Spectroscopic and antimicrobial activity of photoactivatable tricarbonyl Mn(I) terpyridine compounds

Article abstract of DOI:10.1016/j.ica.2020.119806

The photoinduced fac-[MnBr(CO)₃(L–k²N¹,N²)] (L = 4′-(2-pyridyl)-2,2′:6′,2′'-terpyridine (L^Py) (1) and 4′-(4-phenyl morpholine)-2,2′:6′,2′'-terpyridine (L^morph) (2)) and fac-[Mn₂B

Full text of DOI:10.1016/j.ica.2020.119806

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Research paper
Spectroscopic and antimicrobial activity of Photoactivatable tricarbonyl Mn(I)
terpyridine compounds
Ahmed M. Mansour, Krzysztof Radacki
PII:
DOI:
Reference:
S0020-1693(20)31005-7
https://doi.org/10.1016/j.ica.2020.119806
ICA 119806
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Inorganica Chimica Acta
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Revised Date:
Accepted Date:
6 March 2020
3 June 2020
4 June 2020
Please cite this article as: A.M. Mansour, K. Radacki, Spectroscopic and antimicrobial activity of
Photoactivatable tricarbonyl Mn(I) terpyridine compounds, Inorganica Chimica Acta (2020), doi: https://doi.org/
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0.1016/j.ica.2020.119806
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Spectroscopic and antimicrobial activity of Photoactivatable tricarbonyl
Mn(I) terpyridine compounds
a
b
Ahmed M. Mansour,* and Krzysztof Radacki
a.
Department of Chemistry, Faculty of Science, Cairo University, Gamma Street, Giza, Cairo 12613, Egypt. E-mail:
mansour@sci.cu.edu.eg; inorganic_am@yahoo.com
b.
Institut für Anorganische Chemie, Julius-Maximilians-Universität Würzburg,
Am Hubland, D-97074 Würzburg, Germany.

Abstract
The photoinduced fac-[MnBr(CO) (L–k N ,N )] (L = 4'-(2-pyridyl)-2,2':6',2''-terpyridine (L ) (1) and 4'-(4-
2
1
2
Py
3
phenyl morpholine)-2,2':6',2''-terpyridine (Lmorph) (2)) and fac-[Mn Br (CO) (L –k N ,N )] (L = 1,4-
DTP
2
1
2
DTP
2
2
6
bis(2,2':6',2''-terpyridin-4'yl)benzene) (3) complexes, capable of release CO at 525 nm, were synthesized
and fully characterized using different analytical and spectral tools. Compounds 1–3 had poor solubility
and decomposed in most of the organic solvents, and thus they are unsuitable for the phototherapeutic
CO applications. Reaction between azide complexes (4–6), prepared by ligand exchange of the axial Br–
ligand of 1–3, with ethyl 4,4,4-trifluoro-2-butynoate afforded triazolato complexes (7–9), which had good
solubility in the organic solvents. The potential of 7–9 to act as photoinduced CO releasing molecules was
studied at two excitation wavelengths, 468 and 525 nm. The ligand Lmorph and its complex (8) were strongly
potent to Escherichia coli, Candida Albicans and Cryptococcus neoformans. All the ligands and complexes
(except 8) exhibited cytotoxicity to the normal human cell line; human embryonic kidney cells (HEK293)
and good compatibility with the human red blood cells (RBCs) at 32 μg/mL.
Keywords: Photoactivatable; Metal Carbonyls; Biological activity; iClick reaction

Introduction
1
The interesting biological effects (anti-inflammatory, anti-proliferative and signalling properties)
2
of carbon monoxide, in the concentration range of 10–250 ppm, encouraged some research
groups to explore the ways by which CO can be selectively and specifically administrated without
delivering whole toxicity to the whole body. Carbon monoxide releasing molecules (CORMs) were
introduced as alternative way to the inhalation system, which required the patient to be exposed
to elevated levels of CO to build up a realistic concentration in the target issue to attain a desired
3
biological effect. Although different CO triggered methods such as change of pH value, redox-
4
5
6
state, enzymatic, and thermal were used to promote the CO release, the photochemical way
offered advantages of location specification and dose control as well as the choice of the starting
time. However, one of the main challenges in the field of CORMs is how to stop the releasing
process at a certain stage if the induced source turns off. While, the CO release properties of
7
[
Mn (CO) ] (CORM-1) and Fe(CO) were early studied by Motterlini group, the name
2
10
5
'
'PhotoCORM'' was latterly introduced in 2010 by Ford and co-workers to specify the class of
8
photoinduced CO releasers. Some metal carbonyl complexes of manganese, iron, ruthenium,
molybdenum, tungsten and rhenium were investigated in the context of CORMs.9-11 In recent
years, there has been an extensive interest in optimization of the prerequisites of CORMs; the
dark stability, solubility in water or in a medium suitable for the biological applications as well as
leaving of a non-toxic residue (iCORM). One of the synthetic methods to reduce the side effects
1
2
of iCORM is to conjugate metal carbonyls to biomolecules. Initially, fac-Mn(CO) complexes of
3
tris(pyrazolyl)methane ligands were investigated as CO releaser upon the illumination at 365 nm.13
By extension of the conjugation system of the coligand, visible-light induced PhotoCORMs came
to light to increase the penetration depth of light into tissues and minimize the harmful effects of
the UV light.14-16 However, the shift of the MLCT band of PhotoCORMs into the red region may be
1
7
challenged with their instability in the dark. Chardon-Noblat and co-workers used terpyridine

1
8
ligands for synthesizing light sensitive di- and tricarbonyl Mn(I) complexes, in which the mode of
2
1
2
coordination changed during the illumination at 372 nm from ĸ N ,N to tridentate manner. By
replacement of terpyridine ligand system with 2,6-bis(benzimidazole-2´-yl)pyridine, the excitation
wavelength was moved to 468 nm.19,20
2
1
In 2011, the term iClick (inorganic click) reaction was introduced by Veige et al. to characterize
the free catalyst [3+2] cycloaddition reaction of Au(I)-N with Au(I)-CΞC-R. However, reaction of
3
metal azides with some electron deficient organic compounds e.g. alkynes, cyanides and
2
2
21
isothiocyanates were early reported. In addition to gold(I) azide, azide compounds of other
metal ions were investigated in the context of iClick reaction.23,24
In the present contribution, mono- and binuclear photoactivatable manganese(I) complexes 1–3
were synthesized as shown in Scheme 1. Compounds 1–3 had poor solubility or decomposed in
most of the organic solvents. To improve the solubility, the bromo complexes 1–3 were
transformed into triazolate analogues 7–9 (Scheme 1) via azide formation and coupling with
electron poor alkyne. Binuclear complexes (Scheme 1) were synthesized to increase the total
amount of photo-generated CO per the molecular unit upon the illumination at 525 and 468 nm.
TDDFT calculations were executed to get an insight into a correlation between the position of
–
MLCT and the nature of the axial ligand (Br versus triazolato). Finally, the ligands and complexes
(7–9) were screened for their potential antimicrobial activity against representative pathogenic
bacteria and fungi.

3
Scheme 1: Synthesis of fac-Mn(CO) based terpyridine compounds 1–9.

Results and discussion
Synthesis of ligands and complexes
Py morph
DTP
The terpyridine ligands (L , L
and L ) (Scheme 1) were synthesized in a pure and good yield
2
5
by condensation of 2-acetylpyridine with the corresponding aldehyde (Fig. S1–4). In the dark,
2
1
2
reaction of one equivalent of terpyridine ligand with [MnBr(CO) ] afforded [MnBr(CO) (L–k N ,N )]
5
3
Py
morph
DTP
2
1
2
(
L = L (1) and L
(2)) and [Mn Br (CO) (L –k N ,N )] (3). Compounds 1–3 were mainly
2
2
6
characterized by elemental analysis, AT IR (Fig. S5), and ESI-MS because of the poor solubility in
the organic solvents and/or decomposition. Representative spectra for decomposition of 1–3 in
the DMSO are shown in the supporting information (Fig. S6 and Fig. 7). The IR spectra (Fig. S5) of
–1
–1
1
–3 show three strong bands at (2011, 1920, 1892 cm ) (1), (2015, 1945, 1885 cm ) (2) and (2024,
–1
1
920, 1893 cm ) (3) corresponding to the symmetrical and two anti-symmetrical stretching
modes of three CO molecules arranged in a facial mode. The ESI-MS spectra of 1–3 show
+
characteristic peak ({[M–Br]} ) at m/z = 449.0434 (1), 533.1014 (2) and 898.9658 (3).
–
Abstraction of the axial Br ligand of 1–3 was carried out using silver(I) trifluoromethane sulfonate
in the dark at the room temperature. Treatment of the filtrate with a slightly excess of sodium
azide yielded azide complexes (4–6) (Fig. S8–11). Azide complexes 4–6 have better solubility in
chloroform and DMSO than 1–3. The IR spectra of 4–6 (Fig. S8) show ν(N ) band in the range of
3
-1
2
1
2
2
042–2045 cm . The explicit proof of the ĸ N N mode of chelation of the terpyridine ligands was
s
obtained from the X-ray crystallographic analysis of 5 (Fig. 1). Compared to 1–3, the ν (C≡O) mode
–1
as
of 4–6 is observed at a lower wavenumber (2006 cm ), while the ν (C≡O) modes are seen at
–1
higher wavenumbers (1937–1928 and 1898–1897 cm ). The ESI-MS spectra of 4 and 6 show the
+
{
[M–N ]} fragment at m/z = 449.0439 and 860.0589, respectively. Besides, the fragment
3
+
corresponding to ({[M–N ][M]} ) is observed in the spectra of 4 and 5 at m/z = 940.0964 and
3
1
3
13
1
108.2126, respectively. The C NMR spectrum of 5 shows three CO signals at δ = 222.4, 219.1
1
13
2
1
2
and 216.7 ppm (Fig. S10). The H and C NMR of 4–6 display the pattern of the ĸ N ,N mode of
coordination for the terpyridine ligand system (Fig. S9–11).
Stirring compounds 4–6 with ethyl 4,4,4-trifluoro-2-butynoate in acetone for 5 days yielded
triazolate complexes 7–9. The cycloaddition coupling between 4–6 and alkyne was followed by IR
and NMR spectroscopy (Fig. S12–14). The azide and triazolate C=O stretching modes were used as
guide bands. The IR spectra (Fig. S12) of 7–9 are characterized by a band in the range of 1726–

–1
13
1
704 cm assigned to triazolate C=O vibration. The C NMR spectrum of 7, as a representative
1
3
13
example, shows the CO signals at δ = 222.4, 218.7 and 215.7 ppm, ester C=O signal at δ = 164.6
ppm, as well as two characteristic signals for C–CF at δ = 139.1 and 121.8 ppm (Fig. S13). The ethyl
3
1
19
signals are observed at δ = 4.22 and 1.25 ppm in the H NMR of 7 (Fig. S13). Only one singlet F
1
9
1
signal (δ = –59.8 ppm) is detected in the F NMR spectrum of 7. Examination of the NMR ( H and
19F) spectra of 7 confirmed that triazolato ligand binds metal ion through N(2) atom. Therefore,
isomerization from the initially formed N(1)–bonded form to a more favoured type completely
occurred during the reaction. The N(2)–bonded mode, observed here, compares well with the
previously reported published crystal data of fac-[MnL(CO) (N(2)-triazolato)] (L = 1-
3
2
6
24
dimethylamino-2-diphenyl phosphinoethane and bipyridine ).
Crystal structure
Single crystal X-ray diffraction analysis of 5 shows that the complex crystallizes in the monoclinic
space group P2 /c. The single crystals of 5 were obtained by diffusion of n-hexane into the solution
1
of 5 in chloroform. Relevant crystallographic parameters as well as the selected bond lengths (Å)
and angles (°) are shown in Fig. 1. The octahedral structure of 5 is composed of three CO ligands
[
Mn–C(1) = 1.797(2) Å, Mn–C(2) = 1.802(2) Å and Mn–C(3) = 1.826(3) Å], arranged in a facial mode,
2
1
2
morph
k N ,N bidentate L
[MnN1_1 = 2.079(2) Å and MnN7_1 = 2.036(2) Å] and azide ligand
2
1
2
[
(
MnN1 = 2.097(2) Å]. The crystal data of 5 compared well with those of [MnBr(tpy–ĸ N ,N )(CO) ]
3
1
8
tpy = 2,2´:6´,2´´-terpyridine); a difference of ± 0.05 Å is observed for Mn–C bonds as well as the
1
8
MnN1_1 and MnN7_1 bonds are 0.026 and 0.009 Å shorter than that published. The non-
coordinating N14_1 atom is in a cis-position to the azide group with N1_1–C6_1–C13_1–N14_1
dihedral angle of 125.2°. The non-coordinated pyridine ring is rotated from the equatorial plane
as defined by the dihedral angle N1_1–C6_1–C13_1–C18_1 of 59.2°. The azide group is linear (<
1
77.4°) and has an angle of 118.8° with the Mn(I) ion. The azide group is involved in hydrogen
bond with chloroform with a distance of N…C = 3.140 Å and bond angle of 142.1°.

Fig. 1: Molecular structure of 5 (thermal ellipsoids are shown at 50% probability level), H-atoms are omitted for clarity.
3
29 3 7 4 1
C H23Cl MnN O , Mr = 694.83, yellow needle, 0.259 × 0.078 × 0.033 mm , monoclinic space group P2 /c, a = 14.198(4) Å,
3
–3
–1
b = 7.011(2) Å, c = 29.931(6) Å,  = 99.123(10)°, V = 2941.8(14) Å , Z = 4, calcd = 1.569 gcm ,  = 0.771 mm , F(000) = 1416,
2
T = 100 (2) K, R1 = 0.0490, wR = 0.0883, 6739 independent reflections [2 ≤ 55.144°] and 397 parameters. Selected bonds (Å)
and angles (°) MnC1 1.797(2), MnC2 1.802(2), MnC3 1.826(3), MnN1 2.097(2), MnN1_1 2.079(2), MnN7_1 2.036(2),
C1O1 1.151(3), C2O2 1.147(3), C3O3 1.139(3), C1MnC2 88.2(1), C1MnC3 90.4(1), C1MnN1 178.3(1), C1MnN1_1
9
8.00(9), C1MnN7_1 85.04(8), C2MnC3 86.0(1), N1MnC2 90.41(9), C2MnN1_1 171.98(9), C2MnN7_1 96.14(9),
N1MnC3 90.46(9), C3MnN1_1 98.97(9), C3–Mn–N7_1 175.03(9), N1–Mn–N1_1 83.29(8), N1–Mn–N7_1 85.04(8), and
N1_1–Mn–N7_1 78.42(8).
Photoactivatable CO release properties
In the dark, the dichloromethane solution of 1 is stable for 16h with no change in the electronic
absorption spectrum. The UV/Vis spectrum of 1 is characterized by a band at 442 nm with a tail
extended to 600 nm (Fig. 2). The calculated TD-CAM-B3LYP/def2SVP spectrum of 1 shows three
main bands at 358, 291 and 261 nm corresponding to HOMO–1→, HOMO–4→ and HOMO–
6
→LUMO transitions, respectively. As shown in Fig. 3, the lowest energy band has a ground-state
*
composed of d(Mn) and excited state of ligand π orbitals and thus the transition at 358 nm is
MLCT in nature. Illumination of 1 to 468 nm LED for 10s leads to grow of two extra bands at 544
and 785 nm (Fig. 2a). Further illumination results in a decrease in the intensities of the bands at
5
44 and 785 nm and the plateau is reached after one min. The main features of the photolysis
process are not changed upon switching the illumination wavelength from 468 to 525 nm in which
two new electronic transitions are observed at 537 and 777 nm and their intensities are increased
up to 5 min of the illumination (Fig. 2b). Later, and until the end of the observation time at 40 min,
the intensities of all bands decrease. The grownup of the bands at longer wavelengths may be
attributed to an increase in the conjugation π-system of the complex as a result of change of the
Py
coordination mode of L from a bidentate to a meridional tridentate one via the loss of CO
molecule(s) in presence of a noncoordinating solvent.

a)
b)
2 2
Fig. 2 UV/Vis spectral changes of 1 (0.3 mM, in CH Cl ) upon photolysis at a) 468 nm and b) 525 nm for 0–5 and 0-40 min after
pre-incubation in the dark for 16 h.
Fig. 3: Selected Frontier molecular orbitals and the calculated lowest energy transition obtained by B3LYP/def2-SVP and TD-
PCM(DMSO)/CAM-B3LYP/def2-SVP methods, respectively.

Compound 2 behaved similarly to 1 upon the illumination at 468 and 525 nm (Fig. S15). The
binuclear complex 3 had poor solubility in dichloromethane and it was difficult to investigate the
–
photolysis process. Replacement of the axial Br in 1 by triazolato ligand (7) induces a blue-shift
for the lowest energy transition by about 44 nm (Fig. 3). As shown in Fig. 3, the transition at 329
nm (HOMO–1→LUMO) is MLCT in nature. Illumination of a pre-incubated sample of 7 (in
dichloromethane) at 468 nm gives rise to a two-step process. First, two new bands at 513 and 767
nm grow, with an increase in their intensities up to 40 s of illumination time. Till the end of the
exposure time at 5 min, the intensities of these bands decrease (Fig. S16). In comparison, while
compound 1 needs one min to reach a plateau value at excitation wavelength 468 nm, compound
7
attains this state within 5 min under similar experimental conditions. The kinetics of the green-
light induced CO release of 7 (Fig. 4) are slower than that reported for 1. Therefore, it is supposed
–
that introduction of σ-donating Br in the axial position may provide more electron density to the
metal centre than triazolate moiety, which in turn destabilizes the Mn–CO bonds. The illumination
profiles of 9 at the excitation wavelengths, 468 (Fig. S17) and 525 nm (Fig. 5) closely resemble
those obtained for the mononuclear complexes. Complex 9 has poor solubility in CH Cl . A minor
2
2
change in the electronic absorption spectrum of 9 in DMSO when kept in the dark for 16h. This
–
may be attributed for exchange of Br with DMSO molecules as previously reported for other fac-
2
7
MnBr(CO) based complexes. The plateau level of the CO release of 9 is attained after 6 and 200
3
min of illumination at 468 and 525 nm, respectively, compared to 5 and 135 min previously
reported for the mononuclear complex 7.
2 2
Fig. 4 UV/Vis spectral changes of 7 (0.32 mM, in CH Cl ) upon photolysis at 525 nm for 0–145 after pre-incubation in the dark
for 16 h.

Fig. 5 UV/Vis spectral changes of 9 (0.25 mM, in DMSO) upon photolysis at 525 nm for 0–200 after pre-incubation in the dark
for 16 h.
The dark stability and the photo triggered release of CO from 1, 3 and 8, as representative, was
2
8
investigated by myoglobin (Mb) assay. Although, the assay suffers from few drawbacks such as
2
9
CO release dependent on the quantity of the dithionite, interferences from the highly coloured
CORMs, and the instability of the myoglobin solution for the long time, it is still a simple
spectrophotometrically assay to quantitatively estimate the number of photogenerated CO
molecules. In this experiment, a freshly prepared solution of CORM in DMSO (10 μM) was added
to a standard buffered reduced solution of Mb. The stability of the Mb solutions was followed in
the dark for 16h. No spectral changes were observed during the incubation for 16 h. The spectral
change in the Q-band of Mb was investigated at two excitation wavelengths (525 and 468 nm).
The conversion of Mb into MbCO was followed until no more spectral changes were observed.
During the illumination, two new bands assigned to MbCO grow at 540 and 577 nm, while the
intensity of the band at 557 nm decreases (Fig. 6). The photolysis kinetics at 525 nm are slower
than 468 nm illumination. About 4 equivalents of CO were photo liberated upon illumination of 3
at 525 nm for 200 min (Fig. S18). A significant change in the Q-band of Mb was observed upon
illumination of 3 at 468 nm (Fig. 6). Illumination of Mb solution at 468 nm leads to release of 3.00
–
2
±
0
2
0.03 (1), 5.66 ± 0.16 (3) and 2.64 ± 0.03 (8) with a rate constant of (0.76 ± 0.01) × 10 (1), (7.0 ±
–2
–2
-1
.05) × 10 (3) and (5.0 ± 0.03) × 10 (8) s and t value of 1.52 ± 0.03 (1), 1.68 ± 0.04 (3) and
1
/2
–
.22 ± 0.15 (8) min. In comparison, the presence of Br in the axial position of the investigated
PhotoCORMs facilitates the CO release (low t ) with a good yield of MbCO.
1
/2

Fig. 6: a) Relation between the concentration of MbCO (μM) and time (min) upon the exposure of the myoglobin solution at 468
nm for 8 min. b) UV/Vis spectral changes in the Q-band region of myoglobin (60 µM in 0.1 PBS at pH 7.4) with sodium dithionite
(10 mM) and complex 1 (10 µM) under a dinitrogen atmosphere upon the photolysis at 468 nm.
Antimicrobial and cytotoxic activity
The antimicrobial activity of the free ligands and their manganese(I) complexes (7–9) was
evaluated against gram-negative (Escherichia coli, Pseudomonas aeruginosa, Acinetobacter
baumannii and Klebsiella pneumoniae) and gram-positive bacteria (Staphylococcus aureus) in the
−1
dark. The compounds were initially screened at a fixed concentration (32 μg mL ), with a
3
0
maximum of 0.5% DMSO. The toxicity (MIC) is measured by a dose-response assay. The ligands
except Lmorph) are nontoxic to all the test microorganisms. The ligand with morpholine appendage
(
3
1
was potent to Escherichia coli (MIC = 2 μg/mL, equivalent to 5.1 μM). As shown in Table 1,
−1
triazolato complexes 7 and 9 are inactive at the tested concentration 32 μg mL . Morpholine
complex 8 behaves similarly to their parent ligand against Escherichia coli with MIC value of 8
3
4
μg/mL (equivalent to 10.8 μM). Thus, the toxicity of the morpholine ligand was reduced upon
the complexation of metal ion.
The nosocomial bloodstream infections are mainly due to Candida albicans, and Cryptococcus
3
2
neoformans. Numerous classes of antifungal drugs are inadequate to treat life-threatening infections or
3
3
are unavailable to treat the mucosal or systemic infections. Generally, the title ligands and complexes
except LDTP) exhibit antifungal activity, with MIC values in the range of μg/mL (Table 1). The fungus,
(
Cryptococcus neoformans, is more sensitive to the title compounds than Candida albicans. Morpholine
based ligand is more toxic against the fungal species than the other terpyridine ligands.

Table 1 Minimum inhibitory concentration (μg/mL) determined for the terpyridine ligands and their
#
complexes (7–9).
E.
coli
>32
K.
pneumoniae baumanni
A.
P.
aeruginosa
>32
>32
>32
>32
>32
>32
Py
L
L
L
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
morph
DTP
2
>32
>32
8
7
8
9
>32
S.
aureus
>32
>32
>32
C.
C.
albicans
neoformans
Py
L
32
8
>32
4
32
4
>32
4
morph
L
LDTP
7
>32
8
9
>32
>32
16
>32
16
8
#
Full names: Staphylococcus aureus ATCC 43300, Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 700603, Acinetobacter baumannii ATCC 19606,
Pseudomonas aeruginosa ATCC, Candida albicans ATCC 90028 and Cryptococcus neoformans var. grubii H99; ATCC 208821.
As shown in Table 1, compound 7 is more toxic than 8 with lower MIC value against the tested pathogenic
fungi. Complex 9 was found to be potent only against Cryptococcus neoformans. Therefore, coordination
of the inactive LDTP ligand to metal ion led to an improvement the toxicity against the fungal species.
It is believable that many organic and inorganic compounds simply have general toxicity that is not related
to microbes, but also affects normal human cells. To discourse this issue, the toxicity of the compounds
was evaluated by measuring cell viability of the noncancerous human embryonic kidney cells (HEK293)
and blood compatibility with the cell components. Non-toxic compounds were defined with CC >32
5
0
μg/ml and HC >32 μg/ml (the concentration at 10% hemolysis). As shown in Table 2, while the ligands
1
0
(
LPy and LDTP) and complexes (8 and 9) exhibit no cytotoxicity to HEK293, the other tested compounds
cause severe activity; 7 (7.42 μM) and Lmorph (47.3 μM). The haemolysis parameters (HC and HC ) are
1
0
50
given in Table 2. Generally, the title compounds exhibit negligible haemolysis. Based on the biological
assays, complex 8 exhibits a broad spectrum of toxicity against Escherichia coli, Candida albicans, and
Cryptococcus neoformans as well as no toxicity to non-malignant HEK293 cells and hence greatest
potential for further biological studies is required.34

Table 2 CC50 values (μg/mL) and RBCs (HC10, HC50) determined for the terpyridine ligands and their complexes
7–9).
(
HEK293
RBS
HC10
>32
>32
>32
>32
>32
>32
HC50
>32
>32
>32
>32
>32
>32
PY
L
>32
18.62
>32
4.878
>32
morph
L
LDTP
7
8
9
>32
Full name: Human embryonic kidney cells (HEK293). The percentage of growth inhibition was calculated for each well, using the Negative Control (media only) and
Positive Control (cell culture without inhibitors) on the same plate as references
Conclusion
In summary, the photoactivatable CO releasing properties of mono- and binuclear tricarbonyl
terpyridine Mn(I) complexes were investigated. The bromo complexes had poor solubility and
decomposed in some organic solvents. To improve the solubility of this class of manganese(I)
–
–
tricarbonyl complexes, the bromo complexes were initially modified by exchange of Br with N3
followed by coupling with electron poor alkyne to give triazolate complexes. The triazolate
complexes had better solubility in the organic solvents than bromo analogues, but they released
CO slower under the same experimental conditions. Another advantage of the introduction of
triazolato ligand is addressing the concern about the exchange of the axial bromo ligands with
2
7
coordinating solvent molecules during the incubation process and/or dissolution step. The
observed electronic transitions were assigned with the aid of TDDFT calculations. Introduction of
-
σ-donating Br in the axial position of CORMs may provide more electron density to the metal
centre than triazolate moiety, which in turn accelerates the CO release. Functionalization of
terpyridine ligand with morpholine moiety gave rise to compounds with interesting antimicrobial
activity against Escherichia coli, Candida Albicans and Cryptococcus neoformans. The toxicity of
morpholine ligand (5.1 μM) towards Escherichia coli was reduced upon metal carbonyl formation
(10.8 μM). The investigated compounds (except morpholine complex with triazolato ligand)
induced severe toxicity to non-malignant HEK293 cells and consequently the latter mention
compound should have the greatest potential for further investigation as antimicrobial agent.
Experimental section
Materials and instruments

Degassed solvents and argon atmosphere were used in synthesis of terpyridine ligands and their
Mn(I) complexes. The chemicals were purchased from commercial sources and used as received.
MnBr(CO) ] was obtained from Strem Chemicals. Terpyridine derivatives (L and Lmorph) were
Py
[
5
synthesized by following the published procedure.35 1H, C and F NMR spectra were recorded
13
19
1
13
1
19
with Brucker-Avance 500 ( H, 500.13 MHz; C{ H}, 125.77 MHz; F, 470.59 MHz) and Brucker-
1
13
1
Avance 400 ( H, 400.40 MHz; C{ H}, 100.70 MHz) spectrometers. Electrospray mass spectra were
run with a ThermoFisher Exactive Plus instrument with an Orbitrap mass analyzer at a resolution
of R = 70.000 and a solventflow rate of 5 µL min. UV/Vis spectra were recorded on an Agilent 8453
diode array spectrophotometer. Elemental micro-analysis was performed with a Vario Micro Cube
analyzer of Elementar Analysensysteme or an EA 3000 elemental analyzer from HEKtech. For
synthetic organometallic compounds, the sensitivity of M–C, M–N, ….etc. bonds towards
3
6
oxidation often complicate the elemental analysis data. In addition, the elemental analyses of
metal azide and triazolate compounds sometimes fall outside the acceptable error. Therefore, the
reported error (> 0.4%) in the elemental analysis of some of azide and triazolate compounds is
expected. IR spectra were recorded in the solid state on a Nicolet 380 FT-IR spectrometer
equipped with a smart iFTR accessory.
Synthetic procedures
Synthesis of terpyridine ligands
LDTP.37 This terpyridine derivative was prepared in one step reaction rather than that previously
reported in the literature. To a round flask charged with terephthaldehyde (10 mmol, 1.34 g), 2-
acetylpyridine (80 mmol, 9.68 g), potassium tert-butoxide (6.50 g), and ammonia solution (70 mL),
1
00 mL ethanol was added and then the reaction mixture was stirred for 20h, whereupon
yellowish white precipitate was formed. The precipitate collected and washed several times by
water. Recrystallization was performed from 2:1 chloroform/methanol mixture. Yield: 77% (4.17
g, 7.71 mmol). IR (ATR, diamond): ν = 3060 (w, CH), 1578, 1466, 1416, 1387, 1261, 1120, 987, 789,
-1
1
3
7
34 cm . H NMR (CDCl , 400.40 MHz): δ = 8.80 (s, 4H, central py-H), 8.75 (d, J = 4.1 Hz, 4H, py-
3
H,H
H6), 8.68 (d, 3JH,H = 8.3 Hz, 4H, py-H3), 8.05 (s, 4H, ph-H), 7.88 (td, 3JH,H = 7.6 Hz, 4JH,H = 1.5 Hz, 4H,
DTP
py-H4), 7.36 (m, 4H, py-H5) ppm. Because of the poor solubility of L , it was difficult to record
1
3
the C NMR spectrum. C H N ·H O: C 77.40, H 4.69, N 15.04, found: C 77.11, H 4.38, N 15.03.
3
6
24
6
2
Synthesis of 1–3

Py
morph
DTP
Terpyridine ligand (0.36 mmol, L , 112 mg; L
, 143 mg; L , 194 mg) and [MnBr(CO) ] (0.36
6
mmol, 100 mg (1 and 2); 108 mml, 300 mg (3)) were dissolved in anhydrous degassed acetone (20
mL) and the reaction mixtures were heated to reflux for 15 h under argon atmosphere. Red
precipitates were collected by filtration, washed with CHCl , diethyl ether and dried in vacuo.
3
1: Yield: 86% (179 mg, 0.34 mmol). IR (ATR, diamond): ν = 3076 (w, CH), 3059 (w, CH), 2011 (vs,
-1
C≡O), 1920 (vs, C≡O), 1892 (vs, C≡O), 1611 (m, CC/CN), 1587, 1471, 1411, 1306, 992, 780, 741 cm .
1
3
H NMR ([D ] DMSO, 400.40 MHz): δ = 9.25 (s, 2H), 8.97 (d, J = 8.2 Hz, 1H), 8.82 (m, 2H), 8.57
6
H,H
(
d, 3JH,H = 8.9 Hz, 1H), 8.47 (s, 1H), 8.31 (t, 3JH,H = 8.9 Hz, 1H), 8.09 (m, 2H), 7.97 (d, 3JH,H = 7.6 Hz,
H), 7.75 (t, 3JH,H = 7.2 Hz, 1H), 7.63 (m, 2H) ppm. C NMR ([D ] DMSO, 100.68 MHz): δ = 163.2,
13
1
1
1
6
58.1, 157.5, 156.6, 153.1, 151.3, 150.2, 149.3, 148.4, 139.2, 137.8, 137.2, 126.4, 125.5, 125.0,
24.9, 124.4, 123.7, 122.4, 118.9 ppm. Because of the poor solubility of 1, it was difficult to detect
1
3
+
+
the CO signals. ESI-MS (positive mode, acetone): m/z = 528.9695 {[M+H]} , 449.0434 {[M–Br]} ,
+
3
2
97.0484 {[M–2CO–Br]} . C H BrMnN O ·0.33H O: C 51.61, H 2.76, N 10.47; found: C 51.60, H
2
3
14
4
3
2
.95, N 10.62.
2: Yield: 82% (183 mg, 0.30 mmol). IR (ATR, diamond): ν = 3071 (w, CH), 2854 (w, CH), 2015 (vs,
-1
C≡O), 1945 (vs, C≡O), 1885 (vs, C≡O), 1599, 1528, 1215, 1119, 927, 791 cm . The complex has poor
solubility in most of the organic solvents, and decompose in [D ] DMSO, and thus it is difficult to
6
+
record the NMR spectra. ESI-MS (positive mode, acetone): m/z = 613.0276 {[M+H]} , 533.1014
+
+
{
[M–Br]} , 505.1065 {[M–Br–CO]} . C H BrMnN O ·1.5H O: C 52.52, H 3.94, N 8.75, found C
2
8
22
4
4
2
5
2.17, H 3.82, N 9.10.
3: Yield: 78 % (278 mg, 0.28 mmol). IR (ATR, diamond): ν = 3050 (w, CH), 2024 (vs, C≡O), 1920 (vs,
-1 1
C≡O), 1893 (vs, C≡O), 1609 (s, CC/CN), 1429, 787 cm . H NMR ([D ] DMSO, 400.40 MHz): δ = 9.20
6
(d, 1H), 9.13 (s, 1H), 9.06 (d, 1H), 8.83 (s, 1H), 8.44 (m, 1H), 8.35 (m, 1H), 8.11 (m, 1H), 8.04 (m,
1
H), 7.78 (m, 1H), 7.66 (m, 1H) ppm. Complex 3 has poor solubility in [D ] DMSO and it was difficult
6
1
3
+
to record the C NMR spectrum. ESI-MS (positive mode, acetone): m/z 898.9658 {[M–Br]} ,
+
+
6
79.1273 {[M–Br–Mn(CO) Br]} , 627.1322 {[L+Mn+CO+2H]} . C H Br Mn N O : C 51.56, H 2.47,
3
42 24
2
2
6
6
N 8.59; found C 51.10, H 2.66, N 8.65.
Synthesis of 4–6
Caution:

Organometallic azide compounds may be subjected to unexpected violent decomposition. In
addition, scratching of the contaminated complexes with traces of sodium and/or silver azide
leads to explosive reactions. Therefore, handling and purification with great care is critical.
Silver trifluormethane sulfonate (0.5 mmol; 129 mg (1 and 2); 1.0 mmol, 258 mg (3)) was added
to the suspension solutions of complexes (1, 190 mg; 2, 220 mg; 3, 351 mg) in acetone and the
reaction mixtures were stirred in the dark for 3 h. Silver bromide was filtered off. Sodium azide
(65 mg (1 and 2); 130 mg (3)) was added to the filtrate and stirring was continuing overnight. Small
quantity of silver azide was carefully filtered off. Solvent was removed and the resulting
precipitate was washed with water, diethyl ether and dried in vacuo.
4
2
9
: Color: orange powder. Yield: 83% (147 mg, 0.30 mmol). IR (ATR, diamond): ν = 3049 (w, CH),
042 (vs, N ), 2006 (vs, C≡O), 1935 (vs, C≡O), 1898 (vs, C≡O), 1614 (m, CC/CN), 1548, 1403, 1222,
3
-1
1
3
93, 782 cm . H NMR (CDCl , 400.40 MHz): δ = 9.18 (d, J = 8.9 Hz, 1H), 8.99 (s, 1H), 8.85 (d,
3
H,H
3JH,H = 8.9 Hz, 1H), 8.81 (d, 3JH,H = 8.9 Hz, 1H), 8.39 (d, 3JH,H = 8.9 Hz, 1H), 8.24 (s, 1H), 8.05 (t, 3JH,H
=
.9 Hz, 1H), 8.00-7.94 (m, 3H), 7.89 (t, 3JH,H = 6.3 Hz, 1H), 7.53 (m, 2H), 7.44 (m, 1H) ppm. C NMR
13
8
(
CDCl , 100.68 MHz): δ = 207.5 (C≡O), 164.0, 158.3, 157.0, 153.1, 152.0, 150.6, 149.8, 148.8, 138.5,
3
1
37.6, 137.4, 125.9, 125.6, 125.3, 125.1, 124.2, 123.3, 120.1, 121.6, 118.9 ppm. ESI-MS (positive
+
+
mode, acetone): m/z = 940.0964 {[M–N ][M]} , 449.0439 {[M–N ]} . C H MnN O : C 56.22, H
3
3
23 14
7
3
2
.87, N 19.95; found: C 56.14, H 3.33, N 18.72.
5: Color: red powder. Yield: 78% (161 mg, 0.28 mmol). IR (ATR, diamond): ν = 3364 (br), 3070 (w,
CH), 2864 (w, CH), 2042 (vs, N ), 2007 (vs, C≡O), 1937 (vs, C≡O), 1886 (vs, C≡O), 1599, 1477, 1227,
3
-1 1
1
120, 925, 789 cm . H NMR ([D ] DMSO, 500.13 MHz): δ = 9.17 (1H), 9.00 (1H), 8.93 (1H), 8.81
6
1
3
(
1H), 8.31 (1H), 8.11 (4H), 7.97 (1H), 7.75 (1H), 7.63 (1H), 7.12 (2H), 3.76 (4H), 3.26 (4H) ppm. C
NMR ([D ] DMSO, 125.75 MHz): δ = 222.4 (C≡O), 219.1 (C≡O), 216.7 (C≡O), 162.2, 158.0, 156.5,
6
1
1
56.3, 152.7, 152.6, 149.6, 149.4, 149.1, 139.2, 137.1, 128.6, 126.2, 125.0, 124.8, 124.3, 123.8,
22.4, 117.8, 114.3, 65.8, 47.1 ppm. ESI-MS (positive mode, acetone): m/z = 1108.2126 {[M–
+
2+
N ][M]} , 1066.2371 {[M] } . C H MnN O ·1.5H O: C 55.82, H 4.18, N 16.27; found C 55.55, H
3
2
28 22
7
4
2
4
.05, N 15.65.

6: Color: red powder. Yield: 79% (257 mg, 0.28 mmol). IR (ATR): ν = 3068 (w, CH), 2045 (vs, N3),
-1 1
2
007 (vs, C≡O), 1928 (vs, C≡O), 1897 (vs, C≡O), 1610 (s, CC/CN), 1429, 788 cm . H NMR ([D ]
6
DMSO, 400.40 MHz): δ = 9.20 (d, 3JH,H = 6.0 Hz, 1H), 9.13 (s, 1H), 9.06 (d, 3JH,H = 8.1 Hz, 1H), 8.83
(
d, 3JH,H = 4.3 Hz, 1H), 8.44 (s, 2H), 8.32 (m, 2H), 8.11 (m, 1H), 8.04 (m, 1H), 7.77 (m, 1H), 7.66 (m,
1
3
1
1
H) ppm. C NMR ([D ] DMSO, 100.68 MHz): δ = 162.7, 161.6, 157.8, 156.8, 156.3, 152.9, 152.4,
6
49.2, 149.1, 146.3, 139.3, 137.3, 137.0, 128.7, 126.5, 125.2, 125.1, 124.7, 124.3, 124.0, 119.7
+
+
ppm. ESI-MS (positive mode, acetone): m/z = 860.0589 {[M–N ]} , 808.0639 {[M–2CO–N +2H]} ,
3
3
+
6
2
27.1321 {[LDTP +Mn+CO+2H]} . C H Mn N O ·2H O: C 53.74, H 3.01, N 17.91; found C 53.72, H
4
2
24
2
12
6
2
.63, N 17.29.
Synthesis of 7–9
,4,4-trifluoro-2-butynoic acid ethyl ester (166 mg, 1 mmol) was added to the acetone solution
3
8
4
of the azide complexes (0.2 mmol, 100 mg (4); 115 mg (5), 180 mg (6)) and the reaction mixtures
were stirred at room temperature for 5 d. For 7 and 8, the solvent was removed under vacuum
and the orange precipitate was washed with diethyl ether and dried in vacuo. Complex 9 was
precipitated from the reaction mixture, washed with acetone, diethyl ether and dried.
7
2
7
8
4
: Color: orange powder. Yield: 82% (109 mg, 0.16 mmol). IR (ATR, diamond): ν = 3080 (w, CH),
031 (vs, C≡O), 1949 (vs, C≡O), 1912 (vs, C≡O), 1704 (s, C=O), 1524, 1472, 1234, 1193, 1137, 1055,
-1
1
3
78 cm . H NMR (CDCl , 500.12 MHz): δ = 9.34 (d, J = 3.8 Hz, 1H), 8.85 (m, 3H), 8.29 (m, 1H),
3
H,H
.17 (br, 1H), 8.05 (br, 1H), 7.92 (m, 3H), 7.76 (d, 3JH,H = 9.1 Hz, 1H), 7.55 (m, 2H), 7.46 (m, 1H),
.22 (q, 3JH,H = 7.1 Hz, 2H, CH ), 1.25 (t, J = 7.2 Hz, 3H, CH ) ppm. C NMR (CDCl , 125.75 MHz):
3
13
2
H,H
3
3
δ = 222.4 (C≡O), 218.7 (C≡O), 215.7 (C≡O), 164.6 (C=O), 161.2, 158.7, 157.2, 157.1, 153.7, 151.9,
2
1
1
50.4, 149.5, 148.8, 139.1 (q, J = 37.8 Hz, C-CF ), 138.6, 137.5, 137.3, 137.0, 126.1, 125.5, 125.2,
C,F
3
1
19
25.0, 124.5, 123.0, 121.8 (q, J = 265.2 Hz, CF ), 121.6, 118.5, 60.4 (CH ), 14.0 (CH ) ppm. F
C,F
3
2
3
NMR (CDCl , 470.6 MHz): δ = –59.8 (CF ) ppm. ESI-MS (positive mode, acetone): m/z = 696.0408
3
3
{
[M+K]}+,
680.0671
{[M+Na]}+,
658.0852
{[M+H]}+,
449.0442
{[M–triazolate]}+.
C H F MnN O ·0.5H O: C 52.26, H 3.02, N 14.71, found, C 52.55, H 2.82, N 13.81.
2
9
19
3
7
5
2
8
2
1
: Color: orange powder. Yield: 76% (113 mg, 0.15 mmol). IR (ATR, diamond): ν = 2977 (w, CH),
865 (w, CH), 2029 (vs, C≡O), 1927 (vs, C≡O), 1727 (s, C=O), 1598 (s, CC/CN), 1525, 1432, 1255,
-1 1
122, 1030, 928, 790 cm . H NMR (CDCl , 500.12 MHz): δ = 9.30 (1H), 8.87 (1H), 7.90 (2H), 7.79
3
(
3H), 7.54 (2H), 7.0 (2H), 4.22 (2H, CH ), 3.92 (4H, morphine), 3.32 (4H, morphine), 1.27 (3H, CH )
2
3
1
3
ppm (some aromatic signals are overlapped with the solvent signal). C-NMR (CDCl , 125.75 MHz):
3

δ = 222.1 (C≡O), 218.7 (C≡O), 215.8 (C≡O), 164.1 (C=O), 161.2, 158.9, 157.4, 156.6, 153.9, 153.7,
1
4
52.8, 150.8, 150.5, 149.4, 137.3, 136.9, 128.3, 125.7, 125.4, 124.9, 124.1, 115.1, 66.6, 60.5 (CH2),
1
9
8.0, 14.4 (CH ) ppm. F NMR (CDCl , 470.6 MHz): δ = –59.7 (CF ) ppm. ESI-MS (positive mode,
3
3
3
+
+
acetone): m/z = 1505.2605 {2[M]+Na} , 764.1243 {[M+Na]} . C H F MnN O ·H O: C 53.76, H 3.85,
3
4
27
3
7
6
2
N 12.91, found C 53.74, H 3.75, N 12.30.
9
2
1
9
4
: Color: orange powder. Yield: 68% (168 mg, 0.14 mmol). IR (ATR, diamond): ν = 3094 (w, CH),
985 (w, CH), 2026 (vs, C≡O), 1949 (vs, C≡O), 1912 (vs, C≡O), 1720 (s, C=O), 1614 (m, CC/CN), 1534,
-1 1
429, 1330, 1227, 1162, 1130, 1047, 790 cm . H NMR ([D ] DMSO, 500.13 MHz): 9.29 (m, 1H),
6
.01 (m, 2H), 8.84 (m, 1H), 8.36 (m, 3H), 8.07 (m, 2H), 7.88 (m, 1H), 7.77 (m, 1H), 7.67 (m, 1H),
1
3
.10 (m, 2H, CH ), 1.12 (m, 3H) ppm. C NMR ([D ] DMSO, 125.75 MHz): δ = 222.4 (C≡O), 219.5
2
6
2
(
C≡O), 216.5 (C≡O), 163.4 (C=O), 159.7, 158.2, 157.2, 156.6, 153.4, 149.5, 139.5, 137.7 (q, J =
C,F
1
3
=
5
7.7 Hz, C-CF ), 137.4, 137.2, 136.7, 136.1, 128.4, 126.7, 125.0, 124.5, 124.4, 124.2, 121.3 (q, J
3
C,F
1
9
271.2 Hz, CF ), 120.9, 119.2, 60.0 (CH ), 13.7 (CH ) ppm. F NMR ([D ] DMSO, 470.6 MHz): δ = –
3
2
3
6
8.6 (CF ) ppm. ESI-MS (positive mode, acetone): m/z = 1257.1070 {[M+Na]}+.
3
C H F Mn N O ·H O: C 51.77, H 2.90, N 13.42; found C 51.52, H 2.83, N 12.79.
5
4
34
6
2
12 10
2
Quantification of CO release
2
8
The number of photogenerated CO was determined by myoglobin assay. Illumination process
was performed with custom-built LED light sources, 468 nm (King-bright Elec. Co., 5000 mcd, part.
no. BL0106-15-299), and 525 nm (King-bright Elec. Co., 6500 mcd, part. no. L-34ZGC). The sealed
cuvette was also positioned perpendicular to the lamp at a distance of 3 cm, where the
illumination was interrupted in regular intervals to take UV/Vis spectra. Dark stability
measurements were carried out over 16h.
X-ray crystallography
Single crystal of complex 5 was immersed in a film of perfluoropolyether oil, mounted on MiTeGen
sample holders and transferred to a stream of cold nitrogen of the diffractometer. The
crystallographic data was collected on a Bruker D8-Quest diffractometer with a CMOS area
detector and multi-layer mirror or graphite monochromated Mo-K radiation (λ = 0.71073 Å) at
α
3
9
1
00 K. The structure was solved with the SHELXT program using intrinsic phasing method and
4
0
refined with a full-matrix least-squares procedure using the SHELXL program. All the non-
hydrogen atoms were refined anisotropically refined. Hydrogen atoms were included in the
structure factors calculations. All hydrogen atoms were assigned to idealized geometric positions.

Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 1896332.
Density functional theory calculations
4
1
Density functional theory (DFT) calculations were carried out using Gaussian03. Geometry
4
2
optimization was performed by Becke 3-parameter (exchange) Lee–Yang–Parr functional and
4
3
def2-SVP basis set. The atomic coordinates of the optimized structures and energy values are
given in Tables S1–S4. Harmonic frequencies were calculated at the same level of theory. Time-
4
4
dependent density functional theory calculations were carried out by CAM-B3LYP /def2-SVP
method using the default continuum model (PCM) to introduce the solvent effect.
Biological activity testing
The details of the biological activity testing (evaluation of antimicrobial properties, cytotoxicity
against the noncancerous human embryonic kidney cells (HEK293) and RBCs haemolysis) are given
in the supporting information.
Conflicts of interest
There are no conflicts to declare.
Acknowledgments
A. Mansour thanks the Alexander von Humboldt Foundation for Georg Forster postdoctoral
fellowship. A. Mansour thanks Mr. Marvin Schock for supplying the authors with the used alkyne.
Thanks, Dr. Ola Shehab, Cairo University, Faculty of Science, for the mass spectrometry
measurements. Antimicrobial screening was performed by CO-ADD (The Community for
Antimicrobial Drug Discovery), funded by the Wellcome Trust (UK) and The University of
Queensland (Australia).
Notes and references
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0 F. Zobi, Future Med. Chem., 2013, 5, 175.
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0 A. M. Mansour and A. Friedrich, Inorg. Chem. Front., 2017, 4, 1517.
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Highlights:

Toxicity of morpholine ligand towards E. coli was improved by metal carbonyl formation and
decreased by iClick.


Extension of iClick reaction to two metal centers complexes.
photoactivation at 525 nm.



The investigated ligands and complexes exhibited lower haemolysis values.
Interesting cytotoxicty behavior twoards HEK293.
Dr. Krzysztof Radacki’s contribution to the present work was the collection of the X-ray diffraction
data and single-crystal structure analysis of complex 5. The manuscript was written by Ahmed
Mansour and revised by both authors.
There are no conflicts to declare.