Journal of Fluorescence

https://doi.org/10.1007/s10895-020-02570-7

REVIEW

A Review on Schiff Base Fluorescent Chemosensors for Cell

Imaging Applications
Duraisamy Udhayakumari 1 & V. Inbaraj 1

Received: 28 April 2020 / Accepted: 3 June 2020

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Fluorescent determinations of analytes have proven to be a powerful method due to their simplicity, low cost, detection limit,
rapid photoluminescence response, and applicability to bioimaging. Fluorescence imaging as a powerful tool for monitoring
biomolecules within the living systems. Schiff base has been extensively used as strongly absorbing and colorful chromophores
in the design of chemosensors. In recent years, Schiff base based fluorescent probes have been developed for the detection of
various toxic analytes and imaging of various analytes in biological systems. This review gives an overview of the important
fluorescent sensors which are based on Schiff base, their approaches for molecular recognition, and their potential application in
bioimaging studies.

Keywords Schiff base . Analytes . Fluorescence . Detection . Bioimaging

Introduction Fluorescence technology is used by scientists from many

disciplines such as biology, materials science, and biomedical
A challenge for versatile detection of toxic analytes in the sciences. The fluorescence measurement is usually versatile,
environment, biological organs and tissues have been resolv- very sensitive, low detection limit, and offers a sub-
ing by enhancing the interest in developing fluorescent probes micromolar estimation of guest species [16–20]. In
[1–5]. Most of the toxic ions playing an important role in a fluorogenic chemosensors, the interaction between the bind-
variety of industrial operations such as food industry, pharma- ing site and the guest moiety shows the changes in the fluo-
ceutical, paper, textile industry, refinery, water treatment, rescence behavior of the signaling unit. The image processing
manufacturing of batteries and electronic field [6–10]. At the technology was extensively improved from the year the 1960s
same time, toxic analytes are associated with severe neurode- onwards and there has been dramatic growth in the use of
generative diseases such as Parkinson’s disease, Alzheimer’s fluorescence for cellular and molecular imaging that can be
disease, amyotrophic lateral sclerosis (ALS), and Wilson’s seen today in almost every field. The imaging technique is
disease to the human body. Even the trace level distribution widely used as biomarkers for disease identification, progress,
of these elements in living organisms can shift the character of and treatment responses. Fluorescence imaging can divulge
enzyme catalysis, gene expression, protein sequence, DNA the structural, physiological, measurement of intracellular
synthesis, reproductive process and immune function molecules and molecular structure of a cell or tissue
[11–15]. On the basis of consequences and speedy recovery [21–25]. Advances in bioimaging can provide better health
from the above-mentioned disease, there is a greater demand diagnosis and treatment of various diseases in a safe and
to focus study on a fast detecting device for these toxic ions. non-invasive way.
A Schiff base is a nitrogen analog of an aldehyde or ketone
in which the C=O group is replaced by the C=N-R group and
they were discovered by a Nobel Prize winner of German
* Duraisamy Udhayakumari chemist Hugo Schiff in 1864. They are used as pigments,
udhaya.nit89@gmail.com catalysts, intermediates in organic synthesis, polymer stabi-
lizers, dyes, biological activity, molecular memory storage,
1
Department of Chemistry, Rajalakshmi Engineering College,
in imaging systems, pharmaceutical, and agro-industrial
Chennai 602105, India chemistry [26–30]. Schiff base probes are essential in the field
 J Fluoresc

Fig. 1 Sensing mechanism and H

bioimaging of probe 1 with Ag+ 1 HO
O
ion
Ag+
N Ag+
N
1 +Ag+

N OH
N O
1 H
Ag+

Fig. 2 Sensing Mechanism of

Probe 2 with Ag+ H
O N
N
H
O N AgNO3 O
N S Ag S
O NO2 NO2
O O
N
2
O
2 2+Ag+
Ag+

of molecular recognition, especially in the development of the developments of Schiff base fluorescent probes especially
fluorescence sensor of Schiff bases because these compounds in bioimaging applications such as imaging of industrially,
are potentially capable of forming stable complexes with met- biologically and environmentally important (Ag+, Al3+,
al ions [31]; Orojloo and Amani [32]; [33–35]. Schiff base ClO¯, HClO, Cu2+, Hg2+, and Zn2+) ions has been compiled
derivatives containing nitrogen-oxygen rich coordination as by consulting the literature from 2016 onwards.
a receptor site pave a strong platform for fluorescent sensing
with strong noticeable color change. Detecting the metal ions
with a miscellaneous group of mechanisms in the real sample Schiff Base Fluorescent Probes for Bioimaging
by Schiff base based sensors are attracted nowadays [34,
36–40]. Fluorescence Chemosensors for Ag+
Photochemical properties, as well as mechanism and appli-
cations of Schiff base probes, have been well documented in Silver ions (Ag+) are not only a kind of precious metals but
the recent years [2, 41–51]. Avoiding all the topics of early also a truly natural and safe green germicide. Silver has been
reported reviews, the present review is deliberate to focus on used for many ways such as an antimicrobial agent and silver-

Fig. 3 Structure and bioimaging

of Probe 3 with Al3+ and Bi3+
Al3+
O
O
Al3+ HC N N
HC N N N
H N

3
J Fluoresc

Fig. 4 Structure and bioimaging HO

of probe 4 with Sn2+ and Al3+
ions N OH

O
N
O
N
B N
FF
N
4 B
N F
F

Al3+ Sn2+

impregnated filters are used in the purification of water, due to fluorophore. On addition of Ag+ ion solution to Probe
its wide usage in industries, medicine, jewelry, chemistry, 1 + E.coli cells complex induced a strong red fluorescence
pharmacology, photography, electronics, etc., In wastewater, color change in the image which featured practical appli-
silver exists in different chemical forms depending on the cability of 1 in real living cells (Fig. 1).
conditions of the water such as pH, presence of organic and Simple Schiff base based probe 2 was synthesized and
inorganic impurities, etc. The silver ion concentration up to reported for silver ion in aqueous methanol solution [56]. On
0.2 μM is allowed for human health [52]; Chopra [53]; [54]. the addition of Ag+ into 2, a notable hypsochromic shift from
Quinoline hydroxyl derivatives based “Off-On” fluores- 425 nm to 405 nm exhibits selective detection for Ag+ over
cent probe 1 synthesized and applied for Ag+ ion in water competing for metal ions. Binding stoichiometry and associ-
samples [55]. Both fluorescence enhancement and ation constant of Host-Gust complex were 1:1 and Ka =
quenching were observed at 410 nm and 500 nm upon 1.58 × 106 M−1. The detection limit was measured to be
the addition of Ag+ into probe 1. The effective sensing 12 μM. [11]HNMR titration studies state that imine and NH
performance of probe 1 was tested in pH range 5–8 with protons are involved in the binding mechanism. Further, the
a short span of time about 2 min. The calculated detection detection behavior of probe 2 with Ag+ ions in the living cell
limit was 14 μM. The IR spectrum band’s shift was noticed shows fluorescence off-on behavior. E. coli cells, which were
for the strong binding of this probe 1 with Ag+ ion. The exposed to probe 2, exhibited highly intense red fluorescence.
complex formation between probe 1-Ag + ion held through Probe 2 with Ag+ ions shows the high fluorescence intensity
the intramolecular charge transfer process in quinoline inside the E. coli cells (Fig. 2).

Fig. 5 Structure and bioimaging

of precursor 5 with Al3+ and Zn2+ M
ions M
N OH N N O N
N
O M= Al3+, Zn2+ N
N N O
H H
5
5 + Zn2+ 5 + Al3+
5
 J Fluoresc

S S
S
Al3+ Zn2+
NH NH
O N NH O N
O O N O
Al 3+
OH Zn2+
6

6 6+Zn2+
3+ Zn2+
Al

Fig. 6 Sensing mechanism of Al3+ and Zn2+ ions by probe 6

Fluorescence Chemosensors for Al3+ these results, probe 3 could be able to sense the Bi3+ and Al3+
among various competing ions in biological systems with
Aluminium is the most third abundant metal in the earth’s good cell permeability and low toxic nature (Fig. 3).
crust and a lot of applications in biological, environmental, An excellent and low-level detection phenolphthalein-
and industrial. Aluminum has been considered innocuous to diBodipy based probe 4 [61] was synthesized and elaborated
humans for a long time. It plays a significant role in the pa- clearly for the detection of Sn2+ and Al3+ ions in an organic-
thology of Parkinson’s disease, Alzheimer’s disease, micro- aqueous system. Probe 4 displayed a distended emission band
cytic anemia, osteomalacia, and diseases of dialysis. Al3+ was at 560 nm from the fixed excitation at 370 nm, while adding
found to kill fish in acidified water and cause damages to the Sn2+ and Al3+ ions a strong fluorescence emission band was
central nervous system of human beings. Accordingly, as per observed (20-fold). Detection limits of probe 4 for Sn2+ and
the WHO report, in daily life, human uptake should be ap- Al3+ ions found to be 0.63 nM and 0.68 nM respectively. The
proximately 3–10 mg of aluminium [57–59]. detecting of probe 4 towards Sn2+ and Al3+ ions in A549 cells
Novel pyrene linked azomethine (C=N) Schiff base probe demonstrated by fluorescence image studies. The addition of
3 synthesized and reported [60] as a dual metal sensor to Bi3+ Sn2+ and Al3+ ions into incubated A549 cells with probe 4,
and Al3+ in DMSO-H2O, 1:1 v/v, HEPES = 50 mM, pH = 7.4. increases the fluorescence intensity in cell media. From the
Probe 3 selectively detects trivalent metal ions like Bi3+ and bioimaging, it was observed as a token of biocompatibility of
Al3+ over the other counter ions. Probe 3 alone showed an probe 4 for the detection of Sn2+ and Al3+ ions (Fig. 4).
emission band at 462 nm and significant fluorescence en- Picolinohydraxide coupled 4-(diethylamino)salicylaldehyde
hancement was observed upon the addition of Bi3+ and Al3+ based Schiff base probe 5 (H. [62]) synthesized and utilized as a
ions. The fluorescence enhancement is due to the inhibition of rapid detection kit for Al3+ and Zn2+ ions. Probe 5 does not
the photoinduced electron transfer mechanism. Biosensing show any fluorescence until the addition of Al3+ and Zn2+ ions
property of probe 3 with Bi3+ and Al3+ ions in RAW 264.7 into probe 5. After adding Al3+ ion and Zn2+ ions, two redshifts
cells exhibited a strong intensity of green fluorescence. From (405 nm and 435 nm) have noted with chelated fluorescence
enhancement followed by a clear color change. The inhibited
ESIPT mechanism during the binding two nitrogen atoms and
one oxygen atom of precursor 5 with Al3+ and Zn2+ ions
OH OH granted such fluorescence enhancement. The detection limits
H
N for both Al3+ and Zn2+ were calculated as 0.83 nM and
N 12 μM respectively. Incubated Hela cells (BDNOL (20 μM)
7 for 4 h) with probe 5 only exhibited insignificant fluorescence,
when probe 5 has treated with A13+ and Zn2+ in Hela cells it
was observed an obvious blue & orange fluorescence image
respectively (Fig. 5).
Naked-eye detection based on thiophene Schiff base
probe 6 synthesized [63] used for Al3+ and Zn2+ in day
Fig. 7 Structure of probe 7 with Al3+ ion & its bioimaging to life samples. Probe 6 ideally has no fluorescence signal
J Fluoresc

Fig. 8 Sensing Mechanism of O OH

O OH
probe 8 with A13+ ion and its
bioimaging

8 + MCF-7 Al3+ OH2

8+Al3+
Cells
H N H N Al3+ H2O
C C
OH O
O H
H3C

while excited at 375 nm. After the gradual addition of Another hydroxynapthalene derivative as a Schiff base
Al3+ and Zn2+ ions to probe 6 imparted strong emission probe 8 was synthesized and reported for Al3+ ions detection
band at 475 nm with 43-fold (Al3+) and 4.7 fold (Zn2+) [65]. Probe 8 alone exhibits a low fluorescence (343 nm)
increase followed by significance color change. Cell im- when an Al3+ ion was added into a stock solution (MeOH-
age study conducted by Leica TCS SP8 confocal laser H2O 9:1, v /v) of probe 8, a surprise fluorescent enhancement
scanning microscope on HeLa cells incubated in DMEM has noticed. This promises the explicit use of probe 8 to detect
supplemented with 10% fetal bovine serum at 37 °C un- Al3+ ion with negligible commotion by other ions for environ-
der 5% of CO2 atmosphere. The precultured HeLa cells mental wellness. The momentum for CHEF in probe 8 by the
then treated with probe 6 for 30 min at 37 °C. Clear blue slow addition of Al3+ described as a win over reduced ICT and
and green fluorescence image was observed by adding prevented free rotations between molecular moieties. On the
Al3+ and Zn2+ ions respectively to HeLa cells+ probe 6 limited concentration of probe 8 (1.25–50 μM) in MCF-7
(Fig. 6). Probe 6 can detections in living cells and has lined cells indicating 92% cell viability with no toxicity on
good cell-permeability, non-toxic nature. cells. Meantime addition of Al3+ ions into probe 8 incubated
Hydroxynaphthalene based Schiff base probe 7 has been with MCF-7 cells demonstrates turned out to intense fluores-
designed [64] and allowed for greater and better recognition of cence (Fig. 8).
Al3+ ions. Probe 7 showed an incredible fluorescence en- Fluorescence background quinoline based Schiff base
hancement peak at 430 nm upon the addition of Al3+ ions probe 9 was synthesized and used to encounter the pres-
(150-Fold). The enhancement of fluorescence emission due ence of Al3+ ion in methanol solution over other interfer-
to blocked ESIPT process in probe 7 at instant binding with ence ions [66]. The ESIPT involving the phenolic proton
Al3+ ions. The detection limit of probe 7 towards Al3+ ions (salicylaldehyde) and induce the non-fluorescence in
was found to be 13 μM. The intracellular property towards probe 9 when exciting at 467 nm. Suddenly an enhanced
Al3+ ions with probe 7 in living HeLa cells was carried out. fluorescence was observed once the Al3+ ions introduced
Enriched blue color fluorescence appeared due to the complex
of probe 7-Al3+ in cells and indicates cell permeability of H2N
probe 7 to track Al3+ ions in Hela cells. Similar fluorescence 10 a = NH2
changes were observed in three days grown Zebrafish on the HO
addition of Al3+ ions (Fig. 7). O O
N R
HO
OH
HO
H 10 b = H N O CH2OH
O N 2
N
10 c= H2N CO2H HO
N HO N
HO
9
10
Al3+ 9+Al3+ Al3+ 10+Al3+
9

MCF-7

Fig. 9 Structure of probe 9 with Al3+ ions Fig. 10 Structure of probe 10 with Al3+ ions
 J Fluoresc

Fig. 11 Structure of probes 11a-b Cl

and its bioimaging images

HO HO
O O
N N

N N

N O N N O N
11a 11b

11a 11a+Al3+ 11b

11b+Al3+

into probe 9. The Al3+ ion inhibits the ESIPT process and It’s revealed that probes 10b and 10c cannot be used for the
enhances the ICT process when coordinate with probe 9. precise detection of Al3+ ion in living cells. Despite this in-
Knowledge of the response of the fluorometric assay of ability probe 10a + epithelial cells Hs27 shows fluorescence
probe 9 encouraged to test its biocompatibility in cell line stain on the treatment of Al3+ ion with good cell permeability
MCF-7 cells. After cells were incubated in 200 μL 1% and the probe 10a acts as a key element to detect Al3+ ion
TritonX-100 for 15 min and washed twice with methanol in vitro cells (Fig. 10).
then enabled with probe 9 at 310 K for 1 h has not found Fluorescent Rhodamine dyes coupled with salicylaldehyde
any fluorescence intense but when Al3+ ions introduced to derivatives based probes 11a-11b were synthesized [68] and
the cells exhibits a strong red fluorescence (Fig. 9). From applied to detect toxic Al3+ ion in CH3OH-H2O system. The
the results, the images showed evidence to diagnose the performance of probe 11a towards Al3+ ion recoded through
Al3+ ion in living cells by probe 9. fluorescence studies that probe 11a imparts a notable fluores-
Three similar kinds of Schiff base fluorescent probes 10a, cence enhancement peak at 592 nm (100-fold) increase with
10b, and 10c synthesized [67] and used as powerful tools to an understandable color change from colorless to orange.
sense the Al3+ ion in CH3CN-H2O (1:1), v/v).The fluores- Therefore, probe 11a & 11b (probe 11a performance is only
cence studies of metal-free probes 10a-10c showed very low demonstrated) play a vital role in sensing Al3+ ion in the
intensity emission at 433, 433 (λex = 390, Φ = 2.02, 0.38) and methanol-water system due to inner spirolactam ring-
505 nm (λex = 440, Φ = 1.64). However on the addition of opening in rhodamine moiety and formation of delocalized
Al3+ ion towards probes 10a-10c escalates enhanced fluores- π-conjugated compound with Al3+ ion. After finding the same
cence with good quantum yield (Φ = 34.02, 2.24, 63.91). The
fluorescence enhancement changes due to the CHEF mecha-
nism and simultaneously restricts the C=N isomerization.
Props 10b and 10c along with human epithelial cells Hs27
N N
couldn’t be able to give a dominant fluorescence signal while
sufficient addition of Al3+ because of lack of cell permeability.
Al O
O
N N
13
OH

N
13
12+Al3+
Al3+
HS NH
13+Al3+

12
Fig. 12 Structure of probe 12 Fig. 13 Structure of probe 13
J Fluoresc

probe 12 can use to detect the Al3+ ion in bio-media without

any toxicity (Fig. 12).
O N O
MG-63 cells An ‘Off-on’ fluorescent signal way of an idea still
14 14+ClO- existing to detect transition metal ions in aqueous solution
tremendously, here Rajasekaran & co-workers [70] raised
similar kind of Schiff base probe 13 for detection of Al3+
ion in MeOH/H2O (1:9 (v/v), HEPES = 50 mM, pH = 7.4).
N Probe 13 shows a fluorescence band at 500 nm (λex =
N
450 nm) and enhancement of fluorescence observed upon
O N O NH2
the gradual addition of Al3+ ions. The inclined fluores-
N cence behavior is due to the CHEF effect upon binding
with Al 3+ ions. Non-toxic intervene of probe 13 on
14 NCCS cells confirmed, then the probe 13 was subjected
Fig. 14 Structure of probe 14 and its bioimage with ClO− ions
to undergo testing its ability to bind Al3+ ion in NCCS
cells. Significant fluorescence enhancement has recorded
results in cultured SGC-7901 cells by fluorescence imaging taken as proof for its ability to trace Al3+ ion in living cells
studies, these results concluded the applicability of Probes with high cell permeability (Fig. 13).
11a-11b to record the amount of Al3+ ion in living samples
(Fig. 11) with minimum toxicity. Fluorescence Chemosensors for ClO− & HClO
A well defined structured benzothiazole based Schiff base
probe 12 reported [69] for the effective detection of Al3+ ion. Hypochlorite (ClO−) is uniquely prepared by enzyme catalysis
Probe 12 shows an enolic band at a lower wavelength of from hydrogen peroxide and chloride ion. The extreme disin-
450 nm and a keto form band at a higher wavelength of fectant property of hypochlorite to bacteria in water treatment
540 nm (λex = 350 nm). This behavior is commonly known shows its degree of bio-reactivity. Though the excess amount
as excited-state intramolecular proton transfer. The binding of hypochlorite causes tissue damage, respiratory problems
ability of probe 12 to Al3+ ion by fluorometric analysis was and cancer controversially have the main role in the human
conducted and the increase in emission intensity at 480 nm immune system to raise our strength against microorganisms.
after the addition of Al3+ ion gradually. The enhancement is The intimate relationship between oxidative hypochlorite ion
probably due to the formation of an intramolecular hydrogen (ClO−) and the biological system can be utilized for accurate
bonding mechanism. Further, the sensing capacity of pro- detection of hypochlorite ion in bio-medium through cell-
posed probe 12 has tested in human cancer cells, hepatocellu- imaging study [71, 72]. Reactive oxygen species (ROS)
lar carcinoma (Huh7) by MTT study. On the interesting study, hypochlorous acid (HOCl) is involved in a number of physi-
a green fluorescence spotted when probe 12 was treated with ological and pathological processes. HOCl is produced from
Huh 7 cells in the presence of Al3+ ion. From the results, the peroxidation of chloride ions (Cl−) which is a potent oxidant

Fig. 15 Structure of probe 15 & H S OCl S

its bioimaging N
N ClO- N
N
O H OH
N O O N O O
15

Probe 15
OPM TPM OPM 15+ClO-
Probe 15

ClO-

A549 cells
15+ClO-
15 +ClO-

TPM
ClO-

Zebrafish
 J Fluoresc

Fig. 16 Structure of probes 16a-e HO O OH

and its bioimaging with HClO
ions 16a= R= 16b = R=
MeO
N R NO2
N
O
16e = R=

16c = R= 16d = R=

16a+HClO 16b+HClO 16c+HClO 16d+HClO 16e+HClO

Mouse fibroblast cells L929

16a+HClO 16b+HClO 16c+HClO 16d+HClO 16e+HClO

Human Osteosarcoma MG–63cells

and antimicrobial agent for the immune system. However, for the detection of hypochlorite ion in an aqueous solution.
abnormal production of HOCl could lead to various human The fluorescence experiment was executed to check the sens-
diseases such as cardiovascular and kidney diseases, inflam- ing behavior of probe 14 towards ClO− ions. On the addition
matory disease, neuron degeneration, and cancer [73, 74]. of ClO− ions, the fluorescence intensity emission inclined at
A renowned diaminomaleonitrile fluorescent probe 14 508, 554 nm with a descend charge transfer band at 528 nm.
based Schiff base has been designed (Kapil [75]) and applied Transparent color change also has seen on fluorometric

Fig. 17 Structure of probe 17 RAW264.7 cells

NC NH2
NC NH2 17+HOCl
O Cl
NC N
NC N
OH H
HOCl OH
17+HOCl
O N
O N

Rat Tissue
17

H2O

HO
CHO ClO

O O

N N
HO HO
J Fluoresc

Fig. 18 Structure and bioimaging

of probe 18 with Cu2+ H
H Cu2+ N
N N N
N N O
N O
N OH
O Cu2+

18

Cu2+ Cys

18 18 + Cu2+ 18-Cu2++Cys

titration between Probe 14 and ClO− ions with no hope for 50 μM concentration of probe 15 confirmed no toxic interfer-
interference. The above observation concluded that the poten- ence with those cells. The incubated A549 cells with probe 15
tial use of probe 14 for ClO− ions. More than 95% of MG-63 alone exhibit strong green fluorescence in cells by both one-
cells were survived even after the incubation of cells with photon (λex = 458) and two-photon (λex = 810 nm) microsco-
Probe 14 in 10 μM concentrations (24 h). The probe 14 could py imaging. When ClO− ions added to incubated cells along
enable detection ClO− ions in living organisms with no toxic with probe 15 the turn-off fluorescence was observed. A sim-
effect. The incubated MG- 63 cells with probe 14 observed as ilar turn of-off fluorescence change was observed in 2 days-
nil fluorescence change in cells but increased dose of ClO− old zebrafish larvae. The probe 15 exhibits good cell perme-
ions brought a bright green fluorescence that occurred. A sim- ability, low toxicity, good cell membrane penetration, and also
ilar test was conducted with a LPS (5 mg mL−1) and PMA imaging of ClO− ions selectively in living cells (Fig. 15).
(5 mg mL−1) reagent to find endogeneous ClO− ions in living New Fluorescein hydrazine linked Cinnamyl aldehyde
cells (Fig. 14). Further, the detecting ability towards ClO− ions derivative-based probes 16a-e [77] used to examine HClO in
was applied in human urine and blood serum samples. water samples. In the ethanol-water medium for probes 16a-
Coumarin linked Schiff’s base probe 15 has been synthe- 16e not showing any fluorescence. Once the probes 16a-e is
sized via simple route and probe 15 selectively detects ClO− binding with HClO, it resulted in a noticeable fluorescence
ions [76]. Probe 15 shows initially an excellent photophysical enhancement at 535 nm. The other competing anions and
property at 518 nm with good quantum yield (Φ = 0.27) and cations did not show any responses with probes 16a-e. The
highly visible green fluorescence. On gradual addition of colorless probes are changed to yellow color upon the addition
ClO− ions into probe 15 in phosphate buffer /MeOH (6: 4, v/ of HClO. The sensing of application of probes 16a-e towards
v, pH 7.4), a sharp quenching occurred at 495 nm (λex = HClO further applied in MCF-7 cells, Mouse fibroblast cells
455 nm). Under UV light the green fluorescence (probe 15) L929 and Human Osteosarcoma MG–63 cells under laser
changed to blue upon interacting with ClO− ions. Through scanning confocal microscopy. Living cells are incubated
MTT assay investigation on A549 cells with 0 μM to with probes 16a-16e for 4 h at 37 °C and followed by adding
NaClO for another 4 h. The imaging studies clearly demon-
strate the membrane permeability of the probes 16a-e and
CO detecting HClO in living cells (Fig. 16).
n
O ESIPT binding based Schiff base fluorescence probe 17
N O L
O L reported for the selective detection of HClO in PBS buffer
19 + Hg2+ (1.0 mM, pH = 7.4) [78]. The photoinduced electron trans-
19 M2+
O fer mechanism blocks the fluorescence in probe 17 and
O N
N upon the addition of HClO into probe 17, a significant
fluorescence enhancement observed at 440 nm (Φ =
19 0.65). The detection limit of probe 17 for HOCl was cal-
culated to be 0.08 μM. The RAW264.7 cells were treated
19 + Cu2+
with 200 μM HOCl for 30 min then incubated with probe
17. The changes in RAW264.7 cells monitored and imaged
through two-photon microscopy, increased fluorescence
intensity have noted in images, which then considered the
Fig. 19 Structure and bioimaging of probe 19 with Cu2+
ability of probe 17 to trace endogenous HOCl in living
 J Fluoresc

H
S R20 20 + Cu2+ 20 + Zn2+
N
N
O
N O O
20
R20 20 + Cu2+ 20 + Zn2+
R20 20 + Cu2+

20 + Zn2+

Drosophila larvae
Zebrafishes
Fig. 20 Structure and bioimaging of probe 20 with Cu2+ & Zn2+

cells. Tissue imaging studies were also conducted in pre- exploded for their potential application in HeLa cells and
pared hippocampi tissue of two weeks old rat then diffused shows fluorescence turn-off with Cu 2+ ions, and then
with 100 μM of probe 17 and 100 μM of 17-ClO at 37 °C, Cysteine was added a bright green fluorescence was observed
a very strong fluorescence obtained. From these results, the (Fig. 18).
probe 17 can apply externally to measure HOCl in tissues Fluorescent polymeric probe 19 [80] was synthesized by
(Fig. 17). tryptophan and pyridine moieties of the polymer through an
imine bond, was employed for the detection of Cu2+ and Hg2+
ions treated in neuroblastoma cells (U-87) via a fluorescence
Fluorescence Chemosensors for Cu2+
microscope. When exciting at 285 nm, probe 19 showed two
emission bands at 364 and 464 nm. Upon the addition of Cu2+
Copper (Cu2+) was found as the third most essential element
and Hg2+ ions into probe 19, a remarkable fluorescence
for plants, animals, and human beings due to its involvement
quenching at 464 nm was observed. In a competitive environ-
in the biological process like electron transfer, enzyme hydro-
ment probe, 19 selectively sense only Cu2+ and Hg2+ ions over
lysis and is an efficient catalyst for the redox process. The
other anions and cations. The emission behavior observed in
American Medical Association suggests the normal human
normal embryonic lung fibroblast cells WI-38 and neuroblas-
body should contain 1.2–1.3 mg/day of copper. Deficiency
toma cells U-87 indicated fluorescence quenching upon the
of copper cause growth failure and deterioration of the ner-
addition of Cu2+ and Hg2+ ions (Fig. 19).
vous system. When the concentration of copper ion crosses its
A small Schiff base probe 20 shows incredible bioimaging
limit in the living organism, it will produce reactive organic
responding in living cells and zebrafish [81]. Without metal
species (ROS) and consequently causes Wilson’s disease,
ions probe 20 shows intense green fluorescence in both
Alzheimer’s disease, and prion disease [31, 38].
Highly fluorescent Schiff base probe 18 [79] has been syn-
thesized via condensation method and sensitivity detects Cu2+
A549 cells+ MCF-7+
and Cysteine in PBS buffer solution. When exciting at 420 nm
R22 R22
probe 18 results in a decrease in fluorescence intensity with a
color change from yellow to colorless. Probe 18 shows strong
green fluorescence and upon the addition of Cu2+ ions, the
strong fluorescence starts quenching at 488 nm. The incre- N N
N
mental addition of Cysteine into 18-Cu2+ complex results
strongly inclined fluorescence. Molecular probe 18 was SH
N O O Cu2+
O 21+ Cu2+ 22
A549 cells MCF-7+
HC N NH
HO R22+ Cu2+ R22+Cu2+
21

Fig. 21 Structure and bioimaging of probe 21 with Cu2+ & Zn2+ Fig. 22 Structure and bioimaging of probe 22 with Cu2+ ions
J Fluoresc

fluorescence and after treated with Cu2+ ions, enhances the

fluorescence and shows a bright green color. From all the
results the author confirmed probe 21 acts as a low toxicity,
O N O Cu2+ O N O
highly biocompatible, and nontoxic to the RAW 264.7 cells.
The detection limit of probe 21 was found to be 0.26 μM
(Fig. 21).
Coumarin derivative-based fluorescent probe 22 has been
NH N Cu2+ synthesized and executed for the detection of Cu2+ ions [83].
N N
S Probe 22 alone showed a strong fluorescent emission at
S
23 540 nm when exciting at 450 nm. Upon the significant addi-
tion of Cu2+ ions into probe 22 resulted in a quenching in
fluorescence and 5-fold fluorescence declined when com-
pared with probe 22. Fluorescence imaging studies were suc-
cessfully accomplished in A549 cells and MCF-7 cells by a
Fig. 23 Structure and bioimaging of probe 23 with Cu2+ ions single-photon laser confocal fluorescence microscope. A549
and MCF-7 cells were cultured in1640 medium supplied with
hPDLCs cells & MRC-5 cells. Bright green and red fluores- 10% fetal bovine serum (FBS) and DMEM Medium supple-
cence in the cytoplasm was observed when the cell culture mented with 10% FBS at 37 °C in a humidified atmosphere of
was treated with Zn2+ ions incubated with probe 20. In the 5% CO2 respectively and incubated with 1 μM probe 22 for
case of Cu2+ ions displays no fluorescence with pre-incubated 30 min. Probe 22 showed a strong green fluorescence with
cell. In MRC-5 cells with Zn2+ and Cu2+ ions shows similar both cells when induced by excitation light source of 458 nm,
changes were observed in HPDLCs cells. Five days old after treatment with Cu 2+ ions showed fluorescence
zebrafishes are revealed only a luminous green emission with quenching (Fig. 22).
probe 20 and further added into Zn2+ and Cu2+ ions respec- A novel Schiff base probe 23 was synthesized and the
tively, which exhibited no signal emission in Cu2+ ion group probe can recognize Cu2+ ions in CH3CN-H2O (3:1, v/v, pH
and significant signal emission with Zn2+ ions. Interestingly =7.4) medium [84]. Probe 23 exhibits a strong fluorescence
probe 20 can be a very powerful sensing probe Zn2+ and Cu2+ emission at 550 nm (λex = 450 nm, Φ = 0.46). The emission
detection in living cells, good tissue permeability, and able to intensity dramatically quenched upon gradual addition of
visualize Zn2+ and Cu2+ ions in Drosophila larvae (Fig. 20). Cu2+ ions (Φ = 0.01) into the probe 23. The detection limit
Fluorescence enhancing pyrene linked Schiff base probe of probe 23 for Cu2+ ions was calculated to be 9.15 nM.
21 detects Cu2+ ions in the DMSO-H 2O medium [82]. Under UV the bright yellow fluorescence emission (probe
When exciting at 383 nm and upon the gradual addition of 23) was turn-off with Cu2+ ions. The probe 23 also can be
Cu2+ ions into probe 21, it shows remarkably fluorescence successfully applied for human hepatoma cells HepG2. The
enhancement at 467 nm with a small redshift from 463 nm. cells treated with probe 23 alone reveal a strong fluorescence
The fluorescence enhancement is occurring due to inhibition response when the addition of Cu2+ ions a noticeable fluores-
of the photoinduced electron transfer mechanism. Cell perme- cence emission decreasing occurred. The bioimaging studies
ability and biocompatible of probe 21 with Cu2+ ions were confirmed the extremely low cytotoxicity of probe 23 to the
examined in RAW 264.7 cells. Probe 21 demonstrated a weak cells and can use to penetrate the cell membrane and to detect
the presence of Cu2+ ions (Fig. 23).
O
O Liang and his coworkers developed a hydrophilic
naphthalimide based Schiff base fluorescent probe 24 for
HO N HO Cu2+ ion detection [85]. Probe 24 can selectively sense Cu2+
N ions over other common metal ions in pH 7.4 of phosphate
O N
H buffer. Probe 24 demonstrated a strong emission wavelength
24 at 532 nm when exciting at 436 nm. The addition of Cu2+ ion
induces a quenching in fluorescence with probe 24. Based on
the fluorescence titration, the detection limit was calculated to
Cu2+ 24 + Cu2+ be 0.37 nM. The probe 24 has been applied to imaging of Cu2+
24
ions detection in HeLa cells. Hela cells blemished with probe
24 for 20 min at 37 °C gives a strong green fluorescence and
the intracellular fluorescence was quenched when Hela cells
were treated Cu2+ ions (incubation with 50 μmol L−1). The
Fig. 24 Structure and bioimaging of probe 24 with Cu2+ ions author successfully applied probe 24 for detecting Cu2+ in real
 J Fluoresc

H H H H
2+ N N
N N Cu
Cu2+
N N N N

25
Fig. 25 Sensing Mechanism of Probe 25 with Cu2+

water samples are collected from the east lake of Wuhan of probe 26 for bioimaging studies in living cells was carried
(Fig. 24). out. Vero cells initially treated with 10 μM of probe 26 for
A quinoline based Schiff base probe 25 was synthesized as 24 h and IC50 value was found to be approximately 35 μM.
a Cu2+ ion-selective fluorescence sensor [86]. The emission The significant blue fluorescence from the intracellular region
spectrum of probe 25 in 8: 2, v/v MeCN: water solution ex- proves that probe 26 is applicable for imaging Cu2+ in living
hibits a non-fluorescent band at around 475 nm (λex = cells. The bioimaging in the Vero cells confirms the fluores-
410 nm), which could be enhanced with a bathochromic shift cence enhancement with excellent cell permeability. It shows
of about 35 nm in gradual addition of Cu2+ ions. The fluores- that probe 26 is biocompatible in nature and used for detecting
cence enhancement is due to the restriction of C=N bond Cu2+ ions in the cell rapidly (Fig. 26).
isomerization after the complexation of probe 25 – Cu2+ ions. Rhodamine Schiff base probe 27 was synthesized using
Further, the cytotoxic nature and bioimaging properties of the Rhodamine B hydrochloride and hydrazine hydrate [88].
probe 25 were interpreted in vitro on RAW 264.7 macrophage Probe 27 shows an excellent “off-on-type” change in fluores-
cell lines and peripheral blood mononuclear cells (PBMCs) cence with high selectivity toward Cu2+ ions and the probe 27-
respectively. PBMC cells incubated for 1 h at 37 °C with Cu2+ complex could detect Cysteine (“on-off) over other met-
probe 25 revels no fluorescence response. On addition of al ions and amino acids. Free probe 27 does not show any
Cu2+ ions to the pre-incubated cells showed an extraordinary fluorescence changes when Cu2+ ions were added to the probe
intracellular fluorescence enhancement (Fig. 25). 27 solution, a notable fluorescence enhancement has appeared
A pyrene-appended bipyridine hydrazone probe 26 was at 588 nm. The enhancement of fluorescence may be due to
used for the selective detection of Cu2+ ions in water–MeCN the ring-opening of the lactam in rhodamine. Further, the ad-
(8:2, v/v) solvent mixture over the other metal ions [87]. The dition of Cysteine into 27- Cu2+ complex the emission inten-
probe 26 does not show any fluorescence enhancement when sity gradually decreasing. The decreasing fluorescence by the
exciting the probe at 365 nm. Upon the addition of Cu2+ ions, addition of Cys indicated that Cys pulled Cu2+ from the com-
showed a remarkable fluorescence enhancement at 466 nm. plex and that the spirocycle form of probe 27 was recovered
Based on fluorescence enhancement, the sensing applicability via interaction of Cys with probe 27– Cu2+. Cytotoxicity assay
and bioimaging were performed in living cells (HepG2 cells.),
giving strong red fluorescent images (Fig. 27).
26+Cu2+ Another novel rhodamine-based Schiff base probe 28 was
easily synthesized and exhibited excellent selective and sensi-
tive detection of Cu2+ ions [89]. The complexation of the
O probe 28 with Cu2+ showed an enhanced fluorescence change
N
at 572 nm (λex = 550 nm), is presumably due to the ring-
N HN opening of the spirolactam system of rhodamine-B.
N
Upon the addition of copper, colorless probe 28 changed to
26 reddish pink. The detection limit was found to be 30.75 nM.
The significant red fluorescence from the intracellular region
proves that probe 28 is applicable for imaging Cu2+ ions in
living cells. The bioimaging in the AGS cells confirms the
fluorescence enhancement with excellent cell permeability.
It shows that probe 28 is biocompatible in nature and used
for detecting Cu2+ ions in cells rapidly (Fig. 28).
26 Two novel Schiff base probes were synthesized from readily
Fig. 26 Structure and bioimaging of probe 26 with Cu2+ ions available starting materials. N,N′-Bis(2-hydroxynaphthylidene)-
J Fluoresc

Cu2+ 27+Cu2+

O HO 27
O O

Cu2+
N N N N N N
N Cys N
OCH3 OCH3
N O N N O N
27

Fig. 27 Sensing Mechanism of probe 27 with Cu2+ ions

O
28 + Cu2+

28
HO Cu2+ OH
O

N N
N O N
+ Copper Complex
N O N
28

Fig. 28 Sensing Mechanism of probe 28 with Cu2+ ions

4-chlorophenylmethanediamine (probe 29) was reported for sen- accumulation of mercury in the human body can lead to var-
sor study and probe 29 exhibited excellent sensitive recognition ious cognitive and motor disorders, and Minamata disease. A
towards Cu2+, Co2+, and Ni2+ ions over other ions via visual major absorption source is related to daily diet such as fish
color change [90]. In the presence of Cu2+, Co2+ and Ni2+ ions [91–93].
probe 29 shows fluorescence quenching. Probe 29 forms the A simple turn-off probe 30 specific detections for Hg2+
complex with metal ions through –OH group of two naphthyl ions presented by the coordination of probe 30 with Hg2+ ions
rings in a deprotonated fashion and two imine nitrogen atoms. [94]. The detection limit of probe 30 towards Hg2+ ions was to
Probe 29 has been successfully demonstrated as a fluorescent be 0.35 nM, which indicate that the probe 30 is potential
probe for detecting Cu2+ ions in living cells (Hela cells). Once fluorescence probe for Hg2+ ions in physiological and envi-
introduce Cu2+ ions into incubated probe 29 with Hela cells, the ronmental systems. Fluorescent quenching was observed up-
low intensity fluorescence emission was observed (Fig. 29). on the addition of Hg2+ ions and the fluorescence quenching
was probably due to the heavy atom effect of Hg2+ ion follow-
ed by electron transfer. The Hela cells were loaded with 5 μM
Fluorescence Chemosensors for Hg2+
probe 30 (32 min) and the treated cells were washed with PB
solution. Turn-off fluorescence was observed from HeLa cells
Mercury (Hg2+) is well known as one of the most toxic metals
stained with probe 30 with Hg2+ ions without damage to the
and is widespread in air, water, and soil, generated by many
cells. The bioimaging in the HeLa cells confirms the fluores-
sources such as gold production, coal plants, thermometers,
cence quenching with excellent cell permeability and biocom-
barometers, caustic soda, and mercury lamps. As it can cause
patibility (Fig. 30).
strong damage to the central nervous system, the
A novel sensor based on pyrene with a triphenylmethylamine
OCH3 29 + Cu2+ (probe 31) has been developed as a highly sensitive probe for
Hg2+ ions [95]. A prominent fluorescence enhancement was
found to be in the presence of Hg2+ ions into probe 31, which
was accompanied by changes in the absorption peaks at 390,
363, and 288 nm. The fluorescence enhanced intensity due to
N N the donor site (N) hindered the photoinduced electron transfer
process when probe 31 form the coordination compound with
OH HO Hg2+ ions. Furthermore, the cytotoxicity and biocompatibility of
29 the probe 31 for monitoring Hg2+ in living cells also studied
Fig. 29 Structure and bioimaging of probe 29 with Cu2+ ions using a fluorescence microscope. Hela cells first incubated with
 J Fluoresc

N N relatively lower level of mercury in the brain. The probe 32

S had good membrane penetrability and it can be used to image
N SH
Hg2+ in Hela cells and live Zebrafish (Fig. 32).

Hg2+
Fluorescence Chemosensors for Zn2+
30
Zinc ion (Zn2+), which is the second most abundant transition
30 metal ion in the human body, plays an important role in bio-
Hg2+ 30+Hg2+ logical systems such as neuronal signal transmission, a regu-
lator of enzymes, influencing DNA–binding proteins and nu-
merous cellular functions. In addition, disorders arising from
free zinc metabolism are closely associated with many patho-
Fig. 30 Structure and bioimaging of probe 30 with Hg2+ ions logical states, such as Alzheimer’s disease, epilepsy,
Parkinson’s disease, ischemic stroke and infantile diarrhea.
probe 31 (20 min) its shows only weak green fluorescence. A decrease in the concentration of Zn2+ can cause a reduction
When adding Hg2+ ions into probe 31-Hela cells, a strong en- in the ability of the islet cells of the pancreas to produce and
hanced blue fluorescence observed. The bioimaging in the Hela secrete insulin [97–99].
cells confirm the fluorescence enhancement with good cell per- A novel Schiff base probe 33 has been synthesized, and its
meability and prove that probe 31 is biocompatible in nature and detection behavior towards Zn2+ ions is was studied in ethanol
can be used for detecting Hg2+ ions in cell rapidly (Fig. 31). & EtOH/PBS buffer solution [100]. After the addition of Zn2+
The detection of Hg2+ ions using a rhodamine-B with the ions, the solution of probe 33 displays an obvious color
diphenylselenium probe 32 was developed and utilizing turn- change from colorless to bluish green and significant 40-fold
on fluorescence enhancement [96] in H2O-CH3OH (v/v ¼ 9: fluorescence enhancement. The color change and fluores-
1) solution. Upon treatment with Hg2+ ions, the fluorescence cence enhancement are attributed to the excited state intramo-
of the probe was enhanced at 584 nm due to the formation of a lecular charge transfer mechanism, which is induced by Zn2+
2:1 complex between the probe 32 and the Hg2+ ions. At the binding. The potential application of probe 33 towards Zn2+
concentration of Hg2+ ions was increased, the fluorescence was further applied in SW620 cancer cells by fluorescence
emission intensity inclined and simultaneously an obvious imaging experiments. Under a fluorescence microscope, the
color of probe 32 change from colorless to pink. When the green fluorescence was observed upon the addition of Zn2+
ring-opening of the spirolactam in the rhodamine fluorophore ions into incubated probe 33 with living cells (Fig. 33).
and which is induced by Hg2+ binding, the enhanced fluores- Another novel Schiff base based fluorescence turn-on
cence was observed. The probe 32 first treated with 3 days old probe 34 for detecting Zn2+ was ions in the CH3CN/H2O
zebrafish for 30 min and non-fluorescence was found but a (50:50, v/v) over the interference metal ions [101]. Probe 34
strong red fluorescence was observed in zebrafish when alone showed a weak emission intensity due to the conforma-
adding the Hg2+ ions. Interestingly, clear fluorescence was tional flexibility upon isomerization of -C=N double bond
observed in the zebrafish’s heart and liver. At the same time, along with the photo-induced electron transfer mechanism.
lower fluorescence was observed in the brain, this is due to a Chelation-enhanced fluorescence effect (inhibition of the -

N 31+Hg2+
31 N Hg 2+
N Hg2+

31
Fig. 31 Sensing Mechanism of probe 31 with Hg2+ ions
J Fluoresc

Fig. 32 Structure and bioimaging

of probe 32 with Hg2+ ions Zebrafish
32 Se
O Zebrafish Brain
32
32
N N
32+Hg2+

32+Hg2+
N O N
32 32+Hg2+
Hela Cells

C=N isomerization) exhibits in the fluorescence intensity of ions. In addition, probe 36 showed high selectivity and sensi-
the probe 34 and gradually increasing at 517 nm (λex = 293) tivity for Zn2+ ions detection. The detection limit of 36 was
upon the addition of Zn2+ ions. The calculated detection limit 89.3 nM. Upon excitation 360 nm shows non-fluorescence
of probe 34-Zn2+ ions to be 4.35 nM. The detection behavior emission was observed only for probe 36 due to C=N isom-
of probe 34 towards Zn2+ ions was examined in living A549 erization. After the addition of Zn2+ ions into 36, induces a
cells. An incubated cell with probe 34 shows a weak fluores- strongly inclined fluorescence emission (inhibits C=N isom-
cence. But, a bright fluorescence is pragmatic in the presence erization) at 525 nm along with intense yellow color emission.
of Zn2+ ions in the incubated probe 34 - A549 cells (Fig. 34). The detecting behavior of probe 36 for Zn2+ ions in Hela cells
A new naphthofluorescein based probe 35 is synthesized showed a bright green fluorescence image from the intercel-
by the Schiff base condensation method and acts as a highly lular area. Live cell imaging in Hela cells confirmed the cell
selective fluorescence sensor for Zn2+ ions over other compet- permeability of probe 36 and its capability for specific detec-
ing ions [102]. High fluorescence enhancement at 575 nm tion of Zn2+ ions in living cells (Fig. 36).
(39.5 fold) exhibited upon the addition of Zn2+ ions into probe Two new Schiff base probes S,E)-11-amino-8-((2,4-ditert-
35. The trace amount of Zn2+ in real samples was detected butyl-1-hydroxybenzylidene) amino)-11-oxopentanoic acid
with this paper-based device. The tendency of probe 35 as a (37a) & (S,E)-11-amino-8-((8-hydroxybenzylidene)amino)-
bioimaging fluorescent probe to detect Zn2+ ions in human 11-oxopentanoic acid (37b) as a sensitive sensor for Zn2+ ions
cervical HeLa cancer cell lines and their cytotoxicity against over other metal ions [104]. Upon interaction with Zn2+ ions
human cervical (HeLa), SH-SY5Y cells and zebrafish cells in aqueous solution, probe 37a expresses a detectable fluores-
were been investigated. Increasing Zn2+ ions in probe 35 with cence enhancement up to 30 times due to the inhibition of
living cells induce an enhanced green fluorescence emission photoinduced electron transfer mechanism. No intercellular
under fluorescence microscopy. These results clearly demon- fluorescence was noticed upon the addition of Zn2+ ions into
strated the probe 35 could monitor the endogenous/exogenous incubated human epithelial cells Hs27 with probe 37a. A sig-
Zn2+ level changes in living cells and zebrafishes (Fig. 35). nificant fluorescence increase was observed after washing
A Schiff base based fluorescence probe 36 [N-((quinolin-8- with PBS to remove any excess Zn2+ the cells were then in-
yl)methylene)acetohydrazide] was designed and synthesized cubated with compound 37a for 30 min. Confocal fluores-
by a simple synthetic route [103]. The fluorescence probe 36 cence microscopy imaging results reveal that probe 37a can
selectively detects Zn2+ ions in the existence of other metal be used to visualize Zn2+ ions in Human epithelial cells Hs27
with low toxicity (Fig. 37).
The design and synthesis of a simple Schiff base probe 38
CF3 and its application in fluorescence turn-on detection of Zn2+
O O
OH Ar OH
34
O
N CF3 N HO
O
33
N
33 33+Zn2+ N
H
Zn2+ 34+Zn2+
N 34

Fig. 33 Structure and bioimaging of probe 33 with Zn2+ ions Fig. 34 Structure and bioimaging of probe 34 with Zn2+ ions
 J Fluoresc

Fig. 35 Sensing Mechanism of HO

HO
probe 35 with Zn2+ ions
O OH O OH
2+
Zn

N N N N

O O
O
35 HO OH Zn2+ OH

35 35+Zn2+ 35 35+Zn2+

Zebrafish
Hela Cells

ions in semi-aqueous media and bioimaging applications are the probe 39 towards Zn2+ were been examined in the Hela
studied by Wang research group [105]. The signal change of cells and zebrafish. Probe 39 demonstrated low cytotoxicity
the probe is based on Zn2+ ions inhibited the C=N isomeriza- and good biocompatibility to living HeLa cells and zebrafish
tion of the probe 38. It exhibits a high sensitive “turn-on” (Fig. 39).
fluorescence emission intensity response towards Zn2+ ions Another group reported a new and simple turn off-on fluo-
with strong inclined fluorescence (Φ = 0.32). With negligible rescent probe 40 for rapid detection of Zn2+ based on the
toxicity towards live cells, the probe 38 could be successfully inhibition of excited-state intramolecular proton transfer
employed to monitor the Zn2+ ions in live U251 cells. The (ESIPT) and C=N isomerization as well as the chelation en-
U251 cells that had been incubated for 30 min (37 °C) with hanced fluorescence(CHEF) effect [107]. The addition of
probe 38, which exhibited low fluorescence emission. The Zn2+ into probe 40 induced a significant fluorescence en-
cells after treated with Zn2+ ions significantly fluorescence hancement at 507 nm (54-fold) and concurrently a strong
increased in the intracellular area (Fig. 38). green fluorescence emission of the solution can be observed
A simple and efficient fluorescence probe 39 for the detec- under UV lamp irradiation. Moreover, the probe 40 demon-
tion of Zn2+ ions in CH3CN aqueous solution (3:7, v/v, strated excellent sensitivity (detection limit = 21 μM) and out-
HEPES 20 mM, pH 7.4) solution was reported by another standing selectivity toward Zn2+ ions. Furthermore, the probe
group [106]. When excited at 365 nm, the fluorescence emis- 40 could rapidly light-up bioimaging Zn2+ in human hepto-
sion of probe 39 at 485 nm was remarkably increased upon the carcinoma cell line HepG2 cells with low cytotoxicity and
addition of Zn2+ ions. The strong green emission of the solu- good biocompatibility (Fig. 40).
tion can be easily identified by the naked eye under UV light. A simple & novel Schiff base probe 41 synthesized and
Thus, probe 39 behaves as a naked eye fluorescent -turn on the studied their sensing behavior towards [62] Zn2+ ions in
detector for Zn2+ ions. The fluorescence enhancement might MeCN:H2O (V/V = 6:4, pH = 7.0). Due to the isomerization
be attributed to the combination of internal charge transfer of the C=N bond in the excited state and the PET process the
mechanism (ICT) and chelation enhanced fluorescence probe 41 showed weak fluorescence. Upon the addition of
(CHEF) effect. The cell cytotoxicity and biocompatibility of Zn2+ ions, a significant fluorescence enhancement was ob-
served at 570 nm along with a strong yellow-green

36 H2N
N N CH O
O R
N
N Zn2+ N 37a: tBu O
37b: H
36+Zn2+ HO
O R OH
C N N
H 37a Zn2+ 37a + Zn2+
36

Fig. 36 Sensing structure of probe 36 with Zn2+ ions Fig. 37 Structure of probe 37
J Fluoresc

Fig. 38 Sensing Mechanism of

probe 38 with Zn2+ ions N
O

O HN Zn2+
N Zn2+
N
H O N
N
38
N
N
38 38+Zn2+ H
Zn2+ N

fluorescence under UV light. The fluorescence enhancement important species has been reported. Proper bioimaging re-
happens due to the non-bonded electrons of N atom from C=N quires a non-toxic nature, bright particles with well cell per-
took part in coordination with Zn2+ ion to inhibit the PET meability & good biocompatibility.
process. The other metal ions did not show any color change In this review, various Schiff base probes and their fluores-
and fluorescence changes except Co2+, Cu2+ ions (fluores- cence sensing, bioimaging application towards detection of
cence quenching). Probe 41 shows a very low detection limit metal ions, reported in the last few years have been focused.
of 73 nM with Zn2+ ions. The potential application of probe Most of the reported fluorescence probes selectively and sen-
41- Zn2+ in the biological system was studied under fluores- sitively detect one or two metal ions only. In the reported
cence microscopy. First Hela cells incubated for 30 min with references, most of the probes detect analytes in the non-
probe 41 and did not show fluorescence. Strong green fluo- aqueous or semi-aqueous medium. So, the design and synthe-
rescence was observed after being treated with Zn2+ ion and sis of chemosensor, which can work in pure aqueous solution
probe 41 (Fig. 41). with high selectivity and sensitivity towards analytes, have
become more important. The better probes are needed to meet
their strict practical application likely that various types of
Conclusion & Future Perspectives portable practical test kit for detecting and monitoring toxic
ions in drinking water and industrial wastes. In the future, the
Schiff bases are considered as an important group of organic next-generation intelligent fluorescence probes will be capa-
probes due to their ability to detect toxic analytes in the appli- ble of detecting more than one analytes at a time without any
cation of fluorescence sensor. Fluorescence is one of the most difficulties and involving in imaging and therapeutic agents
powerful tools for detecting various heavy toxic analytes & in vivo. This review will help to readers about which material
bioimaging capabilities via confocal microscopy. to be chosen for the better bioimaging application.
Applications of Schiff bases are very large in many fields like
medicinal, bioanalysis, biological, industrial etc. In the last
decade, the application of Schiff base probes based fluores-
cence live-cell imaging for detecting various biologically H
N
N

H
N N O
N
O NH2
OH NC OH
39 40
39 39+ Zn2+
Zn2+ 40 + Zn2+
40 Zn2+

Fig. 39 Structure and bioimaging of probe 39 with Zn2+ ions Fig. 40 Structure and bioimaging of probe 40 with Zn2+ ions
 J Fluoresc

Zn2+
HO 2+ O
N Zn N
O N O N
NH 41 41 + Zn2+
EDTA NH

OH OH

Fig. 41 Sensing Mechanism of probe 41 with Zn2+ ions

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Publisher’s Note Springer Nature remains neutral with regard to jurisdic-
cence mechanism in two new Schiff bases as selective
tional claims in published maps and institutional affiliations.
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