Development of a fused imidazo[1,2-: A] pyridine based fluorescent probe for Fe3+ and Hg2+ in aqueous media and HeLa cells

Article abstract of DOI:10.1039/c9ra04743c

A new fluorescent sensor 5 based on a fused imidazopyridine scaffold has been designed and synthesized via cascade cyclization. The reaction features the formation of three different C-N bonds in sequence. Imidazopyridine based fluorescent probe 5 exhibits highly sensitive and selective fluorescent sensing for Fe³⁺('turn-on') and Hg²⁺('turn-off'). The excellent selectivity of imidazopyridine for Fe³⁺/Hg²⁺ was not hampered in the presence of any of the competing cations. The limit of detection (LOD) of 5 toward Fe³⁺ and Hg²⁺ has been estimated to be 4.0 ppb and 1.0 ppb, respectively, with a good linear relationship (R² = 0.99). Notably, 5 selectively detects Fe³⁺/Hg²⁺ through fluorescence enhancement signalling both in vitro and in HeLa cells.

Full text of DOI:10.1039/c9ra04743c

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Development of a fused imidazo[1,2-a]pyridine
based fluorescent probe for Fe3+ and Hg2+ in
aqueous media and HeLa cells†
Cite this: RSC Adv., 2019, 9, 29856
a
*
Suman Srivastava,
Neha Thakur,b Ashutosh Singh,d Poonam Shukla,c
Vipin Kumar Maikhuri,c Neha Garg,
Ashok Prasad
and Rampal Pandey
d
c
b
*
A new fluorescent sensor 5 based on a fused imidazopyridine scaffold has been designed and synthesized
via cascade cyclization. The reaction features the formation of three different C–N bonds in sequence.
Imidazopyridine based fluorescent probe 5 exhibits highly sensitive and selective fluorescent sensing for
Fe3+(‘turn-on’) and Hg2+(‘turn-off’). The excellent selectivity of imidazopyridine for Fe3+/Hg2+ was not
hampered in the presence of any of the competing cations. The limit of detection (LOD) of 5 toward
Fe3+ and Hg2+ has been estimated to be 4.0 ppb and 1.0 ppb, respectively, with a good linear
relationship (R2 ¼ 0.99). Notably, 5 selectively detects Fe3+/Hg2+ through fluorescence enhancement
signalling both in vitro and in HeLa cells.
Received 24th June 2019
Accepted 15th September 2019
DOI: 10.1039/c9ra04743c
rsc.li/rsc-advances
intramolecular proton transfer (ESIPT) behavior.12 Therefore,
a large number of methodologies have been developed for the
synthesis of imidazo[1,2-a]pyridine derivatives.13 The immense
Introduction
The development of novel and synthetically feasible uorescent
sensors particularly for heavy metal ions (HTMs) is of growing
interest because these metal ions are indispensable owing to
their involvement in a variety of fundamental biological
processes.1 Iron is an essential trace element for both plants
and animals, and plays an important role in cellular metabo-
lism and enzyme catalysis.2 On the other hand, mercury is
known for its toxic effects, is widely distributed in the envi-
ronment and bioaccumulates through the food chain.3 To serve
the purpose of sensing, different small molecule uorescent
probes have been developed for selective detection of iron
(Fe3+)4 and mercury (Hg2+).5,6 Further, reports dealing with the
detection of HTMs under aqueous conditions or in a viable
aqueous-ethanol media are rather scarce.7–9
applications of this class of compounds also prompted us to
explore the synthetic methodologies for the preparation of
fused imidazo[1,2-a]pyridines. Following our interest in the
area of designing and synthesis of small bioactive molecule via
ecofriendly route,14 we report herein the synthesis, character-
ization and application of fused imidazopyridine compound for
the detection of Fe3+ and Hg2+ in aqueous-alcoholic media.
Notably, the systematic uorescence intensity change can be
associated to the detection ability for in vitro measurements
however, sensing of analytes in cellular systems (inside bio-
logical cells) is a daunting task.6b Further, variation in uores-
cence intensity in cellular systems may occur due to several
other reasons.6b,15,16
In addition, imidazo[1,2-a]pyridine ring systems have fasci-
nated a great deal of attention due to their biological activities,
associated with the hybrid structure of imidazole and pyri-
dine.10 Imidazo[1,2-a]pyridine ring systems are also important
in the eld of material sciences,11 because a few of the
compounds belong to this class exhibit excited state
Results and discussion
The imidazo[1,2-a]pyridines probe (5) was synthesized in three
steps with overall yield 63%. Formylation of 4-methox-
yacetophenone furnished 3-chloro-3-(4-methoxyphenyl) acryl-
aldehyde (2).17 Sonogashira coupling of 2 with phenyl acetylene
(3a) gives 2-(2-phenylethynyl) benzaldehyde (4).18
aDepartment of Applied Sciences, National Institute of Technology, Delhi, India.
E-mail: sumanbhu08@gmail.com
bDepartment of Chemistry, National Institute of Technology Uttarakhand, India.
Condensation of o-phenylenediamine with 4 in DMF in
presence of acetic acid under reuxing condition resulted in an
oxidative cyclization to give desired probe 3-(4-methoxyphenyl)-
1-phenylbenzo[4,5]imidazo[1,2-a]-pyridine, (5) (Scheme 1).
Characterization of 5 has been done by NMR (1H & 13C), HRMS
and single X-ray single crystal analysis. It is apparent from the
mechanism that formation of 5 takes place by condensation
cum cyclization as shown below (Scheme 2). Imine formation
E-mail: rppandeysu@gmail.com
cDepartment of Chemistry, University of Delhi, Delhi, India
dIndian Institute of Technology, Mandi, Himachal Pradesh, India
† Electronic supplementary information (ESI) available. CCDC 1921596. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c9ra04743c
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Scheme 1 Synthesis of imidazopyridine: (i) POCl3, DMF, CH3COONa, 0 ꢁC to rt, 3 h; (ii) PdCl2(PPh3)3, Et3N, CH3CN, rt, 5 h; (iii) DMF, acetic acid,
100 ꢁC, 12 h, 63%.
followed by attack of amine nitrogen on imine carbon which methoxyphenyl ring measured through torsion angles calcu-
leads to dihydrobenzimidazole (4b). Nitrogen atom of dihy- lated to be ꢀ27.70ꢁ (cisoid, C10–C9–C18–C23) and 154.80ꢁ
drobenzimidazole attacks on alkynyl carbon as shown to obtain (transoid, C10–C9–C18–C19). The phenyl ring assumes orien-
dihydrobenzimidazo pyridine (4d) aer protonation. Oxidation tation perpendicular to the central pyridine ring. Probe 5 leads
of dihydrobenzimidazo pyridine (4d) yielded benzimidazo to the formation of 1D chain through edge-to-edge p/p
pyridine (5).
stacking interaction which enables it to be a good candidate for
dimer formation in the excited state (Fig. 1 and S7†).
Structural descriptions
Cation detection through absorption and uorescence studies
The structure of 5 has been authenticated by X-ray single crystal
analysis (CCDC no. 1921596,† Fig. 1). It crystallizes in mono- The UV/vis spectrum of 5 displays absorption bands at 365, 326,
clinic system with space group ‘P121/n1’. The molecular 285 and 244 nm (pH, 7.2 in H2O : EtOH, 8 : 2, v/v, at rt) (Fig. 2a).
planarity is an important factor for uorescent probes. The The low energy (LE) bands are assignable to the n–p* transi-
molecular plane of 5 comprises imidazo[1,2-a]pyridine uo- tions and high energy bands may be attributed to the p–p*
rophore whereas p-methoxyphenyl ring assumes twisted posi- transitions.7 Further, to assess the cation binding effect on
tion in a way that half part lying above and half part lying below absorption behavior of 5, various alkali, alkaline and transition
the molecular plane. The molecular plane also divides 1-phenyl metal ions (5 equiv.; Na+, K+, Mg2+, Ca2+, Mn2+, Fe2+, Fe3+, Co2+,
substituent into two equal halves. The C–N, C–O and C–C bond Ni2+, Zn2+, Ag+, Cd2+ and Pb2+; 10 mM) were added to the
lengths are within the normal ranges.7 The twisting in p- solutions of 5 (10 mM; 3 mL). Among tested cations, only Fe3+
Scheme 2 Proposed mechanism for the formation of 5.
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Fig. 1 (Left) X-ray single crystal structure of 5 (ellipsoidal probability 50%); (right) fluorescence image of 5 + Fe3+ and 5 + Hg2+ under UV-light
(365 nm).
and Hg2+ induced signicant changes in the spectral feature of hyperchromic shi at both the LE bands and hypochromic shi
5 (Fig. S8†).
at 285 nm (3, 31 686 Mꢀ1 cmꢀ1) whereas HE band at 244 nm is
Addition of Fe3+ leads to the large hyperchromic shis in blue shied to appear at 236 nm (Fig. 3). Further additions of
both the LE bands however; hyperchromic shis in the HE Hg2+ (2.0–15.0 mL) lead to the similar ratiometric changes along
bands are relatively small to that of LE bands. In contrast, with clear cut isosbestic points at 392, 306 and 245 nm, sug-
addition of Hg2+ to the solution of 5 causes ratiometric changes gesting presence of more than two species in the medium. In
in the absorption bands through hyperchromic shis in the LE addition, selectivity of 5 toward Fe3+ and Hg2+ was examined by
bands and hypochromic shi in HE band along with appear- introduction of Fe3+ (20 mL) to the solution of 5 followed by
ance of a new band at 264 nm.
addition of Hg2+ (20 mL) to the same 5 + Fe3+ solution and the
Considering substantial changes in the presence of Fe3+ and resultant 5 + Fe3+ + Hg2+ solution was le as such for an hour.
Hg2+ as well as to have deep insight about probe-cation binding, Notably, spectral pattern of 5 + Fe3+ was almost completely
UV/vis titration studies were performed (Fig. 3). Gradual addi- altered to 5 + Hg2+ which strongly suggests better selectivity of 5
tion of Fe3+(1.0 mL, 0.1 equiv.) to a solution of 5 leads to the toward Hg2+ over Fe3+.
noteworthy ratiometric change in the absorption bands through
Upon excitation at its LE band (lex, 368 nm), 5 exhibits
hyperchromic shi in the LE bands and hypochromic shi in moderate uorescence at 464 nm and the quantum yield (FF)
the HE band (at 285 nm; 3, 22 769 Mꢀ1 cmꢀ1) (Fig. 3). Further, determined to be 0.37 (Fig. 2b).8 The moderate FF for 5 may be
introducing more concentration of Fe3+(2.0–15.0 mL) to the ascribed to the combined effect of intense LE absorption band
solution of 5 caused incessant hyperchromic shi in both the and photoinduced electron transfer (PET).8 Cation interaction
LE bands whereas HE bands become poorly structured with behavior of 5 was also investigated through uorescence spec-
hyperchromic shis at 244 nm and hypochromic shis at tral technique by individual and excessive addition of various
285 nm. Likewise, aliquot addition of Hg2+(1.0 mL, 0.1 equiv.) to cations (10 equiv.; 100 mM) to the solution of 5. Notably, among
a solution of 5 induced signicant ratiometric changes via introduced cations, only Fe3+ and Hg2+ could cause signicant
Fig. 2 UV/vis (a) and fluorescence (b) plots of 5 (10 mM, H2O–EtOH, 8 : 2, v/v) in presence of various cations.
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Fig. 3 UV/vis titration plots of 5 (10 mM, H2O–EtOH, 8 : 2, v/v) with Fe3+ (left) and Hg2+ (right) ions.
uorescence change whereas presence of other cations was induces ‘turn-on’ uorescence and Hg2+ causes ‘turn-off’ uo-
futile in terms of the spectral change (Fig. 2b) which can be seen rescence. To get profound idea into probe-cation binding,
in the images taken both under natural conditions and UV-light uorescence titration studies were performed by gradual addi-
(Fig. S8 ESI†).
tions of Fe3+ and Hg2+ separately to the solution of 5 (Fig. 4).
Additions of both Fe3+ and Hg2+ lead to the subtle blue shi Aliquot additions of Fe3+ (1.0–15.0 mL) exhibited ‘turn-on’
(820 cmꢀ1 for Fe3+ and 1124 cmꢀ1 for Hg2+) however, Fe3+ uorescence (ꢂ33%) with blue shied emission maxima to
Fig. 4 Fluorescence titration plots of 5 (10 mM, H2O–EtOH, 8 : 2, v/v) with Fe3+ (a) and Hg2+ (b) ions.
Fig. 5 Bar diagrams showing interference of various competing cations with fluorescence of 5 + Fe3+ (blue bars) and 5 + Hg2+ (brown bars).
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appear at 447 nm. Likewise, gradual introduction of Hg2+(1.0– 1.09 ꢃ 105 Mꢀ1 and 1.31 ꢃ 105 Mꢀ1, respectively (Fig. S11;
15.0 mL) displayed ‘turn-off’ emission (ꢂ59%) with hyp- ESI†).19 Moreover, the uorescent detection of cations can only
sochromically shied uorescence maxima to emerge at be claimed if competitive analytes induce insignicant inter-
441 nm. Blue shis in case of both Fe3+ and Hg2+ suggest that ference to the selectivity assured by probe, therefore, we exam-
probe 5 may be interacting with these cations through same ined two sequences of interference: (1) various cations were
binding site. Further, the ‘turn-on’ uorescence of 5 upon successively added to the solution containing complex 5 + Fe3+
binding with Fe3+ may be attributed to an increase in charge and/or 5 + Hg2+; (2) Fe3+ and/or Hg2+ were added separately into
transfer from imidazo nitrogen of 5 to Fe3+ and/or due to the solution containing 5 + Mn+ (M ¼ various tested cations;
chelation enhanced uorescence (CHEF).8 In contrast, ‘turn-off’ (Fig. 5). Notably, none of the other metal ions could interfere to
signaling with Hg2+ may be ascribed to the spin orbit coupling the selectivity of 5 toward Fe3+ and Hg2+. Moreover, 5 offer
and/or the chelation-enhanced quenching (CHEQ) effect.9
The Job's plot analysis revealed 1 : 1 probe-cation stoichi- Cr3+ and Al3+ could also not affect the selectivity assay of 5.
ometry for Fe3+ whereas 2 : 1 for Hg2+ (Fig. S9; ESI†). The The sensitivity of 5 (1.0 mM) toward Fe3+ and Hg2+ was
greater selectivity for Hg2+ over Fe3+. Other trivalent cations like
quenching constant (Ksv) for 5 + Hg2+ has been determined to be examined in the concentration range of 10ꢀ12 M to 10ꢀ6
M
1.52 ꢃ 104 Mꢀ1 derived from the Stern–Volmer plot (Fig. S10; wherein both the cations perturbed the uorescence intensity of
ESI†). Using Benesi–Hildebrand method, the association 5 at a concentration of 10ꢀ9 M. To further get better accuracy,
constants (Ka) for 5 + Fe3+ and 5 + Hg2+ were calculated to be 10ꢀ9 M (1.0 ꢃ 10ꢀ9 ꢀ 9.0 ꢃ 10ꢀ9 M) concentration of Fe3+ and/
1
Fig. 6 (a) H NMR titration plot of 5 with Fe3+ and Hg2+; (b) Binding of probe 5 with Fe3+ and Hg2+ in aqueous-ethanol media.
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or Hg2+ were introduced to the solution of 5 (1.0 mM) and dis- displayed larger downeld shi for H2 proton (adjacent to the
played good plot linearity (R2 ¼ 0.99) with limit of detection nitrogen donor site) relative to other aromatic protons and
(LOD) of 4.0 ppb (Fe3+) and 1.0 ppb (Hg2+) (Fig. S12; ESI†). It thereby strongly suggests imidazo-nitrogen as m downeld shi
suggests that 5 can potentially be used as probe for practical in presence of Fe3+/Hg2+, which rules out the binding of cations
detection of Fe3+ and Hg2+. Further, 5 exhibited almost through methoxy oxygen site. Overall, 1H NMR titration spectra
complete uorescence revival upon excessive addition of EDTA clearly displayed larger downeld shi for H2 proton (adjacent
(5.0 equivalent) to the solution of 5 + Fe3+/Hg2+ suggesting that to the nitrogen donor site) relative to other aromatic protons
probe 5 can serve as reversible probe for said cations.
and thereby strongly suggests imidazo-nitrogen as most prob-
able binding site for both the metal ions.
1H NMR titration studies
ESI-mass spectral studies
The information about binding site of 5 for Fe3+ and Hg2+
cations was obtained though 1H NMR titration studies (Fig. 6a)
which show signicant downeld shi in the protons adjacent
to imidazo-nitrogen both in presence of Fe3+ and Hg2+. Addition
of Fe3+ (2.0 mL) to the solution of 5 led to the downeld shi in
the aromatic protons H2 and H1 to appear at 8.11 ppm (Dd ¼
0.27 ppm) and 7.94 ppm (Dd ¼ 0.10 ppm), respectively (Fig. 6a).
Further addition of Fe3+ (4.0 mL) caused incessant downeld
shi in H2 and H1 protons to resonate at 8.15 ppm (Dd ¼ 0.31
ppm) and Fe3+ and 8.07 ppm (Dd ¼ 0.23 ppm), respectively.
Increasing the concentration of Fe3+ (4.0 mL) to the solution
induced insignicant downeld shi to the resonances of 5.
Likewise, addition of Hg2+ (2.0 mL) to the solution of 5 resulted
in the downeld shi to H2 and H1 aromatic protons to reso-
nate at 8.02 ppm (Dd ¼ 0.18 ppm) and 7.89 ppm (Dd ¼ 0.05
ppm), respectively (Fig. 6a). Further additions of Hg2+ (4.0 mL)
Further to get better idea about the complex ensued from probe-
cation binding, ESI-MS spectra of compound obtained upon
treatment of 5 with Hg2+ and Fe3+ salts, were acquired (Fig. S13;
ESI†). The 5 + Hg2+ complex exhibits a peak at m/z 469 which
corresponds to the half of the [Hg(5)2(H2O)2]2+ entity having at
molecular mass of 938. As the charge (z) in Hg(II)-complex is +2,
it displays [M]+/2 peak at m/z 469 (938/2). Although, the base
peak of Hg(II) complex is in accordance with the [M + 1]+ peak of
probe 5 (m/z,350). Likewise, 5 + Fe3+ complex shows moderately
abundant [M]+/2 peak at m/z 252 which is in accordance with
half of the formula [Fe(5)(NO3)(H2O)2]2+ which have molecular
mass of 504. Overall, the ESI-MS spectra also supported the
probe-cation binding and stoichiometry (Fig. 6b).
Imaging in HeLa cells
induced large downeld shi in H2 proton to appear at To evaluate the feasibility of Fe3+ and Hg2+ sensing by 5 inside
8.29 ppm (Dd ¼ 0.45 ppm) whereas H1 proton resonates at the cells, the HeLa cells were incubated with different concen-
8.00 ppm (Dd ¼ 0.16 ppm). It is noteworthy to mention that tration of the respective ions for 10 min. The phase contrast and
–OCH3 proton exhibits insignicant downeld shi in presence blue channel images of the xed cells aer probing with sample
of Fe3+/Hg2+, which rules out the binding of cations through is shown in Fig. 7. Overlay images showed that the blue uo-
1
methoxy oxygen site. Overall, H NMR titration spectra clearly rescence coincides with the cells. The blue channel displayed an
Fig. 7 Confocal images showing Fe3+ (left) and Hg2+ (right) sensing by 5 inside HeLa cells. The cells were incubated with increasing concen-
tration of the respective ions.
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increase in uorescence with increasing concentration of both
Fe3+ and Hg2+ and the same has been illustrated in the mean
uorescence intensity plot (Fig. S14 and S15; ESI†). Addition-
ally, the cell morphology also indicated cell survival aer 10 min
of incubation with the respective ions. The sharp contrast in the
confocal study indicates the efficient cellular uptake and
micromolar sensing of Fe3+ and Hg2+ by 5.
In summary, a fused imidazopyridine has been synthesized,
thoroughly characterized and used as sensitive and highly
selective uorescent sensor for biologically and environmen-
tally vital Fe3+ and Hg2+ through distinct uorescence readout.
Probe 5 was designed with the view point of having single open
imidazolyl nitrogen as unique interaction site for cations so that
none of the competing cation can interfere with its selectivity
assay. The cation binding has been well examined and sup-
ported by UV/vis, uorescence, 1H NMR titration techniques
and mass spectral studies. The ppb level sensitivity and quite
high selectivity of 5 toward Fe3+ and Hg2+ strongly claimed its
practical application for determination of Fe3+ and Hg2+ in
biological/environmental samples. Eventually, imaging in HeLa
cells incubated with 5 has revealed enhanced uorescence for
Fe3+ and Hg2+ ions which strongly supports the claim that 5 can
potentially be used as uorescent probe for these cations under
cellular conditions.
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
SS and RP acknowledge the Department of Science and Tech-
nology (DST) for nancial support through Inspire Faculty
Award No IFA-13-CH-123 and IFA12-CH-66 respectively. NG
acknowledges Ramanujan Fellowship from SERB, India (SB/S2/
RJN-072/2015) and BioX center and AMRC, IIT Mandi for
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