Ru(II) coordination compounds of N[sbnd]N bidentate chelators with 1,2,3 triazole and isoquinoline subunits: Synthesis, spectroscopy and antimicrobial properties

Article abstract of DOI:10.1016/j.poly.2019.114259

Bidentate chelators 1-(1-benzyl-1,2,3-triazol-4-yl)isoquinoline and 3-(1-benzyl-1,2,3-triazol-4-yl)isoquinoline were prepared from benzyl bromide and trimethylsilylethynylisoquinoline precursors using a tandem deprotection/substitution/CuAAC synthetic approach. Each chelator is capable of forming a stable 3:1 Ru(II) coordination compound, which forms as a geometric isomer mixture. These Ru(II) complexes possess unique MLCT absorbance signatures at 450/472 nm (1-isomer) and 367 nm (3-isomer) relative to their constituent chelating units. Minimum inhibitory concentration values as low as 0.4 μM are observed for Ru(II) complexes against representative Gram-positive bacteria Bacillus subtilis and Staphylococcus epidermidis. Comparing the MIC values of these isoquinoline compounds with analogous 2-(1-benzyl-1,2,3-triazol-4-yl)pyridine compounds shows a 2.5- to 40-fold improvement in potency. This study establishes that increased hydrophobicity introduced at the central chelating units of Ru(II) coordination compounds can be a useful means by which to optimize antimicrobial activity that is complimentary to the variation of peripheral substituent identity at the chelator's N1 triazole position.

Full text of DOI:10.1016/j.poly.2019.114259

Journal Pre-proofs
Ru(II) coordination compounds of N-N bidentate chelators with 1,2,3 triazole
and isoquinoline subunits: Synthesis, spectroscopy and antimicrobial properties
Nicholas W. Kreofsky, Maxwell D. Dillenburg, Eric M. Villa, James T. Fletcher
PII:
S0277-5387(19)30704-1
DOI:
https://doi.org/10.1016/j.poly.2019.114259
POLY 114259
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Polyhedron
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29 August 2019
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4 December 2019
Please cite this article as: N.W. Kreofsky, M.D. Dillenburg, E.M. Villa, J.T. Fletcher, Ru(II) coordination compounds
of N-N bidentate chelators with 1,2,3 triazole and isoquinoline subunits: Synthesis, spectroscopy and antimicrobial
properties, Polyhedron (2019), doi: https://doi.org/10.1016/j.poly.2019.114259
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Ru(II) coordination compounds of N-N bidentate chelators with 1,2,3 triazole and
isoquinoline subunits: Synthesis, spectroscopy and antimicrobial properties
Nicholas W. Kreofsky, Maxwell D. Dillenburg, Eric M. Villa and James T. Fletcher*
Address: Department of Chemistry, Creighton University, 2500 California Plaza, Omaha, NE
68178, U.S.A.
Email: James T. Fletcher - jamesfletcher@creighton.edu
Abstract
Bidentate chelators 1-(1-benzyl-1,2,3-triazol-4-yl)isoquinoline and 3-(1-benzyl-1,2,3-
triazol-4-yl)isoquinoline were prepared from benzyl bromide and
trimethylsilylethynylisoquinoline precursors using a tandem
deprotection/substitution/CuAAC synthetic approach. Each chelator is capable of forming
a stable 3:1 Ru(II) coordination compound, which forms as a geometric isomer mixture.
These Ru(II) complexes possess unique MLCT absorbance signatures at 450/472 nm (1-
isomer) and 367 nm (3-isomer) relative to their constituent chelating units. Minimum
inhibitory concentration values as low as 0.4 μM are observed for Ru(II) complexes against
representative Gram-positive bacteria Bacillus subtilis and Staphylococcus epidermidis.
Comparing the MIC values of these isoquinoline compounds with analogous 2-(1-benzyl-
1,2,3-triazol-4-yl)pyridine compounds shows a 2.5- to 40-fold improvement in potency.
This study establishes that increased hydrophobicity introduced at the central chelating
units of Ru(II) coordination compounds can be a useful means by which to optimize
antimicrobial activity that is complimentary to the variation of peripheral substituent
identity at the chelator’s N1 triazole position.
1

Keywords
Antibacterial; Bidentate chelator; Coordination compound; Tandem synthesis; 1,2,3-
Triazole
1. Introduction
The investigation of coordination compounds comprised of multidentate chelators
containing 1,2,3-triazole subunits has amplified greatly since the establishment of
Sharpless-Meldal copper-catalyzed azide alkyne cycloaddition (CuAAC) methodology as an
efficient means by which to prepare 1,4-disubstituted-1,2,3-triazoles.[1–3] Bidentate and
tridentate neutral N-donor chelators 2-(1-substituted-1,2,3-triazol-4-yl)pyridine (pytz)
and 2,6-bis(1-substituted-1,2,3-triazol-4-yl)pyridine (tzpytz) have been shown to form
stable complexes with a wide range of metal cations, and are now popular chelating motifs
to engineer desired properties due to the ease in which peripheral substituents can be
varied by CuAAC synthetic approaches.[4–7] While applications exploiting the
optoelectronic and catalytic properties of such coordination compounds have been
extensively reported,[8–14] studies probing their antimicrobial activity are significantly
more limited.[12,15–18]
Figure 1. Structures of 2-(1-substituted-1,2,3-triazol-4-yl)pyridine (pytz) and 2,6-bis(1-
substituted-1,2,3-triazol-4-yl)pyridine (tzpytz) chelators.
2

Because antibiotic resistant pathogens are a significant threat to global health, the
discovery and development of new classes of antimicrobial compounds are urgently
important.[19–22] Ru(II) coordination compounds comprised of polypyridyl N-N
bidentate chelators have long been known to display a range of biological activity,
including antimicrobial properties.[23,24] Recently, octahedral 3:1 Ru(II) complexes of
pytz were reported to display potent antibacterial properties in a substituent-dependent
manner.[17] In this study it was determined that an ideal balance of hydrophobicity and
charge was needed for optimal potency, which could be engineered via modular variation
of peripheral substituents on the 1,2,3-triazole subunits using CuAAC methodology. Such
straightforward ability to synthetically tune bioactivity is an important tool for combating
antibiotic resistance.
The aim of this study was to exploit the modularity of the CuAAC reaction to prepare
bidentate chelators where the 2-pyridyl subunit of pytz was replaced with 1- and 3-
isoquinolinyl subunits (Figure 2). Reports describing coordination compounds comprised
of 1-(1-substituted-1,2,3-triazol-4-yl)isoquinolines (1-iqtz) are limited,[25,26] while those
of 3-(1-substituted-1,2,3-triazol-4-yl)isoquinolines (3-iqtz) are entirely lacking. By
examining octahedral Ru(II) complexes of these chelating motifs, the influence of
isoquinoline incorporation (an expanded arene with increased hydrophobicity relative to
pyridine) on both physical and biological properties can be defined. Described herein is
the synthesis, spectroscopic structure-property relationship profiling and antimicrobial
structure-activity relationship profiling of such isoquinoline-containing N-N bidentate
chelators and their 3:1 Ru(II) coordination compounds.
3

Figure 2. Structures of 1-(1-substituted-1,2,3-triazol-4-yl)isoquinoline (1-iqtz) and 3-(1-
substituted-1,2,3-triazol-4-yl)isoquinoline (3-iqtz) chelators.
2. Materials and Methods
2.1 Materials and instrumentation
Trimethylsilylacetylene (GFS Chemicals), benzyl bromide and isoquinoline reactants
(Oakwood Chemical), Ru and Pd compounds (Oakwood), all other reactants (Aldrich),
reaction solvents (Fisher Scientific), and NMR solvents (Cambridge Isotopes) were used as
purchased. 1- and 3-isoquinolinyl triflates[27,28] and 1- and 3-
trimethylsilylethynylisoquinolines[29,30] were prepared as previously described.
Microorganisms were prepared from freeze-dried samples purchased from ATCC (Bacillus
subtilus (ATCC 6051), Staphylococcus epidermidis (ATCC 14990), Escherichia coli (ATCC
25922), Enterobacter aerogenes (ATCC 13048), Candida albicans (ATCC 90028). Mueller-
Hinton broth and YM broth were purchased from Fisher Scientific and prepared as
instructed.
NMR analyses were obtained on a 400 MHz Bruker Ascend system. HRMS analyses
were acquired on a Bruker micrOTOF-Q III system using an elution of 0.1% formic acid in
methanol. UV-visible absorbance measurements were acquired on a Agilent 8453
4

spectrophotometer, and data are reported as λmax = nm (log ε). Crystals were run on a
Rigaku SCX-Mini single-crystal x-ray diffractometer.
2.2 Synthetic methods
Synthesis of 1,4-disubstituted-1,2,3-triazoles by tandem CuAAC method. Alkyne (1.0
mmol), benzyl bromide (1.0 mmol), sodium azide (1.0 mmol), K2CO3 (1.0 mmol), CuSO4 (0.2
mmol), sodium ascorbate (0.4 mmol), tert-butanol (5 ml) and water (5 mL) were added to a
20 mL reaction vial and stirred rapidly at room temperature for 24 h. The reaction mixture
was extracted with CH2Cl2 and 5% NH4OH (aq), and the organic layer separated and dried
over MgSO4. Following gravity filtration, volatiles were removed via rotary evaporation
and the residue air dried to give the desired triazole product.
Synthesis of 1,4-disubstuted-1,2,3-triazoles by direct CuAAC method. Organic azide
(1.0 mmol), alkyne (1.0 mmol), CuSO4 (0.2 mmol), sodium ascorbate (0.4 mmol), tert-
butanol (5 ml) and water (5 mL) were added to a 20 mL reaction vial and stirred rapidly at
room temperature for 24 h. The reaction mixture was extracted with CH2Cl2 and 5%
NH4OH (aq), and the organic layer separated and dried over MgSO4. Following gravity
filtration, volatiles were removed via rotary evaporation and the residue air dried to give
the desired triazole product.
Synthesis of [RuL3]Cl2 coordination compounds. Triazole chelator (0.33 mmol),
ruthenium chloride dihydrate (0.10 mmol), ethanol (20 ml) and water (5 ml) were added
to a 40 ml reaction vial and stirred rapidly at 70 oC for 24 h. The reaction solvents were
removed by rotary evaporation and the crude residue was purified by size exclusion
5

chromatography using Sephadex LH-20 with methanol eluent. The isolated product band
was dried by rotary evaporation to give the desired 3:1 octahedral Ru(II) complex.
2.3 Syntheses
1-(1-benzyl-1,2,3-triazol-4-yl)isoquinoline (Bz-1-iqtz). Prepared by tandem method.
Tan solid, 88% yield, mp 115-117 °C; 1H NMR (400 MHz, CDCl3): δ 9.50 (m, 1H), 8.48 (d, J =
5.6 Hz, 1H), 8.21 (s, 1H), 7.84 (dd, J1 = 7.6 Hz, J2 = 2.4 Hz, 1H), 7.70 (m, 2H), 7.61 (d, J = 5.2
Hz, 1H), 7.39 (m, 5H), 5.64 (s, 2H); 13C NMR (400 MHz, CDCl3): δ 150.0, 149.7, 141.9, 137.1,
134.5, 130.4, 129.4 129.0, 128.5, 128.3, 128.1, 126.9, 124.9, 121.0, 54.5; HRMS (ESI) m/z:
Calcd for C18N4H14Na [M+Na]+ 309.1116, found 309.1119; UV-vis (MeOH): λ = 283 (3.96),
325 (3.96).
1-(1-(4-phenylbenzyl)-1,2,3-triazol-4-yl)isoquinoline (Pbz-1-iqtz). Prepared by
tandem method. White solid, 76% yield, mp 169-170°C; 1H NMR (400 MHz, CDCl3): δ 9.52
(m, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.26 (s, 1H), 7.85 (dd, J1 = 6.0 Hz, J2 = 2.4 Hz, 1H), 7.71 (m,
2H), 7.60 (m, 5H), 7.45 (m, 4H), 7.36 (m, 1H), 5.69 (s, 2H); 13C NMR (400 MHz, CDCl3): δ
150.1, 149.7, 142.1, 141.9, 140.4, 137.2, 133.3, 130.4, 129.0, 129.0, 128.2, 128.1, 128.1,
127.8, 127.3, 126.9, 126.6, 124.9, 121.0, 54.2; HRMS (ESI) m/z: Calcd for C24N4H18Na
[M+Na]+ 385.1429, found 385.1439; UV-vis (MeOH): λ = 252 (4.56), 327 (3.97).
3-(1-benzyl-1,2,3-triazol-4-yl)isoquinoline (Bz-3-iqtz). Prepared by tandem method.
Tan solid, 71% yield, mp 156-158 °C; 1H NMR (400 MHz, CDCl3): δ 9.18 (s, 1H), 8.54 (s, 1H),
8.11 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.70 (m, 1H), 7.58 (m, 1H), 7.38 (m, 5H), 5.61 (s, 2H);
13C NMR (400 MHz, CDCl3): δ 152.5, 149.2, 143.9, 136.6, 134.6, 131.0, 129.3, 129.0, 128.5,
6

128.4, 127.8, 127.4, 127.3, 122.0, 116.3, 54.6; HRMS (ESI) m/z: Calcd for C18N4H14Na
[M+Na]+ 309.1116, found 309.1117; UV-vis (MeOH): λ = 285 (4.26), 297 (4.21).
3-(1-(4-phenylbenzyl)-1,2,3-triazol-4-yl)isoquinoline (Pbz-3-iqtz). Prepared by
tandem method. White solid, 76% yield, mp 186-187°C; 1H NMR (400 MHz, CDCl3): δ 9.19
(s, 1H), 8.55 (s, 1H), 8.15 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.70 (m,
1H), 7.60 (m, 5H), 7.45 (m, 4H), 7.36 (m, 1H), 5.66 (s, 2H); 13C NMR (400 MHz, CDCl3): δ
152.5, 149.3, 143.9, 142.1, 140.5, 136.6, 133.5, 130.9, 129.0, 128.4, 128.1, 127.8, 127.8,
127.4, 127.3 (overlap), 127.3, 122.0, 116.3, 54.3; HRMS (ESI) m/z: Calcd for C24N4H18Na
[M+Na]+ 385.1429, found 385.1436; UV-vis (MeOH): λ = 250 (4.83), 284 (4.32), 297 (4.21).
2-(1-benzyl-1,2,3-triazol-4-yl)pyridine (Bz-pytz). Prepared by tandem method.
Brown solid, 81% yield, mp 111-114 °C; 1H NMR (400 MHz, CDCl3): δ 8.53 (d, J = 4.24 Hz,
1H), 8.18 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.76 (m, 1H), 7.35 (m, 5H), 7.21 (m, 1H), 5.58 (s,
2H) ; 13C NMR (400 MHz, CDCl3): δ 150.4, 149.5, 148.9, 137.0, 134.5, 129.3, 129.0, 128.5,
123.0, 122.0, 120.4, 54.5; HRMS (ESI) m/z: Calcd for C14N4H12Na [M+Na]+ 259.0960, found
259.0962; UV-vis (MeOH): λ = 279 (4.10).
2-(1-(4-phenylbenzyl)-1,2,3-triazol-4-yl)pyridine (Pbz-pytz). Prepared by tandem
method. Brown solid, 84% yield, mp 140-142°C; 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H),
8.19 (d, J = 8,0 Hz, 1H), 8.09 (s, 1H), 7.77 (m, 1H), 7.58 (m, 4H), 7.43 (m, 5H), 7.22 (s, 1H),
5.63 (s, 2H); 13C NMR (400 MHz, CDCl3): δ 150.3, 149.4, 148.9, 142.0, 140.4, 137.0, 133.3,
129.0, 128.9, 128.0, 127.8, 127.2, 123.0, 122.0, 120.4, 54.2; HRMS (ESI) m/z: Calcd for
C20N4H16Na [M+Na]+ 335.1267, found 335.1260; UV-vis (MeOH): λ = 251 (4.35), 274 (sh)
(4.10).
7

2-(1-hexyl-1,2,3-triazol-4-yl)pyridine (Hex-pytz). Prepared by direct method. Tan
solid, 74% yield, mp 56.5-57.4°C; 1H NMR (400 MHz, CDCl3): δ 8.58 (s, 1H), 8.19 (d, J = 7.6
Hz, 1H), 8.13 (s, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.23 (t, J = 6.4 Hz, 1H)), 4.41, (t, J = 6.8, 2H),
1.95, (m, 2H), 1.33, (m, 6H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (400 MHz, CDCl3): δ 150.3,
149.3, 148.1, 136.7, 122.6, 121.6, 120.1, 50.4, 31.0, 30.1, 26.0, 22.3, 13.8; HRMS (ESI) m/z
Calcd for C13N4H19 [M+H]+ 231.1610, found 231.1610; UV-vis (MeOH): λ = 278 (4.34).
1-(1-hexyl-1,2,3-triazol-4-yl)isoquinoline (Hex-1-iqtz). Prepared by direct method.
Dark amber oil, 85% yield; 1H NMR (400 MHz, CDCl3): δ 9.49 (d, J = 8.0 Hz, 1H), 8.51 (s, 1H),
8.27 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.68 (m, 2H), 7.62 (s, 1H), 4.46 (t, J = 7.2 Hz, 2H), 1.99
(m, 2H), 1.32 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (400 MHz, CDCl3): δ 149.7, 149.4,
141.8, 137.0, 130.3, 128.2, 127.9, 126.8, 126.4, 124.7, 120.8, 50.5, 31.2, 30.2, 26.2, 22.4,
14.0; HRMS (ESI) m/z Calcd for C17N4H21 [M+H]+ 281.1766, found 281.1754; UV-vis
(MeOH): λ = 280 (4.18), 327 (4.11).
[Ru(Bz-1-iqtz)3]Cl2. Dark brown solid, 72% yield; 1H NMR (400 MHz, CD3OD): δ (see
Supplementary Data) 2.1:1 mer:fac isomer ratio observed; HRMS (ESI) m/z: Calcd for
C54N12H42Ru [M-2Cl]2+ 480.1344, found 480.1361; UV-vis (MeOH): λ = 253 (sh) (4.68), 309
(4.50), 450 (4.19), 472 (4.17).
[Ru(Pbz-1-iqtz)3]Cl2. Dark brown solid, 88% yield; 1H NMR (400 MHz, CD3OD): δ
(see Supplementary Data) 2.0:1 mer:fac isomer ratio observed; HRMS (ESI) m/z: Calcd for
C72N12H54Ru [M-2Cl]2+ 594.1813, found 594.1838; UV-vis (MeOH): λ = 255 (5.02), 298
(4.55), 350 (sh) (4.26), 444 (4.19), 467 (4.13).
[Ru(Bz-3-iqtz)3]Cl2. Yellow-green solid, 76% yield; 1H NMR (400 MHz, CD3OD): δ
(see Supplementary Data) 2.5:1 mer:fac isomer ratio observed; HRMS (ESI) m/z: Calcd for
8

C54N12H42Ru [M-2Cl]2+ 480.1344, found 480.1351; UV-vis (MeOH): λ = 253 (5.20), 286
(4.83), 294 (4.85), 316 (sh) (4.52), 367 (4.46).
[Ru(Pbz-3-iqtz)3]Cl2. Yellow solid, 80% yield; 1H NMR (400 MHz, CD3OD): δ (see
Supplementary Data) 2.5:1 mer:fac isomers; HRMS (ESI) m/z: Calcd for C72N12H54Ru [M-
2Cl]2+ 594.1813, found 594.1818; UV-vis (MeOH): λ = 253 (5.32), 283 (4.93), 294 (4.89),
317 (sh) (4.53), 370 (4.41).
[Ru(Bz-pytz)3]Cl2. Green solid, 78% yield; 1H NMR (400 MHz, CD3OD): δ (see
Supplementary Data) 2.1:1 mer:fac isomer ratio observed; HRMS (ESI) m/z: Calcd for
C42N12H36Ru [M-2Cl]2+ 405.1109, found 405.1114; UV-vis (MeOH): λ = 269 (4.87), 378
(4.24).
[Ru(Pbz-pytz)3]Cl2. Dark yellow solid, 72% yield; 1H NMR (400 MHz, CD3OD): δ (see
Supplementary Data) 2.2:1 mer:fac isomer ratio observed; HRMS (ESI) m/z: Calcd for
C60N12H48Ru [M-2Cl]2+ 519.1579, found 519.1599; UV-vis (MeOH): λ = 268 (4.88), 379
(3.99).
[Ru(Hex-pytz)3]Cl2. Yellow solid, 94% yield; 1H NMR (400 MHz, CDCl3): δ (see
Supplementary Data) 0.8:1 mer:fac isomer ratio observed; HRMS (ESI) m/z Calcd for
C39N12H54Ru [M-2Cl]2+ 396.1814, found 396.1809; UV-vis (MeOH): λ = 268 (4.88), 381
(4.33).
[Ru(Hex-1-iqtz)3]Cl2. Dark yellow solid, 75% yield; 1H NMR (400 MHz, CDCl3): δ (see
Supplementary Data) 1.8:1 mer:fac isomer ratio observed; HRMS (ESI) m/z Calcd for
C51N12H60Ru [M-2Cl]2+ 471.2048, found 471.2054; UV-vis (MeOH): λ = 252 (4.71), 299
(4.58), 350 (sh) (4.27), 430 (4.31).
9

2.4 Minimum Inhibitory Concentration Assays
Inoculum were prepared following standard microdilution assay procedures[31–
33] using Mueller-Hinton broth for all bacteria and YM broth for yeast. Each triazole and
triazolium bromide compound was prepared as a 10 mM solution in DMSO. 10 μL of each
DMSO stock solution was diluted into 190 μL broth and a 1:1 serial dilution was performed
in a 96 well plate. Addition of 100 μL inoculum to each well resulted in a range of 250, 120,
62, 31, 16, 8, 4 and 2 μM concentrations for each MIC assay. Plates were incubated for 20 h
o
(bacteria) and 24 h (yeast) at 37 C then examined by eye for cloudiness indicating
microbial growth. The most dilute member within a serial dilution that remained
transparent after 24 h was defined as the minimum inhibitory concentration (MIC) value
for that compound/organism combination. Assays were performed in triplicate. Any
compounds displaying activity at the minimum 2 μM concentration of the original assay
were tested again at a 10-fold dilution using the same microdilution procedure with a 1
mM DMSO stock solution.
2.5 XRD Analysis
Crystals of Bz-3-iqtz, Pbz-3-iqtz and Pbz-1-iqtz were grown from evaporation of
CH2Cl2 solutions. Crystals were mounted on MiTeGen Microloop with non-drying
immersion oil. The crystals were then optically aligned on the Rigaku SCX-Mini
diffractometer using a digital camera. Initial matrix images were collected to determine the
unit cell, validity and proper exposure time. Three hemispheres (where φ= 0.0, 120.0 and
240.0) of data were collected with each consisting 180 images each with 1.00° widths and a
1.00° step. CrysAlis PRO 1.171.39.46 was used to integration, scaling and absorption
10

correction.[34] The structures were refined using SHELXT Intrinsic Phasing[35] and
SHELXL.[36] Olex2 was used as a graphical interface.[37] Images for the above
compounds generated using CrystalMaker® version 10.4.3: a crystal and molecular
structures program for Mac and Windows (CrystalMaker Software Ltd, Oxford, England,
www.crystalmaker.com).[38] Crystallographic information for the three obtained
structures are summarized in Supporting Information Table S1, followed by thermal
ellipsoid plots and packing images for each (Figures S11-S17). Lastly, atomic coordinates
and additional structural information are provided in Tables S2-S6.
3. Results and Discussion
3.1 Preparation of chelators
N1-benzyl- and phenylbenzyl-substituted analogs of chelators 1-iqtz and 3-iqtz
were each prepared using a three step synthetic sequence (Scheme 1). Following triflation
of commercially-available 1-hydroxyisoquinoline and isoquinolin-3(2H)-one precursors,
[27,28] Sonogashira coupling was used to prepare 1- and 3-
trimethylsilylethynylisoquinolines.[27–30] An efficient three-step one-pot transformation
involving K2CO3 promoted TMS deprotection, benzylic azide substitution and CuAAC was
used to prepare the desired chelators in 71-88% isolated yields.[39–42] In order to
directly compare the influence of the isoquinoline subunits relative to the pyridine subunit
on coordination, spectroscopic and antimicrobial properties, pytz chelators with identical
N1-substituents were also similarly prepared (Scheme S1).
11

Scheme 1. Preparation of isoquinoline-containing N-N bidentate chelators
3.2 X-ray crystallography
Single crystals of Bz-3-iqtz, Pbz-3-iqtz and Pbz-1-iqtz suitable for XRD structural
analyses were grown from slow evaporation of dichloromethane solutions. The dihedral
angles between isoquinoline and 1,2,3-triazole subunits differ greatly among the 1- and 3-
isoquinoline isomers. In the 3-isoquinoline analogs, the N-C-C-N dihedral angle between
the chelating subunits is 156o and 157o, respectively (Figures 3 and 4). This largely
coplanar anti geometry is typically observed in such non-coordinated 1,2,3-triazole-
containing bidentate and tridentate chelating systems, and has been attributed to favorable
electrostatic interactions between heterocycles.[43] In contrast, the N-C-C-N dihedral angle
between chelating subunits in the 1-isoquinoline isomer is 50o (Figure 5). This adaptation
of a more syn-like geometry is attributed to the six-atom separation between N3 of the
triazole and H8 of the isoquinoline (versus the analogous five-atom separation of the
equivalent atoms in the 3-isoquinoline isomers), which introduces steric hindrance that
precludes the electrostatic stabilization afforded by the nearly coplanar anti orientation.
12

The dihedral angles observed in the phenylbenzyl peripheral substituents also differ
significantly. The 5o biphenyl dihedral angle observed in Pbz-1-iqtz closely resembles the
largely coplanar geometry typically observed in crystalline biphenyl compounds,[44] while
in Pbz-3-iqtz the biphenyl dihedral angle is twisted to 50o. This observed difference is
likely due to differences in crystal packing forces between these two compounds (Figure
S17).
Figure 3. Thermal ellipsoid plot of Bz-3-iqtz shown at 25% probability.
Figure 4. Thermal ellipsoid plot of Pbz-3-iqtz shown at 25% probability.
13

Figure 5. Thermal ellipsoid plot of Pbz-1-iqtz shown at 25% probability.
3.3 Preparation of Ru(II) complexes
Preparation of target 3:1 Ru(II) coordination compounds comprised of these N-N
bidentate chelators was accomplished by heating three equivalents of each analog with
ruthenium trichloride hydrate salt in aqueous ethanol (Scheme 2).[39] Complexes were
purified by size-exclusion chromatography using Sephadex gel eluted in methanol. Due to
the unmatched pairs of heterocycles comprising these N-N bidentate chelators, the
octahedral Ru(II) complexes formed as a mixture of meridional (mer) and facial (fac)
geometric isomers, the relative abundance of which could be quantified by 1H NMR. The
singlet generated from the C5 position of the triazole ring experiences disparate chemical
shifts between the two geometric isomers: each of the three chelating units in the fac
isomer experience equivalent chemical environments revealed as one downfield-shifted
singlet relative to the chelator itself, while each of the three chelating units in the mer
isomer experience unique chemical environments resulting in three unique downfield-
shifted singlets for this analogous triazole position (Figures S1-S8).
14

Both benzyl and phenylbenzyl analogs of 1-iqtz and pytz (Scheme S2) derivatives
show a 2:1 preference for their mer isomers, while the 3-iqtz derivatives show a slightly
higher 2.5:1 mer isomeric excess. Interestingly, this ratio contrasts with previously
reported alkyl substituted [Ru(pytz)3]Cl2 complexes[39] where statistical mixtures (1:1) of
fac:mer isomers were observed. (Similarly, a 1.2:1 fac:mer ratio was observed for the alkyl
analog in the present study.) N1-hexyl-substituted 1-iqtz showed a slightly diminished
1.8-fold preference for the mer isomer (Schemes S3-S5). This dataset illustrates that the
identity of both the chelating subunit as well as the peripheral substituent can significantly
influence the relative populations of geometric isomers, likely attributable to steric
hindrance within the congested octahedral coordination environment. It was previously
reported that fac and mer isomers do not display significant differences in either their
electronic absorption or antimicrobial properties.[17] Therefore, while a partial
separation of 1-iqtz and 3-iqtz isomers was achievable by meticulous use of size-exclusion
chromatography (with the larger phenylbenzyl analogs displaying better resolution than
the benzyl analogs), each of these coordination compounds was utilized as geometric
isomer mixture for the duration of this investigation.
15

Scheme 2. Preparation of octahedral Ru(II) coordination compounds
3.4 UV-visible spectroscopy
UV-visible spectroscopy shows that isoquinoline connectivity within the chelator
significantly impacts the emergent electronic properties of their Ru(II) coordination
compounds. Low energy absorbance signatures indicative of MLCT transitions[17,39]
were observed for all Ru(II) complexes relative to their constituent chelating units (Figure
6). While the energy of this signature in the benzyl-substituted 3-iqtz complex (367 nm)
closely resembles that of the pytz complex (378 nm), the MLCT bands of the 1-iqtz
complex extend into the visible range of the electromagnetic spectrum (450 nm, 472 nm).
16

Similar trends were observed for the phenylbenzyl and hexyl analogs (Figures S9-S10).
None of the complexes studied displayed observable luminescence at room temperature.
50000
45000
40000
35000
30000
25000
20000
15000
10000
5000
180000
160000
140000
120000
100000
80000
60000
40000
20000
0
80000
70000
60000
50000
40000
30000
20000
10000
0
Bz-1-iqtz
Bz-3-iqtz
Bz-pytz
[Ru(Bz-1-iqtz)3]Cl2
[Ru(Bz-3-iqtz)3]Cl2
[Ru(Bz-pytz)3]Cl2
0
250
300
350
400
450
500
550
250
300
350
400
450
500
550
250
300
350
400
450
500
550
Wavelength (nm)
Wavelength (nm)
Wavelength (nm)
Figure 6. UV-Visible absorbance of benzyl-functionalized N-N bidentate chelators and their
3:1 Ru(II) complexes in methanol.
3.5 Antimicrobial Assays
The antimicrobial properties of each N-N bidentate chelator and 3:1 Ru(II)
coordination compound were evaluated using minimum inhibitory concentration (MIC)
assays against exemplary BSL1 Gram-positive bacteria Bacillus subtilis and Staphylococcus
epidermidis, Gram-negative bacteria Escherichia coli and Enterobacter aerogenes, and yeast
Candida albicans.[31,33] None of the chelators themselves showed inhibition at the
concentrations surveyed (up to 250 μM). In contrast, Ru(II) complexes prepared from
these chelators showed MIC values that varied significantly as chelator and peripheral
substituent identity was each varied systematically.
It was recently reported that MIC potency can be optimized in [Ru(pytz)3]Cl2
complexes by achieving an ideal balance of charge and hydrophobicity, accessible by
synthetic variation of n-alkyl chain length at the N1 position of the triazole subunits.[17]
Because the stereochemistry of these previously reported complexes was shown not to
significantly influence antimicrobial properties, and because the balance of charge and
17

hydrophobicity is commonly understood to play an important role in optimizing
cytotoxicity in common antibiotics such as quaternary ammonium compounds,[45,46] it
was hypothesized that hydrophobicity would play a prominent role in tuning the MIC
values of the Ru(II) complexes reported herein. This study focused on evaluating three
structure activity relationships: (1) varying hydrophobicity at the central chelating unit
versus at the periphery, (2) varying aromatic versus aliphatic peripheral substituent
identity, and (3) the impact of isoquinoline incorporation in chelators with aliphatic
peripheral substitution.
Isoquinoline regiochemistry has no impact on antimicrobial properties (Table 1,
entries 1-2 and 4-5), but isoquinoline incorporation itself does significantly alter MIC
values relative to equivalent pyridine analogs (entries 3 and 6). For the benzyl complexes,
the enhanced hydrophobicity of the isoquinoline groups increases potency towards both
Gram-positive bacteria (20- to 40-fold) and Gram-negative bacteria (at least 8-fold). But
for the phenylbenzyl complexes, isoquinoline incorporation decreases potency against all
organisms tested (at least 15-fold). These comparisons exemplify the balance that is
needed between charge and hydrophobicity for antimicrobial Ru(II) complexes.
Isoquinoline incorporation in the benzyl analogs improves this balance, whereas in the
more hydrophobic phenylbenzyl series it appears to reach an excessive amount of
hydrophobicity detrimental to MIC potency. These observations indicate that variation of
hydrophobicity at the chelating unit can be utilized in a complimentary manner to variation
of peripheral group hydrophobicity in tuning antimicrobial potency.
In order to evaluate whether this observed synergy between central and peripheral
aromatic group hydrophobicity might be generally applicable to recently reported aliphatic
18

systems, Ru(II) complexes comprised of n-hexyl substituted pytz and 1-iqtz chelators were
also prepared and assayed (entries 7-8). [Ru(Hex-1-pytz)3]Cl2 was previously shown to
possess optimal antibacterial properties among a series of analogs with varying lengths of
n-alkyl substituents.[17] Under the assay conditions employed in the present study it
similarly displays potent MIC values selectively against Gram-positive bacteria.
Replacement of the pyridine N-N chelator subunit with isoquinoline [Ru(Hex-1-iqtz)3]Cl2
results in a 2.5 to 32-fold improvement in MIC values against both Gram-positive and
Gram-negative bacteria. This supports the general utility of varying hydrophobicity at the
chelating unit as a tool for optimizing the antimicrobial properties of Ru(II) coordination
compounds.
Table 1. Summary of bioactivity for [RuL3]Cl2 complexes.
Minimum Inhibitory Concentration (μM)
Entry L =
B.S.
0.8
0.8
16
S.E.
0.4
0.4
16
E.A.
31
31
>250
>250
>250
62
E.C.
31
31
>250
>250
>250
250
250
8
C.A.
250
250
>250
>250
>250
250
1
2
3
4
5
6
7
8
Bz-1-iqtz
Bz-3-iqtz
Bz-pytz
Pbz-1-iqtz
Pbz-3-iqtz
Pbz-pytz
Hex-pytz
Hex-1-iqtz
>250
>250
4
>250
>250
8
4
0.8
2
0.8
250
31
125
>250
Concentrations surveyed: 250, 125, 62, 31, 16, 8, 4 and 2 μM. B.S. = Bacillus subtilis (ATCC
6051); S.E. = Staphylococcus epidermidis (ATCC 14990); E.C. = Escherichia coli (ATCC
25922); E.A. = Enterobacter aerogenes (ATCC 13048); C.A. = Candida albicans (ATCC
90028).
In general, relative to Gram-positive bacteria these Ru(II) complexes showed
reduced bioactivity against Gram-negative bacteria. This is typically observed for
amphiphilic antimicrobial compound due to the outer membrane of the Gram-negative
19

bacteria serving as an additional barrier to cell wall permeation. MIC values measured
against the yeast strain Candida albicans (a representative eukaryotic organism) were
either very high or not observed for each analog in this study. This organismal selectivity
whereupon the Ru(II) complexes are able to preferentially target prokaryotic organisms
over eukaryotic organisms correlates with the low toxicity and hemolytic activity
previously reported for N-N chelated Ru(II) compounds.[17] Such selectivity is attributed
to the attraction of the cationic Ru(II) center to the negatively charged outer surfaces of
prokaryotic organisms, and follows typical bioactivity observed for cationic amphiphiles
such as quaternary ammonium compounds and antimicrobial peptides.[45–47]
4. Conclusion
A tandem CuAAC synthetic approach has been used to efficiently prepare a series of
1-(1-substituted-1,2,3-triazol-4-yl)isoquinoline and 3-(1-substituted-1,2,3-triazol-4-
yl)isoquinoline compounds. N-N bidentate chelators 1-iqtz and 3-iqtz are demonstrated
herein to be capable units for constructing stable 3:1 Ru(II) octahedral coordination
compounds and expand the breadth of heterocyclic representation among reported 1,2,3-
triazole-containing chelators deriving from CuAAC synthetic approaches. Isoquinoline
subunit connectivity significantly influences the electronic absorbance spectra of such
complexes, with the 1-iqtz isomer producing compounds with MLCT absorbances in the
visible electromagnetic spectrum unique from 3-iqtz and pytz analogs. The mer:fac
distribution of octahedral coordination geometry is also impacted by isoquinoline
connectivity. The antimicrobial evaluation of these isoquinoline containing chelators
relative to pytz analogs demonstrates that increasing central hydrophobicity within this
20

class of 3:1 octahedral Ru(II) coordination compounds can be an effective means by which
to optimize bioactivity that is complimentary to approaches varying peripheral substituent
hydrophobicity. This establishes a new tool available for studies aiming to optimize
biological activity via striking a proper balance of charge and hydrophobicity within
coordination compounds, including the development of next-generation molecular
approaches to combat antibiotic resistance.
Acknowledgements
This publication was made possible by grants from the National Institute for General
Medical Science (NIGMS) (5P20GM103427), a component of the National Institutes of
Health (NIH), and its contents are the sole responsibility of the authors and do not
necessarily represent the official views of NIGMS or NIH.
Appendix. Supplementary Data
Supplementary data related to this article can be found at _______. Experimental
procedures, copies of 1H and 13C NMR spectra and UV-Visible spectra for all newly reported
compounds, and crystallographic information for the SC-XRD analysis of compounds Bz-3-
iqtz, Pbz-3-iqtz and Pbz-1-iqtz are included. Crystallographic data for the structures
presented in this paper have been deposited with the Cambridge Crystallographic Data
Centre: Bz-3-iqtz as CCDC 1946238, Pbz-3-iqtz as 1946240 and Pbz-1-iqtz as 1946239.
Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK (fax: +44-(0)1223-336033 or e-mail: despoit@ccdc.cam.ac.uk).
21

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Declaration of interests
X The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:
First option selected (could not get checkmark to appear in box of template file) = no competing
interests.
James Fletcher
10/29/19
28

Isoquinoline-containing bidentate chelators with varying 1- and 3-connectivity prepared from
tandem CuAAC methods are capable of forming stable 3:1 Ru(II) coordination compounds.
Isoquinoline connectivity influences the spectroscopic properties of these complexes, while
isoquinoline incorporation can significantly improve antibacterial properties relative to analogous
complexes with pyridine-containing chelators.
29