Discovery of potential antifungal triazoles: Design, synthesis, biological evaluation, and preliminary antifungal mechanism exploration

Article abstract of DOI:10.1039/c7md00112f

A series of triazoles as miconazole analogues was designed, synthesized and characterized by IR, NMR, MS and HRMS. All the newly prepared compounds were screened for their antifungal activities against five kinds of fungi. The bioactive assay showed that most of the synthesized compounds exhibited good or even stronger antifungal activities in comparison with the reference drugs miconazole and fluconazole. In particular, the 3,4-dichlorobenzyl derivative 5b showed a comparable or superior activity against all the tested fungal strains to standard drugs, and formed a supramolecular complex with CYP51 via the hydrogen bond between the 4-nitrogen of the triazole nucleus and the histidine residue. Preliminary experiments revealed that both of the active molecules 5b and 9c could intercalate into calf thymus DNAs, which might block DNA replication to exhibit their powerful antifungal abilities. Further studies indicated that compound 5b might be stored and transported by human serum albumin through hydrophobic interactions, specific electrostatic interactions and hydrogen bonds. These results strongly suggested that compound 5b could serve as a promising antifungal candidate.

Full text of DOI:10.1039/c7md00112f

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Received 00th January
20xx,
Discovery of potential antifungal triazoles: Design, synthesis,
biological evaluation, and preliminary antifungal mechanism
exploration†‡
Yuan Zhang,§a Guri L V Damu, §#a Sheng-Feng Cui, §a Jia-Li Mi,b Vijai Kumar Reddy Tangadanchu#a
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
and Cheng-He Zhou*a
A series of triazoles as miconazole analogues were designed, synthesized and characterized by IR, NMR, MS and HRMS
spectra. All the newly prepared compounds were screened for their antifungal activities against five fungi. The bioactive
assay showed that most of the synthesized compounds exhibited good or even stronger antifungal activities in comparison
with reference drugs miconazole and fluconazole. Especially, 3,4-dichlorobenzyl derivative 5b showed comparable or
superior activity against all the tested fungal strains to standard drugs, and formed supramolecular complex with CYP51
via the hydrogen bond between the 4-nitrogen of triazole nucleus and histidine residue. Preliminary experiments revealed
that both of the active molecules 5b and 9c could intercalate into calf thymus DNA, which might block DNA replication to
exert their powerful antifungal abilities. The further study indicated that compound 5b might be stored and transported by
human serum albumin through hydrophobic interactions, specific electrostatic interactions and hydrogen bonds. These
results strongly suggested that compound 5b could be served as a promising antifungal candidate.
of miconazole including the poor aqueous solubility, limited active
spectrum, a lack of oral absorption and occasional undesirable side
effects when administered at therapeutic doses intravenously, have
1. Introduction
The rapidly emerging multidrug resistant microrganisms over the
world have exerted a great threat to human health. The development
of novel antimicrobial drugs is an important approach to combat the
increasingly frequent pathogenic drug resistance, 1 which has been a
major task worldwide for medicinal chemists. Currently, the
modification of available clinic drugs has been acknowledged to be a
prominent method to exploit new drugs with a view of reducing
cross resistance.2
Miconazole is the first wellꢀknown commercially significant
imidazole drug with a structure of αꢀaryl azolyl ethanol, this drug
has a wellꢀestablished treatment for many mycotic infections with
low toxicity and excellent safety profile.3 It has been generally
considered that miconazole acts by competitive inhibition via
directly inhibiting Cytochrome P450 (CYP450)ꢀdependent enzyme,
14αꢀlanosterol demethylase (CYP51), which results in a lethal
disruption in the normal sterol biosynthesis chain in fungi, but it is of
minimal consequence to mammals.4 Nevertheless, the shortcomings
imposed restriction on its efficacy and administrable mode.5 It is
conceivable that conformationally constrained miconazole analogues
mimicing the bioactive conformation might exhibit a higher level of
intrinsic antifungal potency.6 Furthermore, the analogues of
miconazole or other further structural modification of the analogues,
could produce candidates from this series for preclinical
progression.7 Therefore, much effort has been devoted to its
structural modification and the development of its analogues and
many excellent achievements have been obtained.8 Lots of
miconazole analogues such as econazole, fenticonazole, sulconazole
and so on have been successfully developed, marketed and
extensively used in clinic for the treatment of fungal infection with
high safety, low toxicity and few adverse effects.9
Triazole nucleus has been playing an important role in antiꢀ
infective therapy and especially triazoleꢀbased fluconazole as firstꢀ
choice antifungal drug displays advantages like excellent safety
profile, favorable pharmacokinetic characteristics and wide
biological activities. A large number of triazole antifungal drugs
have been widely used in clinic such as fluconazole, voriconazole,
itraconazole and posaconazole.10 Additionally, the toxicity caused by
imidazole antifungal drugs is generally considered to result from its
strong coordination potency with Fe2+ ion, while triazole with lower
electronic density as an isostere of imidazole could helpfully reduce
toxicity due to inferior coordination potency to imidazole nucleus. 11
The structure activity relationship (SAR) also suggests that the
imidazole ring is susceptible to metabolic degradation in vivo and the
introduction of triazole ring to the third generation azole antifungal
a
Institute of Bioorganic
& Medicinal Chemistry, Key Laboratory of Applied
Chemistry of Chongqing Municipality, School of Chemistry and Chemical
Engineering, Southwest University, Chongqing 400715, PR China. E-mail:
zhouch@swu.edu.cn; Fax: +86 23 68254967; Tel: +86 23 68254967
b People’s Hospital of Suining, Sichuan 629000, PR China.
† The authors declare no competing interests.
‡ Electronic supplementary informaꢀon (ESI) available. See DOI: 10.1039/
x0xx00000x
§ These authors contributed equally to this work.
#
Postdoctoral fellow from Indian Institute of Chemical Technology (IICT), India.
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drugs is much less susceptible to metabolic degradation in vivo and single triazolyl compounds by multiꢀsite binding through the
successfully used in clinic.12 Furthermore, so far little literature has incorporation of another triazole fragment, thus enhancing
reported the insertion of triazole ring to miconazole scaffold.
bioactivities and therapeutic effect.14 Some bisꢀtriazole antifungal
drugs like fluconazole and fosfluconazole have been widely used in
clinic with the high stability, low cytotoxicity and efficient
administration mode.15 This encourages the insertion of an additional
triazole ring to target framework. Moreover, it is well known that
coumarin nucleus has a large conjugated system, possesses desirable
electronic and chargeꢀtransport properties, and these characteristics
result in the extensive potential applications in antimicrobial
aspects.16 In particular, along with the rise of resistant Candida
strains, the research on coumarins as antifungal alternative have
become more and more active.17 Thereby, coumarin fragment was
also incorporated into target molecules to study its contribution to
the antifungal activities. Moreover, triazoliums were reported to
helpfully improve antimicrobial activity,18 so some compounds were
further transformed into triazoliums. This triazole type of
miconazole analogues might be expected to exhibit large potentiality
against fungal strains. Therefore, all the newly synthesized
compounds were evaluated in vitro for their antifungal activities and
the SAR was also discussed. The supramolecular interaction of the
most active molecule with miconazoleꢀtargeting CYP51 was
investigated, and deoxyribonucleic acid (DNA) was selected as a
target to further explore the possible antifungal mechanism by
studying the interaction with the active compounds. The binding
behavior of the active compound with human serum albumin (HSA)
by experimental and computational methods was performed in order
to understand its absorption, distribution, and metabolism.
Fig. 1 Design of triazole type of miconazole analogues.
In view of the above observations and on the basis of our
previous work on triazoles,13 herein we introduced triazole nucleus
as isostere of imidazole ring on miconazole, substituted chlorine on
benzene ring by fluorine, and replaced dichlorophenyl group of
miconazole by alkyl chains with different length, various substituted
benzenes and heterocyclic substituents to generate a triazole class of
miconazole analogues (Fig. 1). Bisꢀtriazoles have been
acknowledged to possess better water solubility, strengthened
targeting ability and improved physicochemical properties than
o
Scheme 1. Reagents and conditions: (i) ClCH2COCl, AlCl3, CH2Cl2, 20 C; (ii) triazole, K2CO3, CH3CN, 25−0 oC; (iii) NaBH4, MeOH, 0−2 5 oC, 4 h; (iv) substituted
benzyl halides, NaH, dry THF, N2, 0−74 oC, 5−7 h; (v) substituted benzyl halides, K2CO3, CH3CN, 80 oC, 8–12 h; (vi) alkyl halides, NaH, dry THF, N2, 0−45 oC, 4–6
h; (vii) NaH, dry THF, dibromoalkanes, N2, 0–45 oC, 6–8 h; (viii) NaH, dry THF, N2, coumarin alkyl halides, 0−75 oC, 8–12 h.
weak base potassium carbonate to afford triazole derivative 3 in a
high yield of 85%. Compound
borohydride to yield the triazolyl ethanol 4 in an almost quantitative
3 was reduced with sodium
2. Chemistry
Commercially available mꢀdifluorobenzene
1 was acylated to
yield of 97%, which was further treated with a series of substituted
produce intermediate 2, and then was reacted with triazole in the
2 | J. Name., 2012, 00, 1-3
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benzyl halides in dry tetrahydrofuran (THF) using sodium hydride as comparable efficacies (MIC = 4–16 ꢁg/mL) than miconazole
base under the atmosphere of nitrogen to afford the corresponding (MIC = 4–256 ꢁg/mL) and prominently its antiꢀA. flavus
ether triazoles 5a–h with yields ranging from 33.4% to 92.9% and activity was 16ꢀfold more potent than fluconazole and
alkyl triazole derivatives 7a–e with yields of 21.9–75.6%. Bisꢀ miconazole. However, 4ꢀnitrobenzyl compound 5d had nearly
triazoles 8a–c in yields of 62.1–67.2% could be obtained by no inhibitory potentiality against the tested fungi with MICs
nucleophilic substitution of triazolyl ethanol 4 with dibromoalkanes. more than 256 ꢁg/mL. Additionally, 2ꢀfluorobenzyl miconazole
Coumarin alkyl halides19 were coupled with triazolyl alcohol 4 to analogue 5e (MIC = 0.5 µg/mL) gave strong antifungal
produce coumarin derivatives 9a–c with yields of 42.6–62.6%. The efficacies against C. albicans strain, which was superior to
further quaternization of triazoles 5a–h by halobenzyl halides standard drug fluconazole (MIC = 1 µg/mL) and miconazole
produced the corresponding triazoliums 6a–e in moderate to good (MIC = 4 µg/mL). Thus, 2ꢀfluorobenzyl analogue 5e might be
yields after purification. All the new synthesized conjugates were hopeful to be served as a new potential antiꢀC. albicans drug
characterized using IR, 1HNMR, 13C NMR, MS and HRMS (ESI‡).
that deserves further investigation. Against fungi C. utilis and
B. yeast, 2ꢀchlorobenzyl compound 5f and 3ꢀchlorobenzyl
compound 5g showed comparable inhibitory activities with
fluconazole (MIC = 8 and 16 ꢁg/mL, respectively), while the 4ꢀ
chlorobenzyl analogue 5h presented enhanced potencies in the
inhibition of C. utilis and A. flavus with MIC of 4 and 8 ꢁg/mL
respectively as compared to compounds 5f and 5g, indicating
that the 4ꢀchloro substitution on benzene ring was more
beneficial than replacement at other position. It could also be
deduced that chloro and fluoro substituents on benzene ring
exerted more important influence on antifungal activities than
nitro group, since 3,4ꢀdichlorobenzyl compound 5b, 2,4ꢀ
difluorobenzyl derivative 5c and 2ꢀfluorobenzyl miconazole
analogue 5e could effectively inhibit the growth of most tested
fungal strains at low concentrations, which were much more
effective than nitrobenzyl compound 5d. It was also noticed
that disubstituted benzyl triazoles (MIC = 0.5–16 ꢁg/mL)
generally exhibited higher potency than these monosubstituted
benzyl compounds (MIC = 0.5–32 ꢁg/mL).
3. Results and discussion
3.1 Antifungal activities
The obtained results were depicted in Table 1. Minimal
inhibitory concentration (MIC, ꢁg/mL) is defined as the lowest
concentration of target compounds that completely inhibited the
growth of fungi (provided by the School of Pharmaceutical
Sciences, Southwest University and the College of Pharmacy,
Third Military Medical University), and determined by means
of standard twoꢀfold serial dilution method in 96ꢀwell microtest
plates according to the National Committee for Clinical
Laboratory Standards (NCCLS).20 Table 1 revealed that most of
the newly synthesized triazoles showed comparable or even
superior inhibitory activities against all the tested fungal strains
to standard drugs fluconazole and miconazole except for
compounds
efficacy.
4
,
5d
,
6c
,
8c and 9a without obvious antifungal
The quaternization of halobenzyl compounds 5a–e could afford
corresponding triazoliums 6a–e, which got totally decreased
antifungal activities in comparison with their precusors 5a–e.
Especially, the ionized product 6c with MICs more than 256 ꢁg/mL
showed much lower efficiencies than 2,4ꢀdiflurobenzyl compound
5c and reference drugs. Therefore, it was suggested that the Nꢀ3
unsubstituted triazole ring was a necessary functional group to exert
the antifungal activity against fungal strains. Nonetheless, most of
them with MICs in the range of 16–64 ꢁg/mL showed better antiꢀA.
flavus activity than fluconazole and miconazole (MIC = 256 ꢁg/mL).
On the other hand, alkyl derivatives 7a–e exhibited moderate to
weak antifungal efficiencies towards the tested fungi in comparison
with aryl compound 5a-h and reference drugs. However, target
compounds 7a–e showed better antifungal activities against A. flavus
than fluconazole and miconazole. Furthermore, the propyl
miconazole analogue 7a displayed comparable antiꢀC. albicans
potencies and 8ꢀfold more potent inhibitory activity against C.
mycoderma (MIC = 4 and 1 ꢁg/mL, respectively) in comparison
with miconazole (MIC = 4 and 8 ꢁg/mL, respectively). Butyl
substituted compound 7b gave comparable or 2ꢀfold more potent
potency against C. utilis in comparison with fluconazole (MIC= 8
ꢁg/mL) and miconazole (MIC= 16 ꢁg/mL). When the alkyl group
was extended to octyl group, the produced octyl derivative 7d could
restrain the growth of C. albicans at 4 ꢁg/mL, which was identical to
miconazole. The replacement of alkyl substituent with dodecyl
group produced dodecyloxyl derivative 7e, which had a 2ꢀfold
increased potentiality (MIC = 8 µg/ mL) against B. yeast in
The substitution of hydroxyl group in compound
4
by
halobenzyl halides yielded the triazole type of miconazole
analogues 5a–h (MIC = 0.5–32 µg/mL) with comparable or
even superior inhibitory activities against all the tested fungal
strains to standard drugs fluconazole (MIC = 1–16 µg/mL) and
miconazole (MIC = 4–32 µg/mL) except for 4ꢀnitrobenzyl
compound 5d with MICs more than 256 ꢁg/mL. Especially
compounds 5a, 5b, 5c and 5e could efficiently inhibit the
growth of A. flavus strain in vitro with MIC values ranging
from 8 to 16 µg/mL, which were 16ꢀfold and 32ꢀfold more
active than fluconazole and miconazole (MIC = 256 µg/mL)
respectively. B. yeast strain was quite sensitive to target
compounds 5a (MIC = 8 µg/mL), 5b (MIC = 0.5 µg/mL) and
5c (MIC = 4 µg/mL) in comparison with miconazole (MIC = 32
µg/mL) and fluconazole (MIC = 16 µg/mL) and it was apparent
that 3,4ꢀdichlorobenzyl compound 5b exhibited the highest
antifungal activity among these conjugates, which was 64ꢀfold
more potent than miconazole. Prominently, the 3,4ꢀ
dichlorobenzyl derivative 5b displayed not only stronger
antifungal efficacies, but also broader bioactive spectrum
against all the tested strains at low inhibitory concentrations
(MIC
= 0.5–8 µg/mL) in comparison with references
fluconazole and miconazole. This revealed that 3,4ꢀ
dichlorobenzyl triazole 5b could be served as a lead compound
in the development of more effective boardꢀspectrum antifungal
agents. 2,4ꢀDiflurobenzyl triazole also exhibited superior or
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comparison with standard drug miconazole (MIC = 16 µg/mL). utilis and B. yeast to corresponding reference drugs fluconazole
These results indicated that the length of alkyl chain exerted no and miconazole, which might be a consequence of the
obvious effects on biological activities. Nevertheless, these alkyl shortening of the alkyl linker length between triazole ether. In
substituted analogues behaved less active than aryl containing addition, the substitution of one triazole fragment on
compounds, which manifested that aryl groups were more favorable compounds 8a–c by coumarin scaffold could generate
than alkyl chains to some extent.
The incorporation of another triazole fragment at the alkyl comparison with 8a–c and precursor
coumarins 9a–c with increased inhibitory efficacies in
and especially
4,
end of compounds 7a-c afforded bisꢀtriazole compound 8a–c coumarins 9b and 9c containing (CH2)4 and (CH2)6 moieties
with lower antifungal potencies than 7a–c. Especially, butylꢀ exhibited extremely high antifungal activities against C.
and hexylꢀbridged bisꢀtriazoles 8b and 8c showed middle to albicans and C. mycoderma with MIC values ranging from 1 to
poor antifungal activity against all the tested strains. However, 4 µg/mL. Particularly, compound 9c gave the most prominent
compounds 8a–c generally gave better activities against almost antiꢀC. mycoderma activity with MIC of
1 ꢁg/mL in
the tested fungi than triazole alcohol and it was noteworthy comparison with standard drugs. It was indicated that in the
4
that propylꢀlinked bisꢀtriazole 8a with MIC of 8 ꢁg/mL coumarin series the suitable increase of carbon linker length
displayed comparable or better fungistatic abilities against C. was favourable to the fungi inhibitory efficacies.
Table 1 In vitro antifungal data as MIC (µg/mL) for triazoles 4–9 a
Fungi
Fungi
Compds
Compds
C.
utilis
A.
flavus
B.
yeast
C.
albicans
C.
C.
utilis
A.
flavus
B.
yeast
C.
C.
mycoderma
albicans mycoderma
4
256
4
1
>256
16
8
16
>256
32
16
32
8
32
>256
8
0.5
4
>256
16
16
16
16
64
16
128
8
1
256
16
4
6e
7a
7b
7c
7d
7e
8a
8b
32
32
8
16
16
>256
8
128
>256
256
16
64
128
128
32
128
128
256
64
256
256
32
16
256
256
32
64
128
32
16
8
32
4
64
64
4
>256
64
128
256
128
4
8
1
5a
5b
5c
5d
5e
5f
5g
5h
6a
6b
6c
6d
64
32
16
>256
256
128
256
256
2
4
4
8
>256
4
8
8
4
>256
0.5
8
16
8
16
32
>256
8
>256
2
8
16
16
32
64
>256
16
8
64
128
128
4
16
16
32
8c
9a
9b
8
32
>256
32
64
>256
16
128
64
9c
16
8
16
2
1
4
1
4
8
Fluconazole
Miconazole
a C. utilis, Candida utilis; A. flavus, Aspergillus flavus; B. yeast, Beer yeast; C. albicans, Candida albicans; C.mycoderma, Candida mycoderma.
3.2 Molecular modeling
3.3 Interactions of compounds 5b and 9c with calf thymus DNA
DNA as a significant information molecule encoding genetic
instructions has been regarded as an important target for studies of
bioactive molecules like antimicrobial drugs to explore the possible
antimicrobial action mechanism. The interaction studies of
compound 5b (exhibiting good inhibition against all fungal strains)
and 9c with a coumarin scaffold (displaying high efficiency in
inhibiting the growth of C. albicans and C. mycoderma) with calf
thymus DNA (SigmaꢀAldrich, St. Louis, MO, USA) on molecular
level were carried out in vitro by UV–vis method.
Fig. 2 Three-dimensional conformation of compound 5b docked in the active
3.3.1 Absorption spectra of DNA in the presence of compounds
5b and 9c
site of CYP51.
To further rationalize the observed antifungal activity, a flexible
ligandꢀreceptor docking investigation was undertaken. The crystal
structure data (CYP51, PDB code: 5V5Z) was obtained from the
RCSB protein data bank. Miconazole analogue 5b was selected to
dock with CYP51. According to the docking results (Fig. 2), the
binding energy and constant of CYP51 with target compound 5b is ꢀ
7.97 kcal/mol and 7 × 105 Mꢀ1, respectively. The triazolyl moiety
could bind with the active sites of CYP51 through a nonꢀcovalent
binding mode. Noticeably, the nitrogen atom at 4ꢀposition in triazole
ring formed hydrogen bond with histidine residue of CYP51.
It is wellꢀknown that hypochromism and hyperchromism are very
important spectral features to distinguish the change of DNA doubleꢀ
helical structure in absorption spectroscopy. The UV–vis spectra
(Figs. 3 and 4) showed that the maximum absorption peak of DNA
at 260 nm exhibited proportional increase with the increasing
concentration of compounds 5b and 9c. Furthermore, it was
indicated that the measured value of 5b–DNA complex was a little
smaller than the absorption value of the simply sum of free DNA and
free compound 5b (inset of Fig. 3). This meant a weak hypochromic
effect existed between DNA and compound 5b, which was a
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between the 5b–DNA complex and the sum values of free DNA and free
compound 5b.
consequence of interaction between the electronic states of
intercalating chromophore and that of the DNA base, and it also
indicated a close proximity of the aromatic chromophore to the DNA
bases, while the measured value of 9c–DNA complex was higher
than the sum of free DNA and free compound 9c (inset of Fig. 4),
which suggested a hyperchromism between 9c and DNA and further
proved the conformational change in the DNA duplex. This might be
resulted from nonꢀcovalent interactions between the complexes and
DNA, which led to the part uncoiling of the DNA helix and the
exposure of some previously embedded DNA bases.
1.8
1.1
DNA+compound 9c
1.0
DNA-9c complex
0.9
1.5
0.8
0.7
i
1.2
0.9
0.6
0.3
0.0
0.6
0.5
0.4
0.0
0.5
1.0
1.5
2.0
10-5[Q]
a
On the basis of the variations in the absorption spectra of DNA
upon binding to 5b and 9c, equation 1 can be utilized to calculate the
binding constant (K).
DNA
250
300
Wavelength (nm)
350
A0
A − A0 ξD−C − ξC ξD−C − ξC K[Q]
ξC
ξC
1
=
+
×
Fig. 4 UV absorption spectra of DNA with different concentrations of
compound 9c at pH 7.4 and room temperature. c(DNA) = 5 × 10-5 mol/L, and
c(compound 9c) = 0–2.1 × 10-5 mol/L for curves a–i respectively at an
increment of 0.26 × 10-5 mol/L. Inset: comparison of absorption at 260 nm
between the 9c–DNA complex and the sum values of free DNA and free
compound 9c.
(1)
A0 and A represent the absorbance of DNA in the absence and
presence of compounds 5b and 9c at 260 nm, ξC and ξD–C are the
absorption coefficients of compounds 5b or 9c and 5b–DNA or 9b–
DNA complexes respectively. The plot of A0/(A–A0) versus
1/[compound 5b or 9c] is constructed by using the absorption
titration data and linear fitting (ESI‡, Figs. S10 and S11), yielding
the binding constant, K = 1.04 × 104 or 5.06 × 104 L/mol, R = 0.9936
or 0.9964, SD = 0.3181 or 0.0729 respectively (R is the correlation
coefficient. SD is standard deviation). Coumarin 9c had a higher
binding constant than triazole 5b, demonstrating that compound 9c
could combine more tightly with DNA, which might be resulted
from the existence of large conjugated coumarin backbone.
3.3.3 Absorption spectra of competitive interaction of
compounds 5b or 9c and NR with DNA
The competitive binding between NR and 5b or 9c with DNA was
observed in the absorption spectra (ESI‡, Figs. S13 and S14). With
the increasing concentration of compound 5b or 9c, an obvious
intensity increase was observed around 275 nm. In comparison with
the absorption around 460 or 530 nm of NR–DNA complex, the
absorbance at the same wavelength presented a reverse process
(ESI‡, inset of Figs. S13 and S14). These various spectral changes
suggested that compound 5b or 9c could intercalate into DNA by
substituting NR in the DNA–NR complex, which might further
block DNA replication and thus exert their powerful antifungal
activities.
3.3.2 Absorption spectra of NR interaction with DNA
Neutral red (NR) as a planar phenazine dye with low toxicity, high
stability and convenient application is structurally similar to other
planar dyes acridine, thiazine and xanthene and it has been
evidenced that the binding of NR with DNA belongs to intercalative
binding type.21 Therefore, NR was used as a spectral probe to
investigate the binding mode of 5b or 9c with DNA in this work.
The absorption spectrum of NR upon the addition of DNA (ESI‡,
Fig. S12) indicated that a gradual decrease with the increasing
concentration of DNA at absorption peak of NR around 460 nm
appeared and a new band around 530 nm developed, which
suggested the formation of the new DNA–NR complex. This was
3.4 Iodide quenching experiments
Steadyꢀstate quenching could provide further information about the
binding mode of a molecule with DNA. It is generally accepted that
if a molecule is protected from being quenched in the presence of an
anionic quencher due to the repulsion between anionic quencher and
the negatively charged phosphate backbone of DNA, the binding
mode belongs to intercalation.22 Accordingly, the intercalative
binding of the fluorophore should reduce the extent of fluorescence
quenching in the DNA environment in comparison to reference
solution and hence the value of quenching constant (KSV) of the
intercalative bound molecule should be lower than that of the nonꢀ
intercalative molecule. In this work, KI quenching was introduced to
investigate the possible binding mechanism. Quenching curves of
compound 5b in the absence and presence of DNA were shown in
Fig. 5 and Fig. 6.
further proved by the isosbestic point at 504 nm.
1.4
1.1
1.0
0.9
0.8
0.7
0.6
0.5
DNA+compound 5e
DNA-5e complex
1.2
1.0
0.8
0.6
0.4
0.2
0.0
i
0.0
0.5
1.0
1.5
2.0
2.5
10-5[Q]
a
SternꢀVolmer equation (2) was used to deduce quenching
constant:
DNA
F
240
260
280
300
0
(2)
=1+ KSV [Q]
F
Wavelength (nm)
where F0 and F represent the fluorescence intensity of compound
5b/5b−DNA system in the absence and presence of the quencher KI,
respectively. KSV (L/mol) is the Stern–Volmer quenching constant,
and [Q] is the concentration of KI. Hence, KSV was calculated by
Fig. 3 UV absorption spectra of DNA with different concentrations of
compound 5b at pH 7.4 and room temperature. c(DNA) = 5 × 10-5 mol/L, and
c(compound 5b) = 0–2.3 × 10-5 mol/L for curves a–i respectively at an
increment of 0.29 × 10-5 mol/L. Inset: comparison of absorption at 260 nm
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Journal Name
1.0
0.8
0.6
0.4
0.2
0.0
a
linear regression of plot of F0/F versus [Q]. The KSV value of
compound 5b (10.7 L/mol, R = 0.999, SD = 0.019) in the presence
of DNA was lower than that (11.6 L/mol, R = 0.992, SD = 0.067) in
the absence of DNA. It was apparent that iodide quenching effect
of compound 5b by anionic quencher in presence of DNA was
decreased, which further evidenced that compound 5b
intercalated into the base pairs of DNA.
1500
1200
900
HSA
0
10
20
30
40
50
60
Compound [10-6
]
mol/L
k
600
1.8
1500
1200
900
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
R
= 0.992 SD = 0.067
Compound 5b
300
a
330
360
390
420
450
0
2
4
6
8
10
12
KI (mol/L, 10-3)
Wavelength (nm)
g
Fig. 7 Emission spectra of HSA in the presence of various concentrations of
compound 5b: c(HSA) = 1.0 × 10-5 mol/L; c(compound 5b) = 0–2.0 × 10-5
mol/L for curves a–k at an increment of 0.20 × 10-5 mol/L; blue dash line
shows the emission spectrum of compound 5b only; T = 286 K, λex = 295 nm.
600
300
375
400
425
450
475
500
The fluorescence quenching data can also be analyzed by the
wellꢀknown SternꢀVolmer equation (2):
Wavelength (nm)
Fig.
5 The fluorescence spectra of compound 5b with increasing
concentration of KI. c(compound 5b) = 1.0 × 10-5 mol/L; c(KI) = 0–12 × 10-3
mol/L for curves a–g respectively at an increment of 2 × 10-3 mol/L; red line
shows the fluorescence spectrum of compound 5b only; T = 298 K, λex = 290
nm. Inset: The Stern–Volmer plot of the fluorescence titration data of
compound 5b.
F0
(2)
= 1 + K [Q ] = 1 + K qτ 0 [Q ]
S V
F
where F0 and F represent fluorescence intensity in the absence and
presence of compound 5b, respectively. Kq is the bimolecular
quenching rate constant (L/mol/s), τ0 is the fluorescence lifetime of
1.6
1500
1.4
R
= 0.999 SD = 0.019
the fluorophore in the absence of quencher, assumed to be 6.4×10ꢀ9
s
Compound 5b + DNA
1.2
1.0
0.8
0.6
0.4
0.2
0.0
1200
900
600
300
for HSA, and [Q] is the concentration of compound 5b. The results
also manifested that the binding constants were moderate. Therefore,
compound 5b might be stored and carried by HSA.
a
0
2
4
KI
6 8
mol/L, 10-3)
10
12
(
g
Molecular docking evaluation was also performed to understand
the binding mode between compound 5b and HSA. The docking
mode was shown in Fig. 8 with the lowest binding free energy and
binding constant of ꢀ17.32 kJ/mol and 6×104 Mꢀ1, respectively. As
clearly evidenced, compound 5b was surrounded by Lysꢀ413, Lysꢀ
541, Argꢀ410, Euꢀ418, Alaꢀ406, Trpꢀ214 and Thrꢀ540. Moreover,
compound 5b partly occupied subdomain IIA, resulting in
fluorescence quenching of Trpꢀ214. Hydrophobic interactions
existed between the aromatic ring of compound 5b and HSA. Except
for the hydrophobic contacts, hydrogen bonds of 2ꢀF, 4ꢀF on
benzene ring as well as 4ꢀN atom on triazole ring with Lysꢀ413, Lysꢀ
541 and Alaꢀ406 in HSA and specific electrostatic interactions and
were also involved in the binding process. All these indicated that
the simulation results coincided well with the above experimental
analysis.
375
400
425
450
475
500
Wavelength (nm)
Fig. 6 The fluorescence spectra of compound 5b and DNA system with
increasing concentration of KI. c(compound 5b) = 1.0 × 10-5 mol/L; c(DNA) =
2.0 × 10-5 mol/L; c(KI) = 0–12 × 10-3 mol/L for curves a–g respectively at an
increment of 2 × 10-3 mol/L; red line shows the fluorescence spectrum of
compound 5b and DNA system only; T = 298 K, λex = 290 nm. Inset: The
Stern–Volmer plot of the fluorescence titration data of compound 5b and
DNA system.
3.5 Binding behavior of compound 5e with HSA
The investigations of interactions between drugs or bioactive small
molecules and HSA are not only beneficial to provide a proper
understanding of the absorption, transportation, distribution,
metabolism and excretion properties of drugs, but also significant to
design, modify and screen drug molecules.23 Therefore, the binding
behavior between compound 5e and HSA (SigmaꢀAldrich, St. Louis,
MO, USA) was investigated (Fig. 7). It was obvious that HSA had a
strong fluorescence emission with a peak at 348 nm owing to the
single Tryꢀ214 residue. The intensity of this characteristic broad
emission band regularly decreased with the increasing
concentrations of compound 5b, but the maximum emission
wavelength of HSA remained unchanged. This suggested that Trpꢀ
214 did not undergo any change in polarity, and hence compound 5b
was likely to interact with HSA via the hydrophobic region located
in HSA.
Fig. 8 Hydrophobic pocket of HSA-target and binding model of compound 5b
to HSA.
4. Conclusion
6 | J. Name., 2012, 00, 1-3
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ARTICLE
Rev., 2014, 34, 340ꢀ437.
A triazole class of miconazole analogues were designed and
synthesized in good yields via an easy, convenient and efficient
synthetic route. All the newly synthesized compounds were
characterized by IR, 1H NMR, 13C NMR, MS and HRMS spectra.
The in vitro antifungal activities of these miconazole analogues were
evaluated against five fungal strains. The biological results revealed
that most of the new target compounds exhibited moderate to good
antifungal activities against most of the tested strains in comparison
with the reference drug miconazole. Especially the 3,4ꢀ
dichlorobenzyl triazole compound 5b displayed not only stronger
antifungal efficacies, but also broader bioactive spectrum against all
the tested strains at low inhibitory concentrations (MIC = 0.5–8
µg/mL) in comparison with miconazole. SAR suggested that both
the Nꢀ3 unsubstituted triazole ring and the substituents on ether
linkage were important influence factors on antifungal potency and
the introduction of chlorine to benzene ring would improve the fungi
inhibitory effect. The docking study showed that the highly bioactive
miconazole analogue 5b could bind with the active sites of CYP51
through the formation of hydrogen bond with histidine residue. The
interactive investigations with DNA validated that both of the two
active molecules 5b and 9c could effectively intercalate into calf
thymus DNA to form compound–DNA complexes, which might
block DNA replication to exert their powerful antifungal abilities.
The binding behaviors and molecular modeling of compound 5b
with HSA suggested that compound 5b might be stored and
transported by HSA, where the hydrophobic interactions, specific
electrostatic interactions and hydrogen bonds played important roles.
All of these indicated that compound 5b was a promising antifungal
candidate with good curative effect. Further researches, including the
in vivo bioactive evaluation, timeꢀkill kinetic assay, toxicity, drug
resistance and some effect factors on antifungal activities such as
other heterocyclic azole rings (benzotriazole, thiazole, oxazole and
their derivatives) linked at methylene end are now in progress in our
group.
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This work was partially supported by National Natural Science
Foundation of China [(No. 21372186, 21672173), the Research
Fund for International Young Scientists from International
(Regional) Cooperation and Exchange Program (No.
81250110089, 81350110338)] and Chongqing Special
Foundation for Postdoctoral Research Proposal (Xm2016039).
The authors thank Prof. S. Rajagopal from Department of Plant
Sciences, School of Life Sciences, University of Hyderabad,
India for the help in docking study.
Conflict of Interest
The authors declare no competing author
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8 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7MD00112F
Discovery of potential antifungal triazoles: Design, synthesis, biological evaluation, and
preliminary antifungal mechanism exploration
Yuan Zhang,§a Guri L V Damu,§#a Sheng-Feng Cui,§a Jia-Li Mi,b Vijai Kumar Reddy Tangadanchu#a and
Cheng-He Zhou*a
a
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing
Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR
China.
b People’s Hospital of Suining, Sichuan 629000, PR China.
§ These authors contributed equally to this work.
# Postdoctoral fellow from Indian Institute of Chemical Technology (IICT), India.
Synthesis of a novel triazole type of miconazole analogues as potential antifungal agents, and
molecular modeling with CYP51 and experimental investigation with DNA suggested the possible
antimicrobial mechanism.