Unique para-aminobenzenesulfonyl oxadiazoles as novel structural potential membrane active antibacterial agents towards drug-resistant methicillin resistant Staphylococcus aureus

Article abstract of DOI:10.1016/j.bmcl.2021.127995

A class of structurally unique para-aminobenzenesulfonyl oxadiazoles as new potential antimicrobial agents was designed and synthesized from acetanilide. Some target para-aminobenzenesulfonyl oxadiazoles showed antibacterial potency. Noticeably, hexyl derivative 8b (MIC = 1 μg/mL) was more active than norfloxacin against drug resistant MRSA. Compound 8b was able to disturb the membrane effectively and intercalate into deoxyribonucleic acid (DNA) to form a steady 8b-DNA complex, which might be responsible for bacterial metabolic inactivation. Molecular docking indicated that 8b could interact with DNA topoisomerase IV through noncovalent interactions to form a supramolecular complex and hinder the function of this enzyme. These results indicated that hexyl derivative 8b deserved further investigation as a new lead compound.

Full text of DOI:10.1016/j.bmcl.2021.127995

Bioorg. Med. Chem. Lett. 41 (2021) 127995
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Unique para-aminobenzenesulfonyl oxadiazoles as novel structural
potential membrane active antibacterial agents towards drug-resistant
methicillin resistant Staphylococcus aureus
Juan Wang, Mohammad Fawad Ansari, Cheng-He Zhou*
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, Southwest University, Chongqing
400715, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
A class of structurally unique para-aminobenzenesulfonyl oxadiazoles as new potential antimicrobial agents was
designed and synthesized from acetanilide. Some target para-aminobenzenesulfonyl oxadiazoles showed anti-
Benzenesulfonyl
Oxadiazole
Antibacterial
DNA
bacterial potency. Noticeably, hexyl derivative 8b (MIC = 1 μg/mL) was more active than norfloxacin against
drug resistant MRSA. Compound 8b was able to disturb the membrane effectively and intercalate into deoxy-
ribonucleic acid (DNA) to form a steady 8b-DNA complex, which might be responsible for bacterial metabolic
inactivation. Molecular docking indicated that 8b could interact with DNA topoisomerase IV through non-
covalent interactions to form a supramolecular complex and hinder the function of this enzyme. These results
indicated that hexyl derivative 8b deserved further investigation as a new lead compound.
Drug resistance
The antimicrobial resistance to available antibiotics is one of the
most severe threats to healthcare community worldwide.1 Abuse and
misuse of antibiotics in anthropic life, animal safety, and agriculture for
decades have caused terrible bacterial infections.2 In particular, the
emerging clinical problem for treatment of stubborn methicillin-
resistant Staphylococcus aureus (MRSA) infection is exacerbated by the
lack of new treatment options over the past few decades,3 which results
in a serious social burden. Indeed, without safe and effective antibiotics,
the entire edifice of modern medicine itself will collapse due to the
spread of antimicrobial resistance.
effort for antibacterial discovery concentrated on reinvigorating existing
antimicrobial drugs by dexterously chemical modification. The exploi-
tation of benzenesulfonyl oxadiazoles as novel alternative antibacterial
agents with good therapeutic power opened up a new way to develop
drug candidates.
Oxadiazole is a five-membered heterocycle containing nitrogen and
oxygen atoms.8 Oxadiazole with unique electronic-rich nature can easily
bind with lots of therapeutic targets including DNA, enzymes and re-
ceptors through weak interactions, which is responsible for broad
pharmacological activities.9,10 Applications of specific interactions be-
tween biological macromolecules and oxadiazole are especially vital in
drug discovery and development. However, there are very few reports
about oxadiazoles as clinical antibacterial drugs, which makes the bio-
logical potential of oxadiazole buried. Therefore, the potential efficacies
of oxadiazole make it a good choice by the hybrid approach.
Benzenesulfonyl analogues show a variety of biological activities and
perform a high degree of structural diversity, which is beneficial to
discover new therapeutic agents.4 The characteristics of SVI-containing
species such as strong electron withdrawing nature and stability towards
hydrolysis have already made them applicable to various productive
fields. Presently, plentiful benzenesulfonyl-based drugs are available in
the market, for example, antiphlogistic celecoxib, benemid to treat hy-
peruricemia, antidiabetic diabinese and antibacterial sulphanilamide.5
Benzenesulfonyl compounds have grabbed significant attention due to
their excellent biological profile and effective prevention and therapy
towards infective diseases in biological systems.6 Unfortunately, the
emergence of drug-resistant bacteria cuts down the efficacy of antimi-
crobial benzenesulfonyl drugs and limits their clinic applications.7 Much
In view of the above observations, a class of unique benzenesulfonyl
oxadiazoles as novel structural membrane active inhibitors was
designed (Fig. 1).11,12 Diverse substituents were introduced into target
compounds to investigate their effects on bioactivity. The structur-
e–activity relationship was constructed to guide the future design of
bioactive molecules to combat the microbial infection. To further
explore the antibacterial mechanism of the promising molecule, mem-
brane disruption, interaction with DNA, metabolic activity as well as
* Corresponding author.
E-mail address: zhouch@swu.edu.cn (C.-H. Zhou).
https://doi.org/10.1016/j.bmcl.2021.127995
Received 28 January 2021; Received in revised form 16 March 2021; Accepted 18 March 2021
Available online 26 March 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

J. Wang et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127995
Fig. 1. Design of novel para-aminobenzenesulfonyl oxadiazoles as antibacterial agents.
Scheme 1. Synthetic route of para-aminobenzenesulfonyl oxadiazoles. Reagents and conditions: (i) chlorosulfonic acid, 0 ◦C; (ii) NaHCO3, Na2SO3, H2O, 80 ◦C; (iii)
ethyl bromoacetate, H2O, 70 ◦C; (iv) hydrazine hydrate, EtOH, reflux; (v) CS2, KOH, EtOH, reflux; (vi) halide, K2CO3, acetonitrile, r.t.; (vii) benzyl halide, K2CO3,
acetonitrile, r.t.; (viii) halogenated hydrocarbon, K2CO3, acetonitrile, r.t.
molecular docking were carried out.
The synthetic route for
the yields ranging from 19.2% to 89.4%. The structures of all the pre-
pared compounds were characterized by 1H NMR, 13C NMR and HRMS
spectra.
the
preparation
of
para-
aminobenzenesulfonyl oxadiazoles was outlined in Scheme 1. The sul-
fonylation of acetanilide 1 was carried out with chlorosulfonic acid at
0 ◦C for 2 h to produce 4-acetamidobenzenesulfonyl chloride 2 in a high
yield of 84.7%. The later was further reacted with sodium bicarbonate
and sodium sulfite in water at 80 ◦C for 3 h to generate sodium 4-acet-
amidobenzenesulfinate 3 with the yield of 96.4%, and then was stirred
with ethyl bromoacetate in water at 70 ◦C for 6 h to produce ethyl 2-((4-
acetamidophenyl)sulfonyl)acetate 4 in a moderate yield. The hydrazi-
nolysis of molecule 4 with hydrazine hydrate afforded N-(4-((2-hydra-
zineyl-2-oxoethyl)sulfonyl) phenyl)acetamide 5, which was then
cyclized with carbon disulfide in ethanol under reflux to give key in-
termediate 6 in a low yield of 21.9%. Further structural modifications of
compound 6 by a series of halides were performed in acetonitrile at
room temperature using potassium carbonate as a base for 5 h to pro-
duce aminobenzenesulfonyl oxadiazoles 7a–7j, 8a–8c and 9a–9b with
All target compounds were evaluated for their ability to inhibit the
growth of microbial pathogens in vitro. The biological assay was per-
formed according to the National Committee for Clinical Laboratory
Standards (NCCLS) taking antimicrobial norfloxacin as positive control
and the experiment was performed in triplicate.13 We attempted to
establish a structure–activity relationship for these benzenesulfonyl
oxadiazoles by incorporating alkyl, alkenyl, alkynyl, halogenated benzyl
groups into oxadiazole ring to investigate the effects of different sub-
stituents on the antibacterial activity. The antibacterial efficacy of
aminobenzenesulfonyl oxadiazoles 6–9 was evaluated and provided in
Table 1. The prepared hybrids exhibited highly selective activity
particularly toward MRSA strain. Unsaturated alkyl-substituted benze-
nesulfonyl derivatives 7a–b gave the same low antibacterial activities
against the tested strains as the corresponding unsubstituted compound
2

J. Wang et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127995
Table 1
In vitro antibacterial MIC (µg/mL) for para-aminobenzenesulfonyl oxadiazoles 6–9.a,b
Compdsc
Gram-positive bacteria
Gram-negative bacteria
MRSA
E. f.
S. a.
S. a. 25,923
S. a. 29,213
K. p.
E. c.
E. c. 25,922
P. a.
P. a. 27,853
A. b.
6
256
256
256
8
128
64
256
256
128
64
256
256
256
64
256
256
256
32
256
256
256
256
16
256
256
256
128
32
256
256
256
128
64
256
256
256
64
256
256
256
256
128
128
128
128
128
64
256
256
128
128
64
7a
7b
7c
7d
7e
7f
256
128
32
32
2
64
32
32
32
64
64
128
64
32
32
32
64
64
64
32
2
64
128
64
64
64
32
128
64
128
64
32
7g
7h
7i
64
128
64
32
16
16
64
16
32
8
128
64
128
128
128
128
256
256
64
64
64
32
128
128
128
256
128
256
128
64
64
32
64
64
128
128
256
8
64
128
64
32
7j
64
64
64
8
64
64
8a
8b
8c
9a
9b
Nord
256
1
256
128
128
128
128
8
256
256
256
64
256
256
256
32
128
256
256
8
256
256
256
64
256
256
256
64
256
32
128
16
2
64
256
64
128
16
64
256
8
32
16
64
256
8
32
16
4
8
16
8
8
4
8
a
Minimal inhibitory concentrations (MIC, μg/mL) were determined by micro broth dilution method for microdilution plates.
b
MRSA, methicillin-resistant Staphylococcus aureus; S. A., Staphylococcus aureus; S. A. 25923, Staphylococcus aureus ATCC 25923; S. A. 29213, Staphylococcus aureus
ATCC 29213; E. F., Enterococcus faecalis; K. P., Klebsiella pneumonia; E. C., Escherichia coli; E. C. 25922, Escherichia coli ATCC 25922; P. A., Pseudomonas aeruginosa; P. A.
27853, Pseudomonas aeruginosa ATCC 27853; A. B., Acinetobacter baumanii.
c
d
Compds = Compounds.
Nor = Norfloxacin.
Fig. 3. Inner membrane disruption of drug-resistant MRSA in the existence of
Fig. 2. Resistance study for hexyl derivative 8b against drug resistant MRSA.
hexyl derivative 8b at the concentration of 4 × MIC.
Norfloxacin was employed as a positive control.
7j showed the same activity against E. coli and MRSA, the MIC values
6. However, cyano derivative 7c (MIC = 8 µg/mL) showed better ac-
were 8 µg/mL. Exploration of alkyl-modified compounds 8a–c led to
tivity toward MRSA than norfloxacin (MIC = 16 µg/mL). Ethoxyl-
another antibacterial story. Target compound 8b with an alkyl chain of
substituted hybrid 7d displayed moderate activity against Gram-
six carbons displayed excellent activity against MRSA with an MIC value
negative bacteria (MIC = 32–64 µg/mL). Fluoroethyl derivative 7e
of 1 µg/mL, which was 16-fold more active than norfloxacin. However,
(MIC = 2 µg/mL) exhibited 8 times higher inhibitory efficiency toward
both extending (8c) and shortening (8a) the length of the alkyl chain
MRSA than norfloxacin.
sharply decreased the inhibitory activity towards MRSA. The haloge-
This result demonstrated that the introduction of fluoroethyl moiety
nated benzyl derivatives 9a–b also showed consistent antibacterial
was better than hydroxyl group in improving susceptibility against
behavior, however, the 2,4-dichloro hybrid 9b showed considerably
MRSA. The incorporation of carboxyl moiety aimed to ameliorate the
high anti-MRSA activity with an MIC value of 2 µg/mL. Besides, the anti-
water solubility and thus enhanced the inhibitory potency, nevertheless,
E. coli effect of 2,4-difluorine compound 9a was in accordance with that
the bioactivity of carboxyl one 7f was not as good as we expected.
of norfloxacin.
However, the activity of ester-based hybrid 7h (MIC = 16 µg/mL)
The developed series of para-aminobenzenesulfonyl oxadiazoles
against MRSA was equivalent with that of the reference drug. Surpris-
including cyano, alkyl, ester and benzyl ones exhibited effective anti-
ingly, acetonyl compound 7g was active against MRSA (MIC = 2 µg/mL)
microbial activity against MRSA. Particularly, MRSA was very sensitive
and showed moderate antibacterial activity against K. pneumonia and
to hexyl-derived hybrid 8b, suggesting that this type of molecular
E. coli with MIC values of 16 µg/mL. In addition, cyclopropyl derivative
modification would highlight on developing novel potential clinical
3

J. Wang et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127995
Fig. 5. Hexyl derivative 8b docked in DNA topoisomerase IV (PDB
code: 4Z4Q).
Fig. 4. UV absorption spectra of calf thymus DNA with different contents of
hexyl derivative 8b (pH = 7.4, T = 290 K). c(DNA) = 7.41 × 10ꢀ 5 mol Lꢀ 1 and
c(hexyl derivative 8b) = 0–2.67 × 10ꢀ 5 mol/L. Inset: Comparison of the ab-
sorption at 260 nm between the value of hexyl derivative 8b–DNA complex and
the sum values of free DNA and free hexyl derivative 8b.
changes, which disclosed the formation of compound 8b-DNA complex.
Furthermore, the molecular docking (Fig. S1) showed that 8b could
embed in DNA (PDB code: 1AMD) in silico as well. These results implied
the high antibacterial potency of the compound 8b.
The organic dye AO has been proven to be a very sensitive fluores-
cent probe and emits green fluorescence when it binds to DNA.17 The
fluorescence intensity of DNA-AO complex decreased at 537 nm with the
increased addition of hexyl derivative 8b (Fig. S4), which indicated that
it could embed into DNA by competing with the AO. This provided
theoretical basis for the design of new and effective drugs to some
extent.
drug candidates with highly selective and excellent anti-MRSA
capabilities.
The MRSA developed resistance to almost all frontline antibiotics
became a serious threat for human health.14 The active compound 8b
was screened for resistance study against MRSA strain taking nor-
floxacin as positive control. The experimental result in Fig. 2 showed
that susceptibility of MRSA towards compound 8b nearly unaffected
even after 16 passages, while the MIC value of norfloxacin toward MRSA
got dramatically increased after several passages, which showed that
MRSA was more difficult to develop resistance against compound 8b
than reference drug norfloxacin.
Bacterial topoisomerase IV can control the topological state of DNA
during the processes of transcription, replication and recombination.18
Considering the membrane disruption obtained above, we speculated
that hexyl derivative 8b might attack and cause damage to bacterial cell
membrane and then entered the cells to destroy the functions of topo-
isomerase IV in the cytoplasm, which could in turn lead to cell death.
Therefore, a flexible ligand-receptor docking investigation was per-
formed with topoisomerase IV (PDB code: 4Z4Q) as a representative
target to rationalize the action mechanism of compound 8b (Fig. 5).
Docking results showed that there was a hydrogen bond between the
hydrogen atom of sulfonamido fragment and MET-1116 residue with a
distance of 2.4 Å. The hydrogen atom of acetamido moiety could
interact with the ASP-1078 residue through hydrogen bond with the
distance of 2.5 Å. In addition, the nitrogen atom of oxadiazole could
form hydrogen bond with the ARG-1117 residue, which further revealed
that the introduction of oxadiazole was beneficial. These non-covalent
interactions pointed out that molecule 8b could disturb the biosyn-
thesis of bacterial DNA through interaction with topoisomerase IV,
which provided a theoretical basis for 8b with high antibacterial
activity.
To further explore the possible antibacterial mechanism, compound
8b was investigated for bacterial membrane disruption using propidium
iodide (PI) a common dye, which entered only through impaired
membrane of MRSA and displayed florescence after interaction with
cellular DNA.15 The maximum fluorescence intensity was observed after
treatment with compound 8b (at 4 × MIC) within 14 min as shown in
Fig. 3, indicating hexyl derivative 8b might cause certain damage to
MRSA membrane due to the formation of PI-DNA complex. Especially at
4 × MIC value, the fluorescence change was the most obvious (Fig. S2).
The above results showed that the disruption of bacterial membrane by
molecule 8b enhanced the antibacterial effect.
Deoxyribonucleotide (DNA) is an important drug target in many
clinical drugs and has been widely exploited for rational design of novel
efficient DNA-targeting antibacterial drugs with low drug resistance.16
Calf thymus DNA is frequently served as DNA model owing to its medical
importance, low price and ready availability properties. Therefore, the
in vitro interaction between 8b with calf thymus DNA was explored using
Acridine orange (AO) as a spectral probe to investigate the possible
mechanism of action at a molecular level.
Alamar blue assay is a simple, one-step procedure to be used to
evaluate the planktonic bacterial susceptibility.19 On chemical reduc-
tion, the changes in fluoresces and color are observed and the extent of
the conversion is a reflection of cell viability.20 Sustained growth
maintains a reduced environment, while growth inhibition holds an
oxidized surrounding. As shown in Fig. S5, the metabolic activity of
MRSA decreased after treatment with hexyl derivative 8b. Meanwhile,
compound 8b could induce inactivation of metabolism in a dose-
dependent behavior, which finally led to bacterial death. Therefore,
the above results indicated that the disruption of membrane of MRSA
cells upon exposure to molecule 8b resulted in metabolic stagnation and
loss of cell viability.
The absorption spectroscopy as one of the excellent techniques is
extensively employed in DNA-binding studies. Hyperchromism and
hypochromism are crucial spectral features examined by absorption
spectroscopy to certify the variation of double-helical DNA.16 The
enhancement in maximum absorption of DNA was proportional to the
increased concentration of hexyl derivative 8b along with a slight red-
shift under a fixed content of DNA (Fig. 4). Meanwhile, the 8b-DNA
complex showed lower absorption value than free DNA and free hexyl
derivative 8b. Furthermore, the intercalation of 8b into DNA double-
helical structure was in accordance with the observed spectral
A variety of highly active molecules can not be further developed as
clinical candidates due to their poor pharmacokinetics, low
4

J. Wang et al.
Bioorganic & Medicinal Chemistry Letters 41 (2021) 127995
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Table 2
The ADME data of hexyl derivative 8b.
Compound 8b
Norfloxacin
MW (g/mol) < 500
Mlog P ≤ 4.15
397.51
319.33
2.05
6
1.04
5
H-bond acceptors < 10
H-bond donors < 5
Lipinski violations
Bioavailability Score
BBB permeant
1
2
0
0
0.55
No
0
0.55
No
0
3
4
5
6
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block DNA replication to exert powerful antimicrobial activities. In
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nation and loss of cell viability. This work provided a new possibility to
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Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
9
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Acknowledgments
This research was supported in part by grants from the National
Natural Science Foundation of China (21971212), Postdoctoral Science
Foundation Project of Chongqing Science and Technology Bureau
(cstc2019jcyj-bshX0124), China Postdoctoral Science Foundation
(2019M653821XB) and Chongqing Special Foundation for Postdoctoral
Research Proposal (XmT2018082).
Tangadanchu VKR, Gao WW, Zhou CH. Novel naphthalimide nitroimidazoles as
multitargeting antibacterial agents against resistant Acinetobacter baumannii. Future
Med Chem. 2018;10:711–724.
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Zhou CH. New progress in azole compounds as antimicrobial agents. Mini Rev Med
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Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127995.
11 (a) Ghorab MM, Alsaid MS, El-Gaby MSA, Safwat NA, Elaasser MM, Soliman AM.
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