Bioorganic & Medicinal Chemistry Letters
Synthesis and BK channel-opening activity of
2-amino-1,3-thiazole derivatives
,
,
,*
Xiao-Lei Qia 1, Heeji Job 1, Xue-Ying Wanga, Tong-Tong Jia, Hai-Xia Lina, Chul-Seung Parkb
,
,
*
Yong-Mei Cuia
a Department of Chemistry, Innovative Drug Research Center, College of Sciences, Shanghai University, Shanghai 200444, China
b School of Life Sciences and National Leading Research Laboratory, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Keywords:
BK channels
Openers
Synthesis
Thiazole
SAR
A series of 2-amino-5-arylmethyl- or 5-heteroarylmethyl-1,3-thiazole derivatives were synthesized and evaluated
for BK channel-opening activities in cell-based fluorescence assay and electrophysiological recording. The assay
results indicated that the activities of the investigated compounds were influenced by the physicochemical
properties of the substituent at benzene ring.
Large-conductance calcium-activated K+ channels (also called maxi-
K or BK channels) are widely distributed in a number of organ systems,
such as smooth muscle cells,1 skeletal muscle cells,2,3 neuronal cells,4
and secretory epithelial cells,5 and participate in numerous physiolog-
ical functions by coupling transmembrane K+ flux, changes in mem-
brane potential, and intracellular Ca2+ concentration.6–8 The BK
channel plays important physiological roles in modulating muscle
contraction or neurotransmitter release and hormone secretion.9–12 The
physiological role and widespread distribution of BK channels suggest
that agents that open these channels could have profound impacts on
diseases such as ischemic stroke, epilepsy, asthma, and bladder over-
activity.13–17 During the past few years, various classes of BK channel
openers such as the synthetic benzimidazolin-2-one derivative
NS1619,18 the bisarylurea NS1608,19 the bisarylthiourea NS11021,20,21
the oxindole BMS-20435222, the benzofuroindole derivative CTBIC (4-
chloro-7-(trifluoromethyl)-10H-benzofuro[3,2-b]indole-1-carboxylic
acid)23 and the natural modulator dihydrosoyasaponin-1,24 etc (Fig. 1),
as well as their pharmacology have been described.25 Well-
characterized BK channel openers not only are expected to have thera-
peutic potential, but also should be of assistance in understanding the
function, structure and role of BK channels.
mol. wt. and absence of an acidic function. Therefore, NS19504 repre-
sents an interesting lead in the search for new BK channel modulators
and provides a template from which more potent derivatives might be
obtained by suitable substitution. In this letter, we survey the BK
channel-opening properties of a series of 2-amino-1,3-thiazole de-
rivatives of general structure 4 (Fig. 1) with the aim of studying the
space around the terminal group and exploring the requirements for BK
channel-opening activity.
Firstly, a series of 5-arylmethyl-2-amino-1,3-thiazole compounds 4a-
u were synthesized. As shown in Scheme 1, Meerwein reaction of the
arenediazonium chlorides resulted from anilines, with acrolein gave 3-
aryl-2-chloropropanals, followed by cyclocondensation with thiourea,
resulted in 2-amino-5-aryl-1,3-thiazoles 4a-s. However, starting from
pyridin-3-amine, using similar conditions failed to give the target
compound 4t. Therefore,
α-bromine aldehyde was first prepared by
Dess-Martin oxidation of the corresponding alcohol and subsequent
bromination using Br2 and HBr. Treatment of the α-bromine aldehydes
5c and 6c with thiourea in EtOH under heating at reflux afforded the
corresponding target compounds 4t and 4u.
To investigate the importance of the methylene linker, 5-aroyl-2-
amino-1,3-thiazole compounds 9a-b were synthesized. Thiourea was
firstly activated as bis-thiazadiene 7 with excess of commercially
available N,N-dimethylformamide dimethylacetal in methanol. The
thiazole ring was formed after addition of the corresponding
NS19504, reported by Bernhard Nausch, 26 represents a novel che-
motype among BK activators. The structure of NS19504 is markedly
different from that of the well-known BK activators, because of its low
* Corresponding authors.
1
These authors contributed equally to this work.
Received 12 March 2021; Received in revised form 23 April 2021; Accepted 1 May 2021
Available online 6 May 2021
0960-894X/© 2021 Published by Elsevier Ltd.