1,2,3-Triazole-derived naphthalimides as a novel type of potential antimicrobial agents: Synthesis, antimicrobial activity, interaction with calf thymus DNA and human serum albumin

DOI: 10.1016/j.bmcl.2013.11.013

Source and publish data:

Bioorganic and Medicinal Chemistry Letters p. 308 - 313 (2014)

Update date:2022-08-29

Topics:

Authors:

Lv, Jing-Song

Peng, Xin-Mei

Kishore, Baathulaa

Zhou, Cheng-He

Read Full Text PDF DownLoad Join now for total 90,000,000 free articles

Article abstract of DOI:10.1016/j.bmcl.2013.11.013

A series of 1,2,3-triazole-derived naphthalimides as a novel type of potential antimicrobial agents were synthesized and characterized by IR, NMR and HRMS spectra. All the new compounds were screened for their antimicrobial activity against four Gram-positive bacteria, four Gram-negative bacteria and three fungi. Bioactive assay manifested that 3,4-dichlorobenzyl compound 9e and its corresponding hydrochloride 11e showed better anti-Escherichia coli activity than Norfloxacin and Chloromycin. Preliminary research revealed that compound 9e could effectively intercalate into calf thymus DNA to form compound 9e-DNA complex which might block DNA replication and thus exert antimicrobial activities. Human serum albumin could effectively store and carry compound 9e by electrostatic interaction.

Full text of DOI:10.1016/j.bmcl.2013.11.013

Accepted Manuscript

1,2,3-Triazole-derived naphthalimides as a novel type of potential antimicrobial

agents: Synthesis, antimicrobial activity, interaction with calf thymus DNA and

human serum albumin

Jing-Song Lv, Xin-Mei Peng, Baathulaa Kishore, Cheng-He Zhou

PII:

S0960-894X(13)01292-4

DOI:

http://dx.doi.org/10.1016/j.bmcl.2013.11.013

BMCL 21040

Reference:

Bioorganic & Medicinal Chemistry Letters

To appear in:

Received Date:

Revised Date:

Accepted Date:

22 June 2013

26 October 2013

9 November 2013

Please cite this article as: Lv, J-S., Peng, X-M., Kishore, B., Zhou, C-H., 1,2,3-Triazole-derived naphthalimides as

a novel type of potential antimicrobial agents: Synthesis, antimicrobial activity, interaction with calf thymus DNA

and human serum albumin, Bioorganic & Medicinal Chemistry Letters (2013), doi: http://dx.doi.org/10.1016/j.bmcl.

2013.11.013

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers

we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and

review of the resulting proof before it is published in its final form. Please note that during the production process

errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract

Leave this area blank for abstract info.

1,2,3-Triazole-derived naphthalimides as a

novel type of potential antimicrobial agents:

Synthesis, antimicrobial activity, interaction

with calf thymus DNA and human serum

albumin

Jing-Song Lv^a,b, Xin-Mei Peng^a, Baathulaa Kishore^a,#, Cheng-He Zhou^a,*

N N

R¹

R²

R¹

R²

R³

: R = H, R = Cl, R = Cl

MIC = 1 μ /mL (E. coli )

Bioorganic & Medicinal Chemistry Letters

journal hom epage: www.elsevier.com

1,2,3-Triazole-derived naphthalimides as a novel type of potential antimicrobial

agents: Synthesis, antimicrobial activity, interaction with calf thymus DNA and

human serum albumin

Jing-Song Lv^a,b, Xin-Mei Peng^a, Baathulaa Kishore^a,#, Cheng-He Zhou^a,*

^aLaboratory of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China

^bSchool of Chemistry and Chemical Engineering, Bijie University, Guizhou 551700, China

ARTICLE INFO

ABSTRACT

Article history:

Received

Revised

Accepted

Available online

A series of 1,2,3-triazole-derived naphthalimides as a novel type of potential antimicrobial

agents were synthesized and characterized by IR, NMR and HRMS spectra. All the new

compounds were screened for their antimicrobial activity against four Gram-positive bacteria,

four Gram-negative bacteria and three fungi. Bioactive assay manifested that 3,4-

dichlorobenzyl compound 9e and its corresponding hydrochloride 11e showed better anti-E.

coli activity than Norfloxacin and Chloromycin. Preliminary research revealed that compound

9e could effectively intercalate into calf thymus DNA to form compound 9e−DNA complex

which might block DNA replication and thus exert antimicrobial activities. Human serum

albumin could effectively store and carry compound 9e by electrostatic interaction.

Keywords:

Antibacterial

Triazole

Human serum albumin

Naphthalimide

DNA

The increasing emergence of drug resistance, intractable

pathogenic microorganisms and newly arising pathogens have

become an increasingly serious and challenging problem for

human health all over the world. This situation stimulates an

urgent need to develop novel antimicrobial agents with

completely different chemical structures possibly exerting

different action mechanisms from current clinical drugs.¹The

related research has become a major topic worldwide.

the treatment of antibacterial and antifungal infections.⁴This

encourages our strong interest in investigating naphthalimide-

based compounds as a novel type of potential antimicrobial

agents.

With the introduction of ‘click chemistry’, 1,2,3-triazole

derivatives have opened up a new opportunity to azole

antimicrobial agents. The large dipole moment of 1,4-substituted

1,2,3-triazoles makes them to be served as hydrogen bond

acceptor, which is favor for binding to biological target sites and

improving solubility.⁵Moreover, 1,2,3-triazole could act as an

attractive bridge group to connect two pharmacophores and/or

biologically beneficial fragments into one molecule to generate

innovative multifunctional compounds.⁶Many investigations

showed that the incorporation of alkyl chains and/or variable

aromatic substituents has an important effect on the antimicrobial

activities.⁷In particular, halogen-containing aromatic compounds

can efficiently improve the bioactivity due to the lipophilicity,

inductive and mesomeric effects that affect the diffusion and

interaction of these compounds with bacterial cells and tissues by

enhancing solubility and membrane permeability.⁸

Naphthalimides contain desirable π-conjugated backbone with

double amide moieties. This type of unique structure can easily

exert non-covalent forces such as π-π stacking, strong

hydrophobicity, hydrogen bonds and so on. Naturally,

naphthalimide-based compounds can readily interact with various

active targets in biological system, and thus exhibit diverse

biological activities.²Especially, naphthalimides as anticancer

agents have been investigated very well and shown large clinical

potentiality. A lot of work revealed that their anticancer

mechanisms were possibly involved in the intercalation into

deoxyribonucleic acid (DNA).³Recently, some researches have

also found that naphthalimides exhibited quite large possibility in

———

^#Postdoctoral fellow from Department of Chemistry, Kakatiya University, India

^*Corresponding author: Tel/Fax: +86 23 68254967; e-mail: zhouch@swu.edu.cn (C.-H. Zhou)

the combination of 1,2,3-triazole with napthalimide skeleton has

been seldom reported.

Based on above considerations and as an extension of our

continuous work,^9a,10it is of great interest for us to investigate

1,2,3-triazole-derived naphthalimides as a novel type of potential

antimicrobial agents with completely new structure from clinical

drugs. Herein, we would like to report the synthesis of novel

compounds 8a−c, 9a−j and their hydrochlorides with different

lengths of alkyl chains or halogen-substituted aralkyl moieties via

Cu(I) catalyzed 1,3-dipolar cycloaddition reaction. The prepared

compounds were screened for their antibacterial and antifungal

activities in vitro. With the aim to explore the preliminary

mechanism of action, the strong active compound 9e was further

investigated for the interaction with calf thymus DNA. The

transportation behavior of human serum albumin (HSA) to the

highly active compound 9e was also evaluated.

1. Z = C

2. Z = N

Our previous work revealed that the introduction of nitrogen-

containing heterocyclic moieties into naphthalimide backbone is

beneficial for antimicrobial activity. Imidazolyl naphthalimide

(1), 1,2,4-triazolyl compound (2) and 5-thioxo-1,2,4-triazolyl

derivative (3) all exhibited comparable or even superior

antimicrobial activity to the standard drugs Norfloxacin,

Chloromycin and Fluconazole.⁹However, to our best knowledge,

NH₂

R³

R²

R¹

CH₃

iii

R³

N N

CH₃

N₃

R²

R¹

R²

R¹

R²

6a-c

CH₃

N₃

X = Cl, Br

7a-j

R³

6,8,10:

n = 3, 5, 7

8a-c

9a-j

7,9,11:

a, R¹= H, R²= H, R³= Cl

b, R¹= H, R²= Cl, R³= H

c, R¹= Cl, R²= H, R³= H

d, R¹= Cl, R²= H, R³= Cl

e, R¹= H, R²= Cl, R³= Cl

f, R¹= F, R²= H, R³= H

g, R¹= H, R²= F, R³= H

h, R¹= H, R²= H, R³= F

i, R¹= F, R²= H, R³= F

j, R¹= H, R²= H, R³= NO₂

N N

R¹

R²

CH₃

R¹

R²

2HCl

R³

2HCl

11a-j

10a-c

Scheme 1 Reagents and conditions: i) NH₂NH₂·H₂O, CH₃CH₂OH, r.t.; ii) DMF, 3-bromoprop-1-yne, 80 ^oC; iii) corresponding alkyl azides, 1%mol

CuSO₄·5H₂O, 2%mol sodium ascorbate, THF/H₂O (2: 1, V/V), 30 ^oC; iv) corresponding halogen-substituted aryl azides, 1%mol CuSO₄·5H₂O, 2%mol sodium

ascorbate, THF/H₂O (2: 1, V/V), 30 ^oC; v) hydrogen chloride saturated THF solution, r. t.; vi) NaN₃, benzene, THF, 70 ^oC.

The target triazole naphthalimides 8a−c and 9a−j were

prepared via multi-step reactions and the synthetic process was

outlined in Scheme 1. Commercially available 4-bromo-1,8-

naphthalic anhydride was treated by hydrazine hydrate to give

intermediate N-amino-naphthalimide 4 in 86% yield. The latter

was reacted with 3-bromoprop-1-yne in DMF at 70 ºC to afford

diprop-2-ynylamino-naphthalimide 5 in 95% yield and the crystal

structure of compound 5 was obtained (CCDC 956371, see the

supplementary information). Compounds 8a-c and 9a-j were

easily synthesized in high yields ranging from 75% to 94% by

the cycloaddition of compound 5 with alkyl azides 6a−c or the

substituted benzyl ones 7a−j¹¹using catalytic amount of copper

sulfate and sodium ascorbate in THF/H₂O at room temperature.

Compounds 8a−c and 9a−i were treated by hydrogen chloride

saturated THF solution at room temperature to produce the

corresponding hydrochlorides 10a−c and 11a−i. These new

compounds were confirmed by IR, ¹H NMR, ¹³C NMR and

HRMS spectra (See the supplementary information).¹²

four Gram-negative bacteria and three fungi by two folds serial

dilution technique (See the supplementary information).¹³

All the target compounds were evaluated for their

antimicrobial activity in vitro against four Gram-positive bacteria,

Table 1

In vitro antibacterial and antifungal activities as MIC^a,b,c(μg/mL) for compounds 8−11

Gram-positive bacteria

Gram-negative bacteria

E. P.

luteus proteus coli aeruginosa dysenteriae abicans

Fungi

Compds.

MRSA

flavus

aureus

subtilis

yeast

﹥512

256

﹥512

512

﹥512

256

﹥512

﹥512 ﹥512

﹥512

512

﹥512

256

﹥512

512

﹥512 ﹥512

﹥512 64

﹥512 ﹥512

256

﹥512

128

﹥512

256

﹥512

256

﹥512

256

﹥512

256

﹥512

256

﹥512

256

﹥512

256

512

﹥512 ﹥512

512

256

512

﹥512

256

﹥512

512

﹥512

256

﹥512

512

﹥512 ﹥512

﹥512

512

﹥512

256

﹥512

10b

10c

﹥512

512

﹥512

512

256

﹥512

512

﹥512

11a

11b

11c

11d

11e

11f

11g

11h

11i

256

﹥512

256

512

256

﹥512

512

﹥512

128

256

512

256

512

﹥512

256

512

﹥512

256

﹥512 ﹥512

﹥512

256

﹥512

256

﹥512

0.5

﹥512

128

﹥512

512

﹥512

512

﹥512

512

﹥512

﹥512 ﹥512

—

256

^aMinimum inhibitory concentrations were determined by micro broth dilution method for microdilution plates.

^bA = Chloromycin, B = Norfloxacin, C = Fluconazole.

^cA. flavus, Aspergillus flavus; C. albicans, Candida albicans; M. luteus, Micrococcus luteus ATCC 4698; MRSA, Methicillin-Resistant Staphylococcus aureus

N315; S. aureus, Staphylococcus aureus ATCC25923; P. aeruginosa, Pseudomonas aeruginosa; E. Coli, Escherichia coli DH52; S. dysenteriae, Shigella

dysenteriae; B. subtilis, Bacillus subtilis; B. proteus, Bacillus proteus; B. typhi, Bacillus typhi. B. yeast, Beer yeast.

As shown in Table 1, most of the target compounds were

weak or inactive to the tested fungal strains. Interestingly, some

prepared compounds displayed good activity against

Fluconazole-insensitive A. flavus. Specially, compounds 8c and

10c showed high efficacy against A. flavus with MIC value of 16

μg/mL, which was 16-fold more potent than clinical drug

Fluconazole. For antibacterial activity, all the target compounds

also exhibited weak inhibition. However, to our surprise,

compounds 9a−j with differently substituted benzyl halides

showed excellent activity against E. coli in comparison with

other tested bacteria. Noticeably, 3,4-dichlorobenzyl derivative

9e exhibited a quite low MIC value of 1 μg/mL, which was 16-

and 2-fold more active than reference drugs Chloromycin (MIC =

16 μg/mL) and Norfloxacin (MIC = 2 μg/mL). The fluorobenzyl

compounds 9f-i, gave relatively low activity (MIC = 16−256

μg/mL). The preliminary structure activity relationship

demonstrated that substitutents in 1,2,3-triazole ring exerted great

influence on the antibacterial efficiencies. Alkyl 1,2,3-triazole

derivatives 8a−c obviously decreased antibacterial activities

(MIC = 512 μg/mL) in comparison to aryl ones 9a−j (MIC =

2−256 μg/mL). It was also observed that the introduction of

halobenzyl moieties especially 3,4-dichlorobenzyl group could

improve the antibacterial potency. Salts with improved water

solubility have been proved to be favorable for enhancing the

constructed by using the absorption titration data and linear

fitting, yielding the binding constant, K = 2.34×10⁴L/mol, R =

0.994, S.D. = 0.26 (R is the correlation coefficient. S.D. is

standard deviation).

bioactivity. It is remarkable that hydrochloride 11e exhibited

excellent anti-E. coli activity with MIC value of 0.5 μg/mL,

which was 2−fold more potent than the corresponding precursor.

This encouraged us with great interest to study the interactions of

the high bioactive compound 9e with DNA and human serum

albumin (HSA) to further explore the possible preliminary action

mechanism and transport behavior.

0.30

0.25

only NR

It is well known that DNA is an informational molecule

encoding the genetic instructions used in the development and

function of almost all the known living organisms.¹⁴Recently,

DNA as a therapeutic target has attracted much attention in

biomedical science.¹⁵There are several strategies currently used

to inhibit DNA replication. One approach is to use DNA binding

agents that can bind DNA so that it no longer acts as an effective

substrate for the DNA polymerase. Binding studies between

small molecules and DNA are important and helpful to develop

novel and efficient drugs.¹⁶Here calf thymus DNA was selected

as DNA model because of its medical importance, low cost and

ready availability properties to investigate the possible

antimicrobial action mechanism of the highly active compound

9e at molecular level by UV-vis spectroscopic methods.¹⁷

0.20

0.15

0.10

0.05

400

450

500

550

600

wavelength (nm)

Figure 2. UV-vis absorption spectra of neutral red in the presence of

DNA at pH 7.4 and room temperature. c(NR) = 2.0×10^-5mol L^-1and

c(DNA) = 0, 0.48, 0.95, 1.43, 1.90, 2.38, 2.86, 3.33, and 3.81×10^-5mol L^-

¹for curves a−i, respectively.

To further understand the interaction between compound 9e

and DNA, the absorption spectra of competitive interaction of

compound 9e were investigated. In comparison with other

common probes, neutral red (NR) shows lower toxicity, higher

stability and more convenient application than other common

probes. Furthermore, it has been sufficiently demonstrated by

spectrophotometric and electrochemical techniques that NR can

bind to DNA by an intercalative mode.¹⁹Therefore NR was

employed as a spectral probe to investigate the binding mode of

compound 9e with DNA in our work. The absorption peak of the

NR around 460 nm gradually decreased with increasing

concentration of DNA, which suggested the formation of new

DNA-NR complex (Figure 2). Figure 3 displayed the absorption

spectra of a competitive binding between NR and compound 9e

with DNA. As gradually increasing the concentration of

compound 9e, an apparent intensity increase was observed

around 460 nm. Compared to the absorption around 460 nm of

NR-DNA complex, the absorbance at the same wavelength (inset

of Figure 3) exhibited the reverse process. In addition to that, the

absorbance at 282, 350 and 375 nm extensive broadening was

also observed in the spectra. These various spectral changes were

consistent with the intercalation of compound 9e into DNA by

substituting NR in the DNA-NR complex.

1.50

0.9

Compound 9e - DNA complex

Compound 9e

DNA

0.8

0.7

0.6

0.5

1.25

1.00

0.75

0.50

0.25

0.00

Wavelength (nm)

DNA

240

260

280

300

320

Wavelength (nm)

Figure 1. UV absorption spectra of DNA with different concentrations of

compound 9e (pH = 7.4, T = 288 K). Inset: comparison of absorption at

260 nm between the compound 9e-DNA complex and the sum values of

free DNA and free compound 9e. c(DNA) = 6.55 × 10^-5mol L^-1, and

c(compound 9e) = 0, 0.50, 1.00, 1.50 and 2.00 × 10^-5mol L^-1for curves

a−f, respectively.

Hypochromism and hyperchromism are very important

spectral features to distinguish the change of DNA double-helical

structure in absorption spectroscopy. Due to the interaction

between the electronic states of intercalating chromophore and

that of the DNA base, the observed large hypochromism

suggested a close proximity of the aromatic chromophore to the

DNA bases.¹⁸With a fixed concentration of DNA, UV-vis

absorption spectra were recorded with increasing amount of

compound 9e. As shown in Figure 1, UV-vis spectra displayed

that the maximum absorption peak of DNA at 260 nm exhibited

proportional increase and slight blue shift along with the

increasing concentration of compound 9e. Meanwhile the

absorption value of simply sum of free DNA and free compound

9e was greater than the measured value of DNA-compound 9e

complex. This meant that a strong hypochromic effect existed

between DNA and compound 9e. Based on the variations in these

absorption spectra, equation (1) could be used to calculate the

intrinsic binding constant (K):

0.40

2.5

0.35

0.30

2.0

0.25

0.20

0.15

0.10

0.05

1.5

1.0

0.5

0.0

400

450

500

550

600

wavelength (nm)

DNA+NR

250

300

350

400

450

500

550

600

wavelength (nm)

Figure 3. UV Absorption spectra of the competitive reaction between

compound 9e and neutral red with DNA. c(DNA) = 6.55 × 10^-5mol L^-1,

c(NR) = 2.0 × 10^-5mol L^-1, and c(compound 9e) = 0, 0.25, 0.50, 0.75,

1.00, 1.25, 1.50, 1.75 and 2.00 × 10^-5mol L^-1for curves a−i, respectively.

(Inset) UV Absorption spectra of the system with the increasing

concentration of 9e in the wavelength range of 400−600 nm.

A⁰

ξ_C

A − A⁰ξ_D−C−ξ_C

ξ_C

(1)

_D−C−ξ_CK[9e]

A⁰and A represent the absorbance of DNA in the absence and

presence of compound 9e at 260 nm, ξ_Cand ξ_D-Cwere the

absorption coefficients of compound 9e and DNA-9e complex

respectively. The plot of A⁰/(A-A⁰) versus 1/[compound 9e] was

HSA is a transport protein and the principal extracellular

protein with a high concentration in blood plasma.²⁰Thorough

studies involving the interaction of drugs or bioactive small

molecules with serum albumins are not only beneficial to provide

proper understanding of the absorption, transportation,

distribution, metabolism and excretion properties of drugs, but

also significant to design, modify and screen of drug molecules.

Therefore, it is important to study the interaction of compound 9e

with this protein.

constant K_SVin direct proportion to temperature, which indicated

that the probable quenching mechanism of compound 9e-HSA

binding reaction was initiated by excited-state intermolecular

collision and then inactivation by radiation (dynamic quenching).

In order to reconfirm that the probable fluorescence quenching

mechanism of HSA by compound 9e was mainly initiated by

intermolecular collision, the difference absorption spectroscopy

was employed. The UV-vis absorption spectrum of HSA and the

difference absorption spectrum between HSA-compound 9e (1:1)

and compound 9e at the same concentration could be almost

superposed (Figure 5), the slight difference between the curve A

and C suggested that the probable quenching mechanism of

fluorescence of HSA by compound 9e was mainly a dynamic

quenching procedure.

In our experiment, the concentration of HSA solution was 1.0

× 10^-5M, and the concentrations of compound 9e solution

increased progressively from 0 to 1.8 × 10^-5M at an increment of

0.2 × 10^-5M. The effect of compound 9e on fluorescence of HSA

intensity at 298 K was shown in Figure 4. It was observed that a

gradual decrease of the fluorescence intensity was caused by the

increment of compound 9e, accompanied with the slight blue

shift of wavelengths in the albumin spectrum because of the

increase of hydrophobicity. The purple line showed the only

emission spectrum of compound 9e, which indicated that

compound 9e did not possess significant fluorescence features,

thus at the excitation wavelength (295 nm), the effect of

compound 9e on fluorescence of HSA could be negligible.

0.6

0.4

1.0

0.2

0.8

HSA

0.0

0.6

250

300

350

400

450

0.4

Wavelength (nm)

Figure 5. UV-vis spectra of HSA in the presence of compound 9e: A,

absorption spectrum of HSA only; B, absorption spectrum of compound

9e/HSA 1:1; C, difference between absorption spectrum of compound

9e/HSA 1:1 and compound 9e; D, absorption spectrum of compound 5e

only. c(HSA) = c(compound 9e) = 1.0 × 10^-5M.

0.2

Compound 9e only

0.0

320

340

360

380

400

420

440

Wavelength (nm)

The above experiments showed that compound 9e could

effectively interact with HSA, thereby causing hypochromic

effect of ultraviolet spectroscopy. When the electronic transfer

occurs between compound 9e and HSA, it causes energy transfer

without radiation, thereby resulting in the quenching of

fluorescence spectrum. Further molecular electrostatic

potentiality for the compound 9e was investigated by full

geometry optimizations of the studied systems which was

performed by using the B3LYP functional²³with 6-31G* basis

set. Calculation presented in this work was carried out by the

Gaussian 09²⁴program package. The results manifested that the

nucleophilic effect of carbonyl and 1,2,3-triazolyl groups (Figure

6, red region) in compound 9e might induce an electrostatic

effect with positive electricity of Lys199 in HSA. Therefore,

compound 9e and HSA might interact by electrostatic

interactions.²⁵This result was also evidenced by the value of

enthalpy change (ΔH) and entropy change (ΔS) from the van’t

Hoff equation (found, ΔH = 0.118 kJ/mol ≈ 0, ΔS = 478.30 J/mol

k), which was accordant with the literature (when ΔH ≈ 0, ΔS > 0,

the main force is electrostatic interaction).²⁶

Figure 4. Emission spectra of HSA in the presence of various

concentrations of compound 9e. c(HSA) = 1.0 × 10^-5M; c(compound

9e)/(10^-5M), a−j: from 0.0 to 1.8 at increments of 0.20; purple line shows

the emission spectrum of compound 9e only; T = 293 K, λex = 295 nm.

The decreased fluorescence intensity is usually described by

the Stern-Volmer equation (2):²¹

F₀

=1+ K_SV[Q]

(2)

In this equation, the F₀and F represent steady-state fluorescence

intensities in the absence and presence of compound 9e,

respectively. K_SVis the Stern-Volmer quenching constant, and [Q]

is the concentration of compound 9e. Hence, K_SVwas calculated

by linear regression of plot of F₀/F versus [Q] (See the

supplementary information).

Quenching mechanisms are often classified as dynamic

quenching, static quenching etc. depending on temperature and

viscosity. Because higher temperatures result in larger diffusion

coefficients, the quenching constants are expected to increase

with gradually increasing temperature in dynamic quenching.

However, the increase of temperature is likely to result in a

smaller static quenching constant due to the dissociation of

weakly bound complexes.²²

Table 2

Stern-Volmer quenching constants for the interaction of compound 9e with

HSA at various temperatures

T (K)

296

303

310

10^-4K_SV(L/mol)

R^a

0.998

0.996

S.D.^b

0.030

0.037

0.054

5.38

7.32

7.39

7.4

R^ais the correlation coefficient. S.D.^bis standard deviation.

Figure 6. Electrostatic potential of compound 9e.

Therefore, the K_SVwas calculated from Stern-Volmer plots at

each temperature. Table 2 demonstrated that the quenching

In conclusion,

a novel type of 1,2,3-triazole-derived

naphthalimides and their corresponding hydrochlorides were

Genazzani, A. A. Med. Res. Rev. 2008, 28, 278.

successfully synthesized for the first time via an easy, convenient

and efficient synthetic procedure starting from commercial 4-

bromo-1,8-naphthalic anhydride. The antimicrobial tests

demonstrated that some prepared compounds exhibited good or

even superior antibacterial and antifungal activities against the

tested strains to reference drugs. Especially compounds 9a-e and

11a-e showed 2- to 16-fold more potent activity than

Chloromycin against E. coli (MIC = 16 μg/mL). Hydrochlorides

11a-e showed even better inhibitory activities and broad

antibacterial spectrum in contrast to their precursors. The

preliminary interactive investigations of compound 9e with calf

thymus DNA revealed that compound 9e could effectively

intercalate into DNA to form compound 9e-DNA complex which

might block DNA replication and thus exerting its antimicrobial

activities. The binding research demonstrated that HSA could

effectively store and carry compound 9e by electrostatic

interaction. All these results should be a promising starting point

to optimize the structures of azole-derived naphthalimides to

access potent antimicrobial agents. Further researches, including

the extraction of E. coli DNA and its interaction with compound

9e, the in vivo bioactive evaluation, the incorporation of different

linkers (alkyl, aryl and heterocyclic moieties) and diverse azole

heterocycle (pyrazole, oxazole, carbazole, benzimidazole,

benzotriazole etc.) into naphthalimide backbone as well as

various functional groups (ester, ketone, amino ones and metal,

etc.) linked to azole ring, are now in progress in our group. All

these will be discussed in future paper.

(a) Akri, K. E.; Bougrin, K.; Balzarini, J.; Faraj, A.; Benhida, R.

Bioorg. Med. Chem. Lett. 2007, 17, 6656; (b) Karthikeyan, M. S.;

Holla, B. S.; Kumari, N. S. Eur. J. Med. Chem. 2008, 43, 309.

El-Azab, A. S.; Alanazi, A. M.; Abdel-Aziz, N. I.; Al-Suwaidan, I.

A.; El-Sayed, M. A. A.; El-Sherbeny, M. A.; Abdel-Aziz, A. A. M.

Med. Chem. Res. 2013, 22, 2360.

(a) Zhang, Y. Y.; Zhou, C. H. Bioorg. Med. Chem. Lett. 2011, 21,

4349; (b) Wang, Q. P.; Zhang, J. Q.; Damu, G. L. V.; Wan, K.; Zhang,

H. Z.; Zhou, C. H. Sci. China Chem. 2012, 55, 2134; (c) Damu, G. L.

V.; Wang, Q. P.; Zhang, H. Z.; Zhang, Y. Y.; Lv, J. S.; Zhou, C. H.

Sci. China Chem. 2013, 56, 952.

10. (a) Wei, J. J.; Wan, K.; Zhou, C. H. Bull. Korean Chem. Soc. 2011,

32, 229; (b) Wang, X. L.; Wan, K.; Zhou, C. H. Eur. J. Med. Chem.

2010, 45, 4631.

11. Barral, K.; Moorhouse, A. D.; Moses, J. E. Org. Lett. 2007, 9, 1809.

12. Experimental: Melting points are determined on X-6 melting point

apparatus and uncorrected. IR spectra were determined on a Bio-

Rad FTS-185 spectrophotometer in the range of 400–4000 cm . ¹H

-1

NMR and ¹³C NMR spectra were recorded on a Bruker AV 300

spectrometer using TMS as an internal standard. Chemical shifts

were reported in parts per million (ppm), the coupling constants (J)

were expressed in hertz (Hz) and signals were described as singlet

(s), doublet (d), triplet (t), as well as multiplet (m). The following

abbreviation was used to designate aryl group: NAPH,

naphthalimidyl. The high-resolution mass spectra (HRMS) were

recorded on an IonSpec FT-ICR mass spectrometer with ESI

resource.

Synthesis of 2-amino-6-bromo-1H-benzo[de]isoquinoline-1,3(2H)-

dione (4) A mixture of 6-bromobenzo[de]isochromene-1,3-dione

(10.00 g, 36.1 mmol) and hydrazine hydrate (80%，10 mL) in

ethanol was stirred at room temperature over night. After the reaction

came to the end (monitored by TLC, eluent, chloroform), the mixture

was filtrated and dried to give crude product 4 (9.90 g) as khaki

powder. Yield: 94%; mp: 219–220 ^oC

Acknowledgments

Synthesis

6-bromo-2-(diprop-2-ynylamino)-1H-

benzo[de]isoquinoline-1,3(2H) -dione (5) A mixture of compound 4

(1.98 g, 5.0 mmol), potassium carbonate (2.15 g, 15.0 mmol) and

propargyl bromide (1.79 g, 15.0 mmol) in DMF (15 mL) was stirred

at 80 ^oC for 48 h. After the reaction came to the end (monitored by

TLC, eluent, chloroform), the mixture was cooled to room

temperature and filtrated. The crude compound was further purified

by silica gel column chromatography (eluent, chloroform/petroleum,

3/1, V/V) to give the desired compound 5 (2.30 g) as pale yellow

−156

This work was partially supported by National Natural Science

Foundation of China [No. 21172181, 21372186, 81350110338,

81250110554 (The Research Fellowship for International Young

Scientists from International (Regional) Cooperation and

Exchange Program)], the key program from Natural Science

Foundation of Chongqing (CSTC2012jjB10026) and the

Specialized Research Fund for the Doctoral Program of Higher

Education of China (SRFDP20110182110007), the Research

Funds for the Central Universities (XDJK2012B026), Natural

Science Foundation of the Guizhou Province of China

(LKB[2012]05) and the Early Career Development Fellowship

Program of Bijie University (20102002).

solid. Yield: 76%; mp: 154

^oC; ¹H NMR (300 MHz, CDCl₃) δ

8.70 (d, J = 7.2 Hz, 1H, NAPH-H), 8.61 (d, J = 8.4 Hz, 1H, NAPH-

H), 8.46 (d, J = 7.8 Hz, 1H, NAPH-H), 8.07 (d, J = 7.8 Hz, 1H,

NAPH-H), 7.88 (t,

HC≡CCH₂), 2.15 (s, 2H, CH₂C≡CH).

Synthesis of 2-(bis((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-

J = 7.8 Hz, 1H, NAPH-H), 4.25 (s, 4H,

yl)methyl)amino)-6-bromo-1H-benzo[de]isoquinoline-1,3(2H) dione

(9a) To a solution of compound 5 (0.51 g, 1.41 mmol) in mixture (20

mL, 1/1, v/v) of THF and H₂O was added chlorobenzyl azide (0.50 g,

3.00 mmol). Hereafter sodium ascorbate (2% mmol) and copper (II)

sulfate pentahydrate (1% mmol) was added successively, and the

mixture was stirred for 3 h at room temperature. The resulting

mixture was diluted with water (10 mL) and extracted by CHCl₃(3 ×

20 mL). The organic phase was dried over anhydrous sodium sulfate,

and then concentrated under reduced pressure. The residue was

purified by silica gel column chromatography (eluent,

chloroform/methanol, 30/1, V/V) to give compound 9a as yellow

solid. Yield: 75%; mp 193–194 ^oC. IR (KBr, cm^-1): 3129, 2934, 2866,

1675, 1631, 1588, 1570, 1492, 1456, 1400, 1238, 851, 750, 646; ¹H

NMR (300 MHz, CDCl₃) δ 8.54 (d, 1H, J = 8.4 Hz, NAPH-H), 8.40

(d, 1H, J = 7.1 Hz, NAPH-H), 8.17 (d, 1H, J = 7.9 Hz, NAPH-H),

7.99 (d, 1H, J = 7.9 Hz, NAPH-H), 7.79 (t, 1H, J = 7.9 Hz, NAPH-

H), 7.62 (s, 2H, Tri-H), 7.14 (d, 4H, J = 8.3 Hz, 4-ClCH₂Ph 2,6-H),

6.98 (d, 4H, J = 8.3 Hz, 4-ClCH₂Ph 3,5-H), 5.35 (s, 4H, 4-ClPh-CH₂),

4.74 (s, 4H, Tri C⁴-CH₂); ¹³C NMR (75 MHz, CDCl₃) δ 163.57,

144.48, 134.37, 133.49, 133.22, 132.26, 131.39, 131.01, 130.57,

130.51, 129.00, 128.95, 128.53, 127.99, 123.37, 122.97, 122.12,

53.13, 49.57; HRMS (ESI) calcd. for: C₃₂H₂₃BrCl₂N₈O₂[M+Na]⁺,

723.0397; found, 723.0392.

References and notes

(a) Zhang, L.; Peng, X. M.; Damu, G. L. V.; Geng, R. X.; Zhou, C. H.

Med. Res. Rev. 2013, DOI: 2129010.1002/med; (b) Peng, X. M.; Cai,

G. X.; Zhou, C. H. Curr. Top. Med. Chem. 2013, 13 (in press); (c)

Peng, X. M.; Damu, G. L. V.; Zhou, C. H. Curr. Pharm. Des. 2013,

19, 3884; (d) Zhou, C. H, Wang Y. Curr. Med. Chem. 2012, 19, 239.

(a) Horton, J. K.; Wilson, S. H. Mol. Cancer Res. 2013, 11, 13; (b)

Grabchev, I.; Staneva, D.; Betcheva, R. Cur. Med. Chem. 2012, 19,

4976; (c) Jeong, Y.; Yoon, J. Inorg. Chim. Acta 2012, 381, 2; (d)

Baathulaa, K.; Xu, Y.; Qian, X. Nat. Protoc. 2011, 6, 1990; (e) Duke,

R. M.; Veale, E. B.; Pfeffer, F. M.; Kruger, P. E.; Gunnlaugsson, T.

Chem. Soc. Rev. 2010, 39, 3936; (f) Ingrassia, L.; Lefranc, F.; Kiss,

R.; Mijatovic, T. Curr. Med. Chem. 2009, 16, 1192; (g) Lv, M.; Xu,

H. Curr. Med. Chem. 2009, 16, 4797; (h) Sekar, N. Colourage 2009,

56, 58.

(a) Braňa, M. F.; Ramos, A. Curr. Med. Chem. Anti-Cancer Agents

2001, 1, 237.; (b) Costanza, M. E.; Berry, D.; Henderson, I. C.;

Ratain, M. J.; Wu, K.; Shapiro, C.; Duggan, D.; Kalra, J.; Berkowitz,

I.; Lyss, A. P. Clin. Cancer Res. 1995, 1, 699.

(a) Abuo-Rahma, G. E. D. A. A.; Sarhan, H. A.; Gad, G. F. M.

Bioorg. Med. Chem. 2009, 17, 3879; (b) Mohammadkhodaei, Z.;

Mokhtari, J.; Nouri, M. Color. Technol. 2010, 126, 81.

Synthesis

2-(bis((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-

yl)methyl)amino)-6-bromo-1H-benzo[de]isoquinoline-1,3(2H)-dione

(11a) To a solution of compound 9a (0.51 g, 1.41 mmol) in mixture

(20 mL, 1/1, v/v) of THF and H₂O was added anhydrous HCl in THF

(1 mL), the mixture was stirred for 3 h at room temperature. After the

reaction came to the end (monitored by TLC, eluent, chloroform),

Collin, M. P.; Hobbie, S. N.; Böttger, E. C.; Vasella, A. Helv. Chim.

Acta 2008, 91, 1838.

Tron, G. C.; Pirali, T.; Billington, R. A.; Canoniico, P. L.; Sorba, G.;

solvents were removed to give compound 11a as bright yellow solid.

Yield: 98%; mp > 200 ^oC. IR (KBr, cm^-1): 3149, 2934, 2866, 1666,

1632, 1587, 1571, 1492, 1456, 1400, 1229, 839, 747, 649; ¹H NMR

(300 MHz, DMSO-d6) δ 8.54 (d, 1H, J = 8.1 Hz, 1H, NAPH-H),

8.42 (d, 1H, J = 7.1 Hz, NAPH-H), 8.19 (s, 2H, NAPH-H), 8.06 (s,

2H, Tri-H), 7.98 (t, 1H, J = 7.7 Hz, NAPH-H), 7.21 (d, 4H, J = 8.2

Hz, 4-ClCH₂Ph 3,5-H), 7.02 (d, 4H, J = 8.2 Hz, 4-ClCH₂Ph 3,5-H),

5.48 (s, 4H, 4-ClPh-CH₂), 4.64 (s, 4H, Tri C4-CH₂); ¹³C NMR (75

MHz, DMSO-d6) δ 163.30, 143.60, 135.56, 133.15, 132.90, 132.25,

131.78, 131.58, 130.21, 129.71, 129.57, 129.23, 128.85, 128.32,

124.90, 123.40, 122.61, 52.08, 48.77; HRMS (ESI) calcd. for:

₃₂H₂₅BrCl₄N₈O₂[M-2Cl-2H+Na]⁺, 723.0402; found, 723.0404.

13. National Committee for Clinical Laboratory Standards Approved

Standard Document. M27-A2, Reference Method for Broth Dilution

Antifungal Susceptibility Testing of Yeasts, National Committee for

Clinical Laboratory Standards, wayne, PA, 2002.

14. Cui, S. F.; Ren, Y.; Zhang, S. L.; Peng, X. M.; Damu, G. L. V.; Geng,

R. X.; Zhou, C. H. Bioorg. Med. Chem. Lett. 2013, 23, 3267.

15. (a) Paul, B. K.; Guchhait, N. J. Phys. Chem. B. 2011, 115, 11938; (b)

Denning, E. J.; MacKerell, A. D. Jr. J. Am. Chem. Soc. 2011, 133,

5770.

16.

(a) Shi, Y.; Guo, C.; Sun, Y.; Liu, Z.; Xu, F.; Zhang, Y.; Wen, Z.; Li,

Z. Biomacromolecules 2011, 12, 797; (b) Ding, Y. H.; Zhang, L.;

Xie, J.; Guo, R. J. Phys. Chem. B. 2010, 114, 2033; (c) Elder, R. M.;

Emrick, T.; Jayaraman, A. Biomacromolecules 2011, 12, 3870.

17. Berdis, A. J. Biochemistry 2008, 47, 8253.

18. (a) Zhang, G.; Fu, P.; Wang, L.; Hu, M. J. Agric. Food Chem. 2011,

59, 8944; (b) Kanakis, C. D.; Nafisi, S.; Rajabi, M.; Shadaloi, A.;

Tarantilis, P. A.; Polissiou, M. G.; Bariyanga, J.; Tajmir-Riahi, H.

A. Spectroscopy 2009, 23, 29.

19. Ni, Y.; Dua, S.; Kokot, S. Anal. Chim. Acta 2007, 584, 19.

20. (a) Zhang, S. L.; Damu, G. L. V.; Zhang, L.; Geng, R. X.; Zhou, C.

H. Eur. J. Med. Chem. 2012, 55, 164; (b) Zhang, S. L.; Chang, J. J.;

Damu, G. L. V.; Geng, R. X.; Zhou, C. H. Med. Chem. Comm. 2013,

4, 839; (c) Zhang, S. L.; Chang, J. J.; Damu, G. L. V.; Fang, B.;

Zhou, X. D.; Geng, R. X.; Zhou, C. H. Bioorg. Med. Chem. Lett.

2013, 23, 1008.

21. Lakowicz, J. R. Principles of Fluorescence Spectroscopy, third ed.,

Springer, New York, 2006, pp. 11–12.

22. Ibrahim, N.; Ibrahim, H.; Kim, S.; Nallet, J. P.; Nepveu, F.

Biomacromolecules 2010, 11, 3341.

23. Becke, A. D. J. Chem. Phys. 1993, 98, 5648.

24. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,

M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;

Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.

P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada,

M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;

Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;

Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.;

Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;

Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant,

J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.;

Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;

Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin,

A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;

Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;

Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;

Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,

Revision A.02; Gaussian, Inc., Wallingford, CT, 2009.

25. Nakajou, K.; Watanabe, H.; Kragh-Hansen, U.; Maruyama, T.;

Otagiri, M. Biochim. Biophy. Acta 2003, 1623, 88.

26. Ross, P. D.; Subramanian, S. Biochemistry 1981, 20, 3096.

Products guided by the article

Product name:Hexyl azide

Cas No:6926-45-0

R&D Labs maybe for 6926-45-0

TIANJIN GST CHEMICAL TECHNOLOGY CO., LTD

Contact:+86-22-25210964

Address:Room. 208, No. -12-C, No. 13, Xinbei Road, Tanggu District, New Haixin Area, Tianjin City, China
Frapp's Chemical (NFTZ) Co.,Ltd

Contact:+86-576-86137892

Address:General Chamber of Commercial Building, 159 Wanchang Middle Road, Wenling, Zhejiang, China
Xiamen XM-Innovation Chemical Co., Ltd

Contact:+86-592-3216205

Address:Unit Q, 11/F, No.1 Office Building, Wuyuan Bay Business Center, Huli District, Xiamen City, Fujian Province, P.R.C
MENGNA

Contact:18698110882

Address:1303 No2 building,LuoMa Garden,YongAn Road,Hexi District,Tianjin city
Springchem New Material Technology Co.,Limited

website:http://www.spring-chem.com

Contact:86-21-62885108

Address:602B, Building 1, No. 641, Tianshan Road

Relevant to this article

Synthesis and fungicidal activity of N-2-(3-methoxy-4-propargyloxy) phenethyl amides. Part 3: Stretched and heterocyclic mandelamide oomyceticides

Doi:10.1002/ps.1308
(2007)
Doi:10.1021/jo01087a605
(1959)
Synthesis and melting behaviour of Bi, Sn and Sn-Bi nanostructured alloy

Doi:10.1016/j.jallcom.2014.08.122
(2015)
Fibrous testing papers for fluorescence trace sensing and photodynamic destruction of antibiotic-resistant bacteria

Doi:10.1039/d0tb00002g
(2020)
Selective mono- and di{(perfluoroalkyl)acylation} of ferrocene

Doi:10.1016/j.jfluchem.2003.08.002
(2003)
Role of curcumin in the conversion of asparagine into acrylamide during heating

Doi:10.1007/s00726-011-1179-5
(2013)

Article Doi

1,2,3-Triazole-derived naphthalimides as a novel type of potential antimicrobial agents: Synthesis, antimicrobial activity, interaction with calf thymus DNA and human serum albumin

DOI: 10.1016/j.bmcl.2013.11.013

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.bmcl.2013.11.013

Full text of DOI:10.1016/j.bmcl.2013.11.013

Products guided by the article

R&D Labs maybe for 6926-45-0

Relevant to this article

Hot Product