahedron: Asymmetry

    (1999)
  • F. Azam et al.

    Synthesis of some novel N4-(naphtha[1,2-d]thiazol-2-yl)semicarbazides as potential anticonvulsants

    Eur. J. Med. Chem.

    (2009)
  • N.W. Dunham et al.

    A note on a simple apparatus for detecting neurological deficit in rats and mice

    J. Am. Pharm. Assoc. Sci.

    (1957)
  • M.E. Barton et al.

    Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy

    Epilepsy Res.

    (2001)
  • R. Thirumurugan et al.

    2,4-Dimethoxyphenyl semicarbazones with anticonvulsant activity against three animal models of seizure: synthesis and pharmacological evaluation

    Bioorg. Med. Chem.

    (2006)
  • G.B. De Sarro et al.

    Excitatory amino acid neurotransmission through both NMDA and non-NMDA receptors is involved in the anticonvulsant activity of felbamate in DBA:2 mice

    Eur. J. Pharmacol.

    (1994)
  • S.D. Donevan et al.

    GYKI 52466, a 2,3-benzodiazepine, is a highly selective, non-competitive antagonist of AMPA: kainate receptor responses

    Neuron

    (1993)
  • M.A. Rogawski

    Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines

    Trends Pharmacol. Sci.

    (1993)
  • I. Tarnawa et al.

    Electrophysiological studies with a 2,3-benzodiazepine muscle relaxant: GYKI 52466

    Eur. J. Pharmacol.

    (1989)
  • C.E. Stafstrom

    Epilepsy: a review of selected clinical syndromes and advances in basic science

    J. Cereb. Blood Flow Metab.

    (2006)
  • M.L. Scheurer et al.

    The evaluation and treatment of seizures

    N. Engl. J. Med.

    (1990)
  • A. Thiry et al.

    Carbonic anhydrase inhibitors as anticonvulsant agents

    Curr. Top. Med. Chem.

    (2007)
  • K.J.J. Meador

    Newer anticonvulsants: dosing strategies and cognition in treating patients with mood disorders and epilepsy

    Clin. Psychiatry

    (2003)
  • A.V.K. Srivastava et al.

    Synthesis of newer thiadiazolyl and thiazolidinonyl quinazolin-4(3H)-ones as potential anticonvulsant agents

    Eur. J. Med. Chem.

    (2002)
  • Cited by (65)

    • Green synthesis, biological evaluation, molecular docking studies and 3D-QSAR analysis of novel phenylalanine linked quinazoline-4(3H)-one-sulphonamide hybrid entities distorting the malarial reductase activity in folate pathway

      2019, Bioorganic and Medicinal Chemistry
      Citation Excerpt :

      Recently, the approach has speed up the lead optimization process by studying three dimensional features of chemicals.29 3D-QSAR analysis, including CoMFA,30 CoMSIA31 and Topomer CoMFA,32 occupies a dominant position in drug design.33 Currently, 3D-QSAR is widely used in the research and development of TRPV1 inhibitors,34 PI3K inhibitors35 and mTOR inhibitors36 for its definite and rich information.

    View all citing articles on Scopus
    View full text