Bioorganic & Medicinal Chemistry Letters 19 (2009) 5644–5647
Bioorganic & Medicinal Chemistry Letters
Synthesis and in vitro evaluation of 2,4-diamino-1,3,5-triazine derivatives
as neuronal voltage-gated sodium channel blockers
a
c
a,
Xiang Ma a,b, , Thong-Yuen Poon , Peter Tsun Hon Wong , Wai-Keung Chui
*
*
a Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore
b Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive, Singapore 117576, Singapore
c Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Neuronal sodium channels blockers interfere with ion flux and have been used for managing neuropathic
pain, epilepsy, and cerebral ischemic disorders. In the current study, four groups of 2,4-diamino-1,3,5-tri-
azine derivatives were synthesized and investigated for their neuronal sodium channels binding activity.
5-Aryl-1,3,5-triazaspiro[5.5]undeca-1,3-diene-2,4-diamines (4a–4j) were found to have the best neuro-
nal sodium binding activity among the four groups of triazines evaluated. Derivatives 4a–4j blocked
Received 15 June 2009
Revised 24 July 2009
Accepted 5 August 2009
Available online 15 August 2009
the sodium channels with IC50 values ranged from 4.0 to 14.7 lM. The result from this study showed that
Keywords:
analogues of 2,4-diamino-1,3,5-triazines could be used as leads for the discovery of neuronal sodium
channels blockers for managing central nervous system related disorders.
Ó 2009 Elsevier Ltd. All rights reserved.
Sodium channel blockers
2,4-Diamino-1,3,5-triazines
Antiepilepsy
Voltage-gated sodium channels are large transmembrane pro-
teins which are essential for the generation of action potentials
in excitable cells that lead to a rapid transmission of depolarizing
impulses throughout cells and cell networks.1 The neuronal so-
dium channels have been identified as therapeutic targets, either
selectively or in combination with other cellular processes. Inter-
ference of the neuronal sodium channels may be useful to treat
central nervous system (CNS) related disorders such as epilepsy,
neuropathic pain, neurodegeneration associated ischemic stroke,
and other conditions.2,3 Phenytoin (1), an antiepileptic drug, was
the milestone in recognition of neuronal sodium channel blockers’
potential in the treatment of CNS-related disorders.4 Phenytoin has
been shown to be efficacious in treating partial and generalized to-
nic-clonic seizures in humans.4 Lamotrigine (2), a phenyltriazine
derivative, is a novel antiepileptic drug that shares similar mode
of action on neuronal sodium channels as phenytoin.5 It emerged
from the screening process of putative antifolates as anticonvul-
sant agents, prompted by the observation that folates induce sei-
pharmacophore, indicated as one of the hydrogen donor/acceptor
units in the above pharmacophore model, is very common in many
types of antifolates (Chart 1).10 It was once believed that antifolate
activity might be related to several sodium channels blockers’ anti-
convulsant activity.11 Lamotrigine was then developed as an antif-
olate drug. However, as it turns out, lamotrigine does not have
marked antifolate action and there is no correlation between the
antifolate action and antiepileptic effects.
2,4-Diamino-1-(4-chlorophenyl)-1,2-dihydro-1,3,5-triazines (3)
was known to be a potent antifolate.12 However, our investigation
and other SAR studies of this class of triazines suggested that the
spiro triazines 4, the Dimroth rearranged products 5, the N1-benzyl
substituted triazines 6 and the aromatic 1,3,5-triazines 7 were
either weak antifolates or were totally devoid of antifolate activ-
ity.12–15 The triazine derivatives are composed of a phenyl ring,
amino groups, and a 2,4-diamino-1,3-diaza structure, which are
also present in voltage-gated sodium channel blockers such as phe-
nytoin and lamotrigine (Chart 1). We therefore hypothesized that
the 2,4-diamino-1,3,5-triazine scaffold would exhibit neuronal
sodium channels blockade activity; if so, the weak antifolate
activity of the scaffold would avoid antifolate side effect. In this
letter, four groups of 2,4-diamino-1,3,5-triazines (4–7) were used
to elucidate if 2,4-diamino-1,3,5-triazines would block the neuro-
nal sodium channels (Chart 1).
zures in animals.6–8 Unverferth et al. identified
a common
pharmacophore model based on some well known voltage-gated
sodium channel blockers including phenytoin and lamotrigine
(Chart 1).9 The essential structural features which could be respon-
sible for an interaction with the active site of voltage-gated sodium
channels were a hydrophobic unit, an electron donor group, and a
hydrogen donor/acceptor unit (Chart 1). 2,4-Diamino-1,3-diaza
The synthesis of 5-aryl-1,3,5-triazaspiro[5.5]undeca-1,3-diene-
2,4-diamine (4a–4j) was accomplished using a well known ‘3-com-
ponent’ method16 as described in Scheme 1. Three components:
aniline, cyanoguanidine, and cyclohexanone were refluxed in the
presence of catalytic amount of concentrated hydrochloric acid in
* Corresponding authors. Tel.: +65 6516 2657; fax: +65 6779 1554 (X.M.); tel.:
+65 6516 2933; fax: +65 6779 1554 (W.K.C.).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.