Bioorganic & Medicinal Chemistry Letters
The optimization and characterization of functionalized sulfonamides
derived from sulfaphenazole against Mycobacterium tuberculosis with
reduced CYP 2C9 inhibition
,
,
,*
Hui Chenb, Bin Wangc, Peng Lia, Hong Yanb, Gang Lia *, Haihong Huanga *, Yu Luc
a Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation & Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative
Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China
b Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-engineering, Beijing University of Technology, Beijing 100124, PR China
c Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing
Chest Hospital, Capital Medical University, Beijing 101149, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
In this study, a series of sulfonamide compounds was designed and synthesized through the systematic opti-
mization of the antibacterial agent sulfaphenazole for the treatment of Mycobacterium tuberculosis
(M. tuberculosis). Preliminary results indicate that the 4-aminobenzenesulfonamide moiety plays a key role in
maintaining antimycobacterial activity. Compounds 10c, 10d, 10f and 10i through the optimization on phenyl
ring at the R2 site on the pyrazole displayed promising antimycobacterial activity paired with low cytotoxicity. In
Sulfonamide compounds
Optimization
Antimycobacterial activity
CYP 2C9
Cytotoxicity
particular, compound 10d displayed good activity (MIC = 5.69
10
into the combination regimen using sulfonamide as one component for the treatment of M. tuberculosis.
μ
g/mL) with low inhibition of CYP 2C9 (IC50
>
μ
M), consequently low potential risk of drug-drug interaction. These promising results provide new insight
Tuberculosis (TB) is a chronic disease that results from infection with
M. tuberculosis. TB is one of the top 10 causes of death worldwide, and
the leading cause of mortality stemming from a single infectious path-
ogen.1 In addition, the emergence of multidrug-resistant (MDR) TB and
extensively drug-resistant (XDR) TB have worsened the situation,
particularly in low-income countries.2,3 Renewed efforts have therefore
been focused on developing new antibiotics against TB.4 Meanwhile,
repurposing of efficacious antibiotics has emerged as an effective way to
discover new pharmacophores, resulting in the discovery of potentially
new drugs against M. tuberculosis.5
for bacterial viability. Furthermore, the combination of SMX and TMP
(SXT) has emerged as a potential treatment regimen to combat drug-
resistant TB.14 Notably, SXT has been successfully used to treat iso-
lated cases of drug-resistant tuberculosis,15 with further research
showing that several other related sulphonamide derivatives also dis-
played pronounced anti-TB effects.7,16,17 All these results encouraged us
to further evaluate sulfonamide derivatives against M. tuberculosis.
The initial hit compound, SPA, discovered through screening our in-
house library of clinically relevant sulfonamide compounds, displayed
good in vitro efficacy against M. tuberculosis H37Rv (Fig. 1). However,
SPA is also a selective, competitive inhibitor of CYP 2C9, which can
potentially lead to drug-drug interactions.18–20 In this work, a series of
sulfonamide compounds derived from SPA was designed and synthe-
sized to establish and explore structure–activity relationships (SARs),
with the aim to design-out the unwanted CYP 2C9 activity. Systematic
optimization led to compound 10d which displayed good anti-
mycobacterial activity and, importantly, a reduced CYP 2C9 inhibitory
profile.
Sulfonamides have been intensively investigated since their discov-
ery as the first potent antibacterial agents, and notably, are still in use
today.6–10 Sulfonamides generally act as structural analogues of 4-ami-
nobenzoic acid and therefore inhibit dihydropteroate synthase in
bacteria.11–13 The 4-aminobenzenesulfonamides with antibacterial ac-
tivity are represented as sulfamethoxazole (SMX), sulfadiazine (SD),
sulfisoxazole (SIZ) and sulfaphenazole (SPA).
The antibacterial activity observed upon combining SMX with
trimethoprim (TMP) is a result of the sequential inhibition of the
biosynthesis of tetrahydrofolic acid within bacteria, which is essential
The synthesis of compounds 5a-i, 10a-k, 12a-c, 16a-f, 17 and 18a-g
is outlined in Schemes 1–4. Sulfonylation of commercially available 5-
* Corresponding authors.
Received 22 December 2020; Received in revised form 8 February 2021; Accepted 25 February 2021
Available online 9 March 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.