Novel Naphthalimide Aminothiazoles as Potential Multitargeting Antimicrobial Agents

Article abstract of DOI:10.1021/acsmedchemlett.7b00452

A series of novel naphthalimide aminothiazoles were developed for the first time and evaluated for their antimicrobial activity. Some prepared compounds possessed good inhibitory activity against the tested bacteria and fungi. Noticeably, the piperazine derivative 4d displayed superior antibacterial activity against MRSA and Escherichia coli with MIC values of 4 and 8 μg/mL, respectively, to reference drugs. The most active compound 4d showed low toxicity against mammalian cells with no obvious triggering of the development of bacterial resistance, and it also possessed rapid bactericidal efficacy and efficient membrane permeability. Preliminarily investigations revealed that compound 4d could not only bind with gyrase-DNA complex through hydrogen bonds but could effectively intercalate into MRSA DNA to form 4d-DNA supramolecular complex, which might be responsible for the powerful bioactivity. Further transportation behavior evaluation indicated that molecule 4d could be effectively stored and carried by human serum albumin, and the hydrophobic interactions and hydrogen bonds played important roles in the binding process.

Full text of DOI:10.1021/acsmedchemlett.7b00452

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Letter
Novel Naphthalimide Aminothiazoles as
Potential Multi-targeting Antimicrobial Agents
Ying-Ying Chen, Lavanya Gopala, Rammohan R. Yadav Bheemanaboina,
Han-Bo Liu, Yu Cheng, Rong-Xia Geng, and Cheng-He Zhou
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00452 • Publication Date (Web): 01 Dec 2017
Downloaded from http://pubs.acs.org on December 4, 2017
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Novel Naphthalimide Aminothiazoles as Potential Multi-targeting An-
timicrobial Agents
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YingꢀYing Chen, Lavanya Gopala, Rammohan R. Yadav Bheemanaboina, HanꢀBo Liu, Yu Cheng,
RongꢀXia Geng, ChengꢀHe Zhou* iD
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of
Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
KEYWORDS: Naphthalimide, aminothiazole, antibacterial, MRSA DNA, human serum albumin
ABSTRACT: A series of novel naphthalimide aminothiazoles were developed for the first time and evaluated for their antimicroꢀ
bial activity. Some prepared compounds possessed good inhibitory activity against the tested bacteria and fungi. Noticeably, the
piperazine derivative 4d displayed superior antibacterial activity against MRSA and Escherichia coli with MIC values of 4 and 8
ꢁg/mL respectively to reference drugs. The most active compound 4d showed low toxicity against mammalian cells with no obviꢀ
ously triggering the development of bacterial resistance, and it also possessed rapidꢀbactericidal efficacy and efficient membrane
permeability. Preliminarily investigations revealed that compound 4d could not only bind with gyrase−DNA complex through hyꢀ
drogen bonds, but also effectively intercalate into MRSA DNA to form 4d–DNA supramolecular complex, which might be responꢀ
sible for the powerful bioactivity. Further transportation behavior evaluation indicated that molecule 4d could be effectively stored
and carried by human serum albumin, and the hydrophobic interactions and hydrogen bonds played important roles in the binding
process.
The emergence and spread of multidrugꢀresistant bacteria
resulted from the overuse and misuse of antibiotics has been a
major obstacle to the successful treatment of infectious
diseases.1ꢀ3 Methicillinꢀresistant Staphylococcus aureus
(MRSA) is currently a major nosocomial pathogen, which
arises from the acquisition of staphylococcal cassette
chromosome mec (SCCmec) through horizontal gene transfer
in methicillinꢀsusceptible Staphylococcus aureus. An altered
penicillinꢀbinding protein PBP2a expressed by SCCmec has
fairly lower binding affinity for nearly all available βꢀlactam
antibiotics, making them invalid against MRSA.3 Despite
numerous efforts devoted to ensure sterility and limit spread of
MRSA, the morbidity and mortality rates still remain high per
year. This deeply highlights the urgent and unmet medical
need for developing new type of potential antimicrobial agents
against MRSA.4
been recently applied to the rational discovery of potential
antibacterial and antifungal agents, and some great
achievements have been acquired.9ꢀ10
Aminothiazole is a beneficial structural fragment for
bioactivity and prevalently present in a broad range of
therapeutic agents11 due to its unique structure with both
electronꢀdonating groups (NH2, ꢀSꢀ) and an electronꢀaccepting
group (C=N), which could readily interact with DNA and
many other biomacromolecules.12,13 A lot of drugs containing
aminothiazole fragment have been launched into the
market,14,15 such as the antibacterial cephalosporins and
sulfathiazole, the antifungal drug abafungin. The successful
development of various clinical aminothiazole drugs has
provoked extensive studies to construct more bioactive
molecules with aminothiazole fragment in antimicrobial
field.16ꢀ18
Naphthalimides are highly versatile functional compounds,
which have received an increasing attention in the
development of DNAꢀbinding agents,5 and established great
therapeutic importance in medicinal chemistry.6,7 Especially as
anticancer agents, some naphthalimides such as amonafide,
mitonafide and aristolochic acid effectively inhibit the growth
of various human and murine cancer cell lines. This type of
compounds exert their anticancer function by intercalating into
DNA to directly inhibit the normal replication and
transcription of DNA, and/or into topoisomerase (TOP) II to
stabilize supramolecular complex of TOP and DNA, and to
prevent the correction of topology structure of DNA.8 This
special interaction model of naphthalimides with DNA has
In view of this, we introduced aminothiazole moiety into the
Nꢀposition of the naphthalimide backbone to generate novel
naphthalimideꢀaminothiazole hybrids and investigated their
effect on antimicrobial activity.19 It is known that the
bioactivities of naphthalimides are significantly affected by
functional groups on the naphthalimide ring especially at the
3ꢀ or 4ꢀposition,6 which are beneficial for targeting
biomolecules. Alicyclic amines such as piperazine,
morpholine and pyrrolidine are important structural fragments
in regulating the physicochemical properties and improving
pharmacokinetic profiles,20 and they are prevalently present in
numerous clinical antimicrobial agents. Rationally, various
alicyclic amine moieties were incorporated into the 4ꢀposition
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of naphthalimide skeleton to study their influence on bioactive
profiles (Figure 1).9
The antimicrobial screening was executed among
naphthalimide aminothiazoles 3−5 to investigate their
biological activities. Bacterial resistance study, bactericidal
kinetic assay, and cytotoxicity were explored to further assess
the potentiality of the bioactive compounds as new
antimicrobial agents. Additionally, the antimicrobial
mechanism was also investigated through membrane
permeabilization assay, molecular docking study with
gyrase−DNA complex, interaction with MRSA DNA. The
transportation behavior of human serum albumin (HSA) to
highly active compound was also performed.
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Figure 1. Design of novel naphthalimide aminothiazoles.
Scheme 1. Synthetic route of naphthalimide aminothiazoles 3−5a
aReagents and conditions: (i) thiosemicarbazide, DMF, 100 oC, 8 h; (ii) αꢀhalogenated carbonyl compounds, ethanol, 80 oC, 7 h; (iii) alꢀ
icyclic amines, 2ꢀmethoxyethanol, reflux, N2, 7 h; (iv) Nꢀalkylated piperazines, 2ꢀmethoxyethanol, reflux, N2, 7 h; (v) alkyl halides, ethaꢀ
nol, 80 oC, 8 h.
Standards Institute (CLSI)21 were depicted in Table S1. Some
The target naphthalimide aminothiazoles 3−5 were
prepared compounds could effectively inhibit the growth of
the tested strains in vitro. Preliminary active screening showed
that aminothiazole derivative 3a possessed slightly better
antibacterial efficacy than 4ꢀsubstituted aminothiazoles 3b−c,
it suggested that the modification on 4ꢀposition of
aminothiazole ring might be unfavorable for the antibacterial
activity. Among the series of compounds 4a−d, morpholine
modified naphthalimide 4c gave the strongest antiꢀA. baumanii
potency (MIC = 8 ꢁg/mL), 2ꢀfold more potent than
chloromycin (MIC = 16 ꢁg/mL) and equivalent to norfloxacin
(MIC = 8 ꢁg/mL). Notably, piperazinyl derivative 4d could
effectively inhibit the growth of all the tested bacteria, except
for A. baumanii. Especially against Gram positive bacteria,
this compound demonstrated efficient bioactivity against S.
aureus 29213 (MIC = 2 ꢁg/mL), S. aureus 25923 (MIC = 4
ꢁg/mL) and MRSA (MIC = 4 ꢁg/mL), which was more active
than chloromycin (MICs = 4, 8 and 16 ꢁg/mL, respectively).
Besides, it was also effective in inhibiting Gram negative
bacteria including E. coli, E. coli 25922, P. aeruginosa and P.
aeruginosa 27853 at low concentrations (MICs = 4−16
ꢁg/mL), particularly against E. coli 25922 strain, which was 4ꢀ
fold and 2ꢀfold more potent than chloromycin (MIC = 16
ꢁg/mL) and norfloxacin (MIC = 8 ꢁg/mL), respectively. These
indicated that target molecule 4d had immense potentiality to
be a lead compound in the development of more effective
synthesized via multiꢀstep reactions starting from commercial
4ꢀbromoꢀ1,8ꢀnaphthalic anhydride according to Scheme 1.
Condensation of 4ꢀbromoꢀ1,8ꢀnaphthalic anhydride and
thiosemicarbazide afforded compound 2 in 60.1% yield, which
was further cyclized with the αꢀhalogenated carbonyl
compounds in ethanol at 80 oC via the typical Hantsch thiazole
synthesis to give aminothiazole derivatives 3a−c in yields of
21.1−40.2%.17 The Nꢀalkylation of piperazine with alkyl
halides generated monoꢀsubstituted alkyl piperazines 6a−e
with yields of 35.1−80.0%. Compound 3a was further treated
o
with alicyclic amines in 2ꢀmethoxyethanol at 125 C under
nitrogen atmosphere to achieve the desired compounds 4a−d
in yields of 30.0−46.2%, under the same reaction condition,
the substitution of bromo atom in compound 3a by piperazinyl
derivatives 6a−e produced the target naphthalimide
aminothiazoles 5a−e with yields ranging from 26.0% to
40.6%.9 All the new compounds were confirmed by 1H NMR,
13C NMR, IR, and HRMS spectra. Purity was determined with
the help of the quantitative nuclear magnetic resonance
(QNMR) method using 1,3,5ꢀtrioxane as the internal standard.
All the target compounds were found to be > 95% pure, and
the spectral data were in the Supporting Information.
The antimicrobial data evaluated using two folds serial
dilution technique recommended by Clinical and Laboratory
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boardꢀspectrum antimicrobial agents. Compounds 4a and 4b
MRSA, which would provide information about the
bactericidal activity of compound 4d against the tested
bacteria.24 As can be seen from Figure S1, compound 4d could
cause more than 3ꢀLog (CFU/mL) reduction in the number of
viable bacteria within an hour at a concentration of 4 × MIC. It
was suggested that this compound showed rapidꢀbactericidal
activity against MRSA.
with pyrrolidinyl and piperidinyl substituents gave
unfavorable antibacterial profile against the tested strains.
Among sixꢀmembered alicyclic amine derivatives 4b−d, it was
noteworthy that the higher active compound 4d and the lower
active ones 4b−c were attributable solely to the different
substitution on the 4ꢀposition of sixꢀmembered alicyclic
amines, which revealed that the NH group had quite positive
influence on bioactivity than O or CH2 moiety. So it would be
interesting and rational to continue our work to modify the Nꢀ
position on piperazine ring of derivative 4d.
The selectivity toward mammalian cells over bacterial cells
has been one of the major concerns in the development of
clinically available antibacterial agents for biomedical
applications.25,26 The active molecule 4d was further evaluated
for its cytotoxicity against normal rat macrophage cells (RAW
264.7) using the MTT assay. Results in Figure S2 showed that
the cell viability of compound 4d was at least 80.1% within a
concentration of 128 µg/mL. This indicated that compound 4d
exhibited relatively low toxicity toward mammalian cells
within the MIC values against most of the test bacteria.
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Further studies were focused on the effect of alkyl chain in
piperazine ring of compound 4d on antimicrobial activity
because a large amount of work had revealed the importance
of alkyl chain in affecting antimicrobial efficacy.9 Therefore
the alkyl groups were introduced into compound 4d to
produce derivatives 5a−e with conspicuous loss of inhibitory
efficacies against the tested pathogens, which suggested the
necessity of NH group for antimicrobial activity probably due
to its participation in formation of hydrogen bonds so as to
helpfully interact with biomolecules in biological system.
Besides, the lengths of alkyl chains have different effects on
biological activity, in which analogue 5b with hexyl group
gave better antibacterial activity in comparison with other
alkyl derivatives. Moreover, when the alkyl substituents were
extended to decyl, dodecyl and hexadecyl groups, compounds
5c−e displayed weak or no obvious activity in inhibiting the
growth of the tested bacterial strains. This fact pointed out that
only suitable length of alkyl chain in piperazine ring was
necessary for good antibacterial activity. The antifungal
activities (Table S2) were also discussed and showed in the
Supporting Information.
Membraneꢀtargeting antimicrobials provide potential
solutions for the problem of bacterial resistance, for the reason
that the membraneꢀactive nature gives low propensity for the
development of drug resistance unless there are largeꢀscale
changes in the membrane compositions of bacteria. Therefore,
bacterial membrane has been considered as a particularly
valuable antibacterial target to overcome resistance.27
Compound 4d was further assessed for the ability to
permeabilize the cytoplasmic membrane of bacteria using
propidium iodide (PI) dye.28 As can be seen from Figure S3,
the rapid fluorescence intensity enhancements of the mixtures
of compound 4d and PIꢀtreated MRSA and Escherichia coli
appeared and became steady after 60 min, while the two
control groups almost kept constant, which proved that the
tested compound 4d was efficient in permeabilizing the
membranes of both Gram positive (MRSA) and Gram
negative (Escherichia coli) bacteria.
Many of the clinically approved drugs have suffered defeat
from the resistant clinical strains due to the decreased potency
or increased susceptibility to the degradation mechanisms.22
Thereby, it would be important to evaluate the ability of
compound 4d to suppress the development of resistance. The
resistant pathogen MRSA was employed as the tested strains.
Norfloxacin and chloromycin were used as positive control.
As shown in Figure 2, this result indicated that MRSA was
much more difficult to develop resistance against compound
4d than the clinical drugs, and such structure might be a
promising candidate for antiꢀMRSA agent with considerable
therapeutic efficacy and low drugꢀresistance.23
Figure 3. Threeꢀdimensional conformation of compound 4d
docked in the gyrase−DNA complex (PDB code: 2XCS).
500
Compound 4d
Norfloxacin
Chloromycin
400
Molecular docking investigation was performed to
rationalize the observed antibacterial activity and explore the
possible action mechanism of hybrid 4d.29 Crystal structure of
gyrase−DNA complex was selected as a representative target
in the Protein Data Bank (PDB code: 2XCS). The docking
mode with the lowest binding energy (−11.95 kcal mol−1) was
shown in Figure 3 and Figure S4. Molecule 4d could interact
300
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0
0
2
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Time (day)
with gyrase−DNA complex
through the formation of
hydrogen bonds between the two carbonyl groups of
naphthalimide backbone and base pairs of DNA (DGꢀ11 and
DGꢀ9). The amino group of aminothiazole was also adjacent
to DGꢀ9 base pairs with distance of 2.1 Å. Besides, derivative
4d could form two hydrogen bonds with residue SERꢀ1084 of
gyrase−DNA complex through the nitrogen atom of thiazole
Figure 2. Propensity to induce bacterial resistance of compound
4d against MRSA.
To understand the antibacterial nature of the piperazinyl
derivative 4d, time−kill kinetics assay was investigated against
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ring. Furthermore, the NH group of piperazine ring in the 4ꢀ
resistance. Preliminary research revealed that compound 4d
could not only bind with gyrase−DNA complex through
hydrogen bonds, but also form a steady 4d–DNA complex
with MRSA DNA by intercalation, which might be
responsible for the powerful bioactivity. The binding behavior
revealed that the association of HSA with molecule 4d was
spontaneous, and the hydrophobic interactions and hydrogen
bonds played significant roles in the transportation of 4d.
Thereby naphthalimide aminothiazole 4d might be a potential
multiꢀtargeting antiꢀMRSA candidate. Further researches such
as accurate antimicrobial action mechanism, metabolic
stability and synergism with clinical drugs are now underway
in our group.
position of the naphthalimide fragment was in close proximity
to the residue ASPꢀ1083, which demonstrated the necessity of
the NH group for the increased bioactivity and also
rationalized the obtained antimicrobial result that introduction
of alkyl groups at the piperazine ring of compounds 5a−e
could lead to the decreased antimicrobial potency. Compound
4d was also disclosed to be involved in hydrophobic
interactions at the active site with the hydrophobic residues.
All of these cooperative bindings might be helpful to stabilize
the 4d−enzyme−DNA supramolecular complex, which might
be responsible for the good inhibitory efficacy of compound
4d against the tested strains.
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The research of drug−DNA interactions is of great
importance and interest in rational design and construction of
novel and effective DNA−targeting drugs.30 The interaction
between the highly active compound 4d and MRSA DNA was
explored to further study the preliminary mechanism of
antimicrobial action at molecular level by UV–vis
spectroscopy. The results revealed that compound 4d could
effectively intercalate into MRSA DNA to form 4d–DNA
complex which might block DNA replication and thus exert
powerful antimicrobial activity (Supporting Information).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, compounds characterization and antiꢀ
bacterial and antifungal activities data (Table S1, Table S2), bacꢀ
tericidal kinetic assay (Figure S1), cytotoxicity (Figure S2), bacteꢀ
rial membrane permeabilization (Figure S3), molecular docking
data (Figure S4), interactions with MRSA DNA and HSA of
compound 4d (PDF).
Further binding behavior between compound 4d and HSA
was carried out to preliminarily evaluate their transportation
and pharmacokinetic properties. HSA is the principal
extracellular protein of the circulatory system,31 thorough
investigations involving the interactions between drugs and
HSA could not only provide the absorption, transportation,
distribution, metabolism and excretion properties of drugs, but
also be instructive to design, modify and screen new drug
molecules.32,33 The transportation behavior disclosed that the
association of molecule 4d with HSA was spontaneous, and
the hydrophobic interactions and hydrogen bonds played
important roles in the binding process. The calculated
parameters indicated that compound 4d could be effectively
stored and carried by HSA (Supporting Information).
AUTHOR INFORMATION
Corresponding Author
*Tel.: +86ꢀ23ꢀ68254967; Fax: +86ꢀ23ꢀ68254967.
Eꢀmail: zhouch@swu.edu.cn (ChengꢀHe Zhou)
ORCIDiD
ChengꢀHe Zhou: 0000ꢀ0003ꢀ3233ꢀ5465
Present Addresses
Author Contributions
All authors have given approval to the final version of the
manuscript.
Funding Sources
This work was partially supported by National Natural Science
Foundation of China [(No. 21672173, 21372186), the Research
Fund for International Young Scientists from International
(Regional) Cooperation and Exchange Program (No.
81650110529)] and Chongqing Special Foundation for
Postdoctoral Research Proposal (No. Xm2017184, Xm2017185).
Alicyclic amino substituents
DNAꢀtargeting fragment
had great effects on the
antimicrobial
activity.
O
N
O
Piperazine ring was the most
beneficial group for enhancing
the antimicrobial activity,
which could interact with the
gyraseꢀDNA complex.
Z
N
S
N
NH
n
Notes
The authors declare no competing financial interests.
Modification on 4ꢀposition of aminothiazole
ring was unfavorable for antibacterial activity.
The aminothiazole nucleus could interact with
the gyraseꢀDNA complex and thus exert the
powerful antimicrobial activity.
Alkyl groups on piperazine
ring were unfavorable for
the antimicrobial activity.
ACKNOWLEDGMENT
Grateful appreciation for the help of Dr. Gao WeiꢀWei in
polishing language of the revised manuscript.
Figure 4. Preliminary summary of the structureꢀactivity
relationships for naphthalimide aminothiazoles.
ABBREVIATIONS
DMF, dimethyl formamide; MIC, minimal inhibitory
concentration that completely inhibited the growth of microbes;
HSA, human serum albumin.
In conclusion,
a
series of novel naphthalimideꢀ
aminothiazole hybrids were successfully developed via a
convenient synthetic strategy. The structureꢀactivity
relationships were summarized in Figure 4. Piperazinyl
derivative 4d exhibited broad antibacterial spectrum.
Particularly, it could effectively inhibit the growth of MRSA
and Escherichia coli with MIC values of 4 and 8 ꢁg/mL,
respectively. Furthermore, compound 4d was membrane
active and low toxic against mammalian cells, and it could
rapidly kill MRSA and did not obviously trigger bacterial
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