Bioorganic & Medicinal Chemistry Letters
Synthesis and biological evaluation of 4-oxoquinoline-3-
carboxamides derivatives as potent anti-fibrosis agents
Jun Zhu a, , Lin He a, , Liang Ma a, , Zhe Wei a, Jiqiang He a, Zhuang Yang b, Yuzhi Pu a, Dong Cao a,
Yuzhe Wu b, Mingli Xiang a, Aihua Peng a, Yuquan Wei a, Lijuan Chen a,
⇑
a State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University,
Chengdu, Sichuan 610041, PR China
b College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Thirty-one 4-oxoquinoline-3-carboxamides derivatives were synthesized and evaluated for their anti-
Received 3 September 2014
Revised 9 October 2014
Accepted 22 October 2014
Available online 29 October 2014
fibrotic activities by the inhibition of TGF-b1-induced total collagen accumulation and anti-inflammatory
activities by the inhibition of LPS-stimulated TNF-
and 11g) exhibited potent inhibitory effects on both TGF-b1-induced total collagen accumulation and
LPS-stimulated TNF- production. Furthermore, oral administrations of 10l at a dose of 20 mg/kg/day
a production. Among them, three compounds (10a, 10l
a
for 4 weeks effectively alleviated lung inflammation and injury, and decreased lung collagen accumula-
tion in bleomycin-induced pulmonary fibrosis model. Histopathological evaluation of lung tissue con-
firmed 10l as a potential, orally active agent for the treatment of pulmonary fibrosis.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
4-Oxoquinoline-3-carboxamides
Pulmonary fibrosis
TGF-b1
Collagen accumulation
TNF-a
Anti-inflammatory
Pulmonary fibrosis (PF), characterized by the disruption of nor-
mal lung tissue architecture and loss of pulmonary function, is one
of the major clinical problems of cystic fibrosis and chronic
obstructive pulmonary disease.1–4 Its incidence most recently has
been estimated to be between 14 and 42.7 per 100,000 and has
been increasing,5–7 the expected survival time of patients suffered
from PF is estimated to be 2.5–3.5 years.8 However, the pathogen-
esis of PF is still unknown, the excessive deposition of extracellular
matrix (ECM) in lung tissues caused by inflammation has been rec-
ognized as a crucial reason leading to the destruction of the lung
architecture.9,10
sis,16 which is studied for chronic obstructive pulmonary disease
in clinic.17 Treatment with Ivacaftor had significant and sustained
improvement in their lung function in cystic fibrosis.18,19 In our
preliminary studies, Ivacaftor was also observed to reveal in vitro
anti-fibrotic activities by the inhibition of TGF-b1-induced total
collagen accumulation in rat fibroblast cells (NRK-49F), which
has been recognized an effect of good and convenient origin for
anti-fibrotic agent in vitro screening model.20 Therefore, these
pharmacological properties of Ivacaftor provided us the impetus
to develop novel and potent anti-fibrotic agents containing 4-oxo-
quinoline-3-carboxamide moiety by using Ivacaftor as a lead.
Ivacaftor derivatives (9a–9f) were synthesized according to pre-
vious reported procedures (Scheme 1).21–23 The 2,4-di-tert-butyl-
phenol 1 was treated with methyl chloroformate to give 2.
Nitration of 2 with cooled mixture of HNO3 and H2SO4 (v:v 1:1)
obtained 3. Treatment of 3 with 10% Pd/C, HCOONH4 yielded 4.
The pivotal 4-quinolones intermediates 5a–5f were obtained by
the condensation of appropriate anilines with diethyl ethoxymeth-
ylenemalonate, followed by the cyclization of the intermediate to
give 6a–6f. Compound 6a–6f were hydrolyzed to the correspond-
ing acid 7a–7f, the intermediates 7a–7f were reacted with 4 to
afford 8a–8f, further deprotected to give 9a–9f. Ivacaftor analogues
10a–10o and 11a–11j were outlined in Scheme 2. The intermedi-
ate 7e was treated with anilines to afford the desired products
A number of studies have documented that cytokines such as
TGF-b1, TNF-a
play key roles during the pathogenesis of the PF.11
TGF-b1 is a fibrogenic cytokine involved in pathological fibrosis
of PF by regulating extracellular matrix (ECM) deposition in the
response to lung tissues injury.12–14 TNF-
a, an important pro-
inflammatory cytokine released by macrophages and lymphocytes,
involved in regulating the inflammation respond to lung tissue
injury.15
Ivacaftor (Fig. 1), a 4-oxoquinoline-3-carboxamide compound,
has been approved as a small-molecule drug to treat cystic fibro-
⇑
Corresponding author. Tel.: +86 28 85164063; fax: +86 28 85164060.
These authors contributed equally.
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.