Ionic Sal-SG Schiff bases as new synergetic chemotherapeutic candidates: Synthesis, metalation with Pd(ii) and in vitro pharmacological evaluation

Article abstract of DOI:10.1039/c5ra11083a

A series of novel N-(salicylidene)-sulfaguanidines (Sal-SG) bearing ionic liquid (IL) terminals (ILSSGH, 4a-f) have been synthesized by Schiff base condensation of IL-functionalized salicylaldehydes (ILSal, 3a-g) and sulfaguanidine (SG). Metalation trials of these ionic Schiff bases with palladium(ii) chloride affords the corresponding Pd(ii) complexes, [Pd(ii)(ILSSG)Cl(H₂O)] (5a-g). Further, the antimicrobial profiles of the new compounds against a set of common pathogens have been described. Zone of inhibition (ZOI) and minimal inhibitory concentration (MIC) values revealed that most of the new compounds exhibited significant antibacterial and potential inhibitory activity against Staphylococcus aureus (S. aureus), and this activity is modulated by substituents attached to the ionic liquid core as well as the counter-ion.

Full text of DOI:10.1039/c5ra11083a

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Ionic SalꢀSG Schiff bases as new synergetic chemotherapeutic candidates: Synthesis,
metalation with Pd(II) and in vitro pharmacological evaluation.
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Reda F.M. Elshaarawy,a,* Tahia B. Mostafa,b Ayaat A. Refaeeb and Emtithal A. ElꢀSawib
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Faculty of Science, Suez University, Suez, Egypt. Email: reda_elshaarawi@science.suez.edu.eg; Reda.Elꢀ
Shaarawy@uniꢀduesseldorf.de
b
Department of Chemistry, Faculty of Women for Arts, Science and Education, Ain Shams University,
Heliopolis, Cairo, Egypt
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Abstract
A series of novel Nꢀ(salicylidene)ꢀsulfaguanidines (SalꢀSG) bearing ionic liquids (ILs)
terminals (ILSSGH, 4aꢀf) have been synthesized by Schiff base condensation of ILsꢀ
functionalized salicylaldehydes (ILSal, 3aꢀg) and sulfaguanidine (SG). Metalation trials of
these ionic Schiff bases with palladium(II) chloride affords the corresponding Pd(II)
complexes, [Pd(II)(ILSSG)Cl(H2O)] (5aꢀg). Further, the antimicrobial profiles of new
compounds against a set of common pathogens have been described. Zone of inhibitions
(ZOIs) and minimal inhibitory concentration (MIC) values revealed that most of the new
compounds exhibited significant antibacterial and potential inhibitory activity against
Staphylococcus aureus (S. aureus), and this activity is modulated by substituents attached to
the ionic liquid core as well as the counterꢀion.
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Introduction
Sulfonamides (SAs), such as sulfaguanidine (SG), become an increasingly important
class of compounds for medicinal chemists due to their costꢀeffectiveness, lowꢀtoxicity
coupled with their assorted pharmacological effects.1 As well, arylsulfonamide motifs act as
the active pharmaceutically ingredients (APIs) in a large number of pharmaceutical drugs
which are prescribed to control bacterial infections, diabetes mellitus, oedema, hypertension
and gout.2 However, antibiotic resistance genes (ARGs), encoding resistance
to sulfonamide3,4, remains a major impediment for their largeꢀscale use. Moreover, the
progression of drugꢀresistant strains has contributed to the inefficiency of the straight
antimicrobial therapy. Thus, there is an urgent call for the identification of novel targets and
development of novel antimicrobial drugs with divergent and unique structures for the
treatment of infectious diseases. Several approaches to negate antibiotic resistance are
currently being investigated, including inactivation of enzymes in essential metabolic
pathways and inhibiting signal transduction systems.5,6 These approaches involve
development of new antimicrobial agents with unique modes of action that circumvent
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current resistance mechanisms.7,8
In this context, designing of the metal based drugs with synergizing beneficial effect of
the ligands and metals to produce a complex with enhanced activity have been promising and
present focal theme of the contemporary biomedical research. Consequently, selection of
organic ligand and metal ion plays an essential role. As well, Schiff bases have been shown to
exhibit a wide range of pharmacological activities such as antibacterial, antifungal,
antimalarial, antitubercular, antiproliferative, antiꢀinflammatory and antiviral. It has been
suggested that the remarkable biological activity of Schiff bases are essentially attributed to
the presence of azomethine linkage.9
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Recently, ionic liquids (ILs) have become attractive candidates for biomedical
applications due to their tunable properties and the ability to generate biological responses
upon binding to several biological targets. They have been recognized as bactericidal,10
fungicidal,10 acetylcholinesterase (AChE) inhibitor,11 delivery of antiꢀinflammatory drugs,12
local anesthetic,10 antiꢀnociceptive, anticholinergic and anticancer drugs.10b,13
Despite extensive work done on Schiff's bases ligands, little attention has been paid to the
sulfaguanidine (SG)ꢀsalicylaldimine (Sal) Schiff bases. To the best of our knowledge, there is
no reports about the fabrication of ionic liquidsꢀbased Nꢀ(salicylidene)sulfaguanidine ILꢀSalꢀ
SG Schiff bases (ILSSGH).
With an objective of exploring the role of Schiff base metal complexes as antimicrobial
agents and in continuation of our ongoing programs directed toward the development of
novel materials for magnetic14 or biological application,10aꢀc,15,16 we now report a concise,
practical synthetic route and in vitro antimicrobial assessment of novel ILSSGH Schiff bases
(Scheme 1) and their Pd(II) complexes which may allow us to develop a new promising
therapeutic strategy to combat antibiotic resistance.
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Scheme 1 significant pharmacological sites in ILꢀSalꢀSG Schiff bases (ILSSGH, 4a–g) that
used in this work
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Experimental
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Instrumentation, materials and the preparation details of a series of ionic liquidsꢀbased
salicylaldehydes can be found in electronic supplementary information.
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Synthesis of the ionic SalꢀSG Schiff bases (4aꢀg)
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Generally, an ethanolic solution (10 mL) contain (0.214 g, 1 mmol) of sulfaguanidine
(SG) and (1 mmol) of ILꢀsalicylaldehyde salts ILꢀsal (3aꢀf) into a 50 mL RB flask was
refluxed for 6 h. Then the supernatant was partially removed, and the yellowꢀorange products
of 4aꢀg were collected by filtration, washed with ethanol (3 x 3 mL), ether (3 x 3 mL), dried
and then crystallized from ethanol. Samples of the isolated solids were characterized as
follows;
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Nꢀ(5ꢀ(2ꢀmethylpyridinium chloride)ꢀsalicylidene) sulfaguanidine (4a): Yellow crystals, Yield
(0.336 g, 73%), mp: 230ꢀ232 °C. FTIR (KBr, cmꢀ1): 3425 (m, br, ν(OꢀH)), 3356, 3324 (m, sh,
ν(NH )), 3185 (m, br, ν(NꢀH)), 1617 (vs, sh, ν(C=N)Azomethine), 1326 (s, sh, ν(SO )), 1263 (m, sh, ν(Arꢀ
2
2
1
O)), 1162 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Py). H NMR (300 MHz, DMSOꢀd6) δ (ppm): 12.71 (s,
1H, OH), 11.16 (s, 1H, SO2NH), 10.67 (s, 1H, NH), 10.30ꢀ10.22 (m, 1H, PyꢀH), 9.06 (ddd, J
= 10.7, 6.7, 1.5 Hz, 1H, PyꢀH), 8.95 (d, J = 3.9 Hz, 1H, HꢀC=N), 8.73 (dd, J = 5.7, 0.9 Hz,
1H, PyꢀH), 8.59ꢀ8.50 (m, 1H, PyꢀH), 8.37 (td, J = 7.8, 1.7 Hz, 1H, ArꢀH), 8.13ꢀ7.99 (m, 1H,
ArꢀH), 7.86 ꢀ7.74 (m, 1H, ArꢀH), 7.67 (d, J = 2.3 Hz, 1H, ArꢀH), 7.61 (dd, J = 4.3, 2.4 Hz,
1H, ArꢀH), 7.54ꢀ7.37 (m, 1H, ArꢀH), 7.11 (dd, J = 13.3, 8.6 Hz, 1H, ArꢀH), 7.03ꢀ6.95 (m,
1H, ArꢀH), 6.78 (d, J = 9.8 Hz, 2H, NH2), 5.84 (d, J = 14.0 Hz, 2H, CH2ꢀAr), 2.81 (d, J =
11.1 Hz, 3H, CH3). 13C NMR (151 MHz, DMSOꢀd6) δ (ppm): 190.66, 161.70, 160.30,
158.13, 156.03, 151.15, 146.11, 136.61, 132.12, 130.72, 128.83, 127.77, 127.47, 126.35,
124.31, 121.97, 118.90, 113.17, 111.45, 59.88, 39.58 and 20.51. EIꢀMS, (m/z, Int.%): (459.0,
5.46) [M]+. Anal. Calcd. for C30H36Cl2N6O2 (M = 459.95): C, 54.84; H, 4.82; N, 15.23; S,
6.97; Found: C, 55.01; H, 4.63; N, 15.51; S, 7.11. Conductivity = 28.8 ꢁS/cm.
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Nꢀ(5ꢀ(quinolinium chloride)ꢀsalicylidene)sulfaguanidine (4b): Orange powder, Yield (0.315
g, 63.5 %), mp: 223ꢀ225 °C. FTIR (KBr, cmꢀ1): 3436 (m, br, ν(OꢀH)), 3398, 3317 (m, sh,
ν(NH )), 3201 (m, br, ν(NꢀH)), 1625 (vs, sh, ν(C=N)Azomethine), 1325 (s, sh, ν(SO )), 1272 (m, sh, ν(Arꢀ
2
2
1
O)), 1165 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Qn). H NMR (300 MHz, DMSOꢀd6) δ (ppm): 12.89 (s,
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1H, OH), 11.13 (s, 1H, SO2NH), 10.42 (s, 1H, NH), 10.03ꢀ9.95 (m, 1H, QnꢀH), 9.12 (ddd, J
= 10.7, 6.7, 1.5 Hz, 1H, QnꢀH), 8.89 (d, J = 3.9 Hz, 1H, HꢀC=N), 8.61 (dd, J = 5.7, 0.9 Hz,
1H, Qn ꢀH), 8.63ꢀ8.59 (m, 1H, QnꢀH), 8.56ꢀ8.49 (m, 2H, 2 x QnꢀH), 8.45ꢀ8.48 (m, 1H, Qnꢀ
H), 8.31 (td, J = 7.5, 1.7 Hz, 1H, ArꢀH), 8.13ꢀ7.99 (m, 1H, ArꢀH), 7.86ꢀ7.74 (m, 1H, ArꢀH),
7.67 (d, J = 2.2 Hz, 1H, ArꢀH), 7.61 (dd, J = 4.3, 2.5 Hz, 1H, ArꢀH), 7.54ꢀ7.37 (m, 1H, Arꢀ
H), 7.11 (dd, J = 13.1, 8.6 Hz, 1H, ArꢀH), 7.03ꢀ6.95 (m, 1H, ArꢀH), 6.66 (d, J = 9.6 Hz, 2H,
NH2), 5.95 (d, J = 14.0 Hz, 2H, CH2ꢀAr). 13C NMR (151 MHz, DMSOꢀd6) δ (ppm): 191.03,
161.23, 160.10, 158.77, 157.35, 156.03, 150.15, 148.41, 146.11, 139.09, 136.61, 132.12,
130.72, 128.83, 127.77, 126.35, 124.31, 122.83, 121.97, 120.02, 118.92, 117.61, 115.56 and
60.88. EIꢀ MS, (m/z, Int.%): (478.2, 6.18) [M ‒ H2O]+. Anal. Calcd. for C24H22ClN5O3S (M =
495.98): C, 58.12; H, 4.47; N, 14.12; S, 6.46; Found: C, 58.36; H, 4.73; N, 13.96; S, 6.11.
Conductivity = 25.4 ꢁS/cm.
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Nꢀ(5ꢀ(1,2ꢀdimethylimidazolꢀ3ꢀium chloride)ꢀsalicylidene) sulfaguanidine (4c): Orange
crystals, Yield (0.39 g, 84 %), mp: 246ꢀ248 °C. FTIR (KBr, cmꢀ1): 3419 (m, br, ν(OꢀH)), 3340,
3308 (m, sh, ν(NH )), 3192 (m, br, ν(NꢀH)), 1622 (vs, sh, ν(C=N)Azomethine), 1323 (s, sh, ν(SO )),
2
2
1
1267 (m, sh, ν(ArꢀO)), 1169 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Im). H NMR (300 MHz, DMSOꢀd6) δ
(ppm): 12.62 (s, 1H, OH), 11.10 (s, 1H, SO2NH), 10.29 (s, 1H, NH), 8.96 (s, 1H, HꢀC=N),
7.82 (d, J = 8.4 Hz, 2H, 2 x ArꢀH), 7.75ꢀ7.70 (m, 1H, ArꢀH), 7.69ꢀ7.63 (m, 2H, 2 x ArꢀH),
7.57ꢀ7.50 (m, 1H, ArꢀH), 7.47 (d, J = 8.5 Hz, 1H, ArꢀH), 7.38 (d, J = 7.8 Hz, 1H, ArꢀH), 7.09
(dd, J = 20.5, 8.5 Hz, 2H, 2 x ArꢀH), 6.84 (s, 2H, NH2), 5.38 (d, J = 14.3 Hz, 2H, CH2ꢀAr),
3.76 (d, J = 6.6 Hz, 3H, CH3), 2.62 (d, J = 10.1 Hz, 3H, CH3). 13C NMR (151 MHz, DMSOꢀ
d6) δ (ppm): 190.78, 163.89, 161.49, 160.62, 144.98, 143.08, 136.51, 134.01, 131.96, 127.69,
127.49, 125.85, 121.95, 121.52, 120.11, 118.56, 117.88, 112.78, 50.45, 35.26 and 10.04. EIꢀ
MS, (m/z, Int.%): (445.0, 25.00) [M ‒ H2O]+. Anal. Calcd. for C20H23ClN6O3S (M = 462.95):
C, 51.89; H, 5.01; N, 18.15; S, 6.93; Found: C, 52.13; H, 5.33; N, 18.02; S, 6.68.
Conductivity = 33.0 ꢁS/cm.
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Nꢀ(5ꢀ(1ꢀ butylimidazolꢀ3ꢀium chloride)ꢀsalicylidene) sulfaguanidine (4d): Yellow crystals,
Yield (0.38 g, 77.5 %), mp: 220ꢀ222 °C. FTIR (KBr, cmꢀ1): 3419 (m, br, ν(OꢀH)), 3336, 3304
(m, sh, ν(NH )), 3200 (m, br, ν(NꢀH)), 1620 (vs, sh, ν(C=N)Azomethine), 1328 (s, sh, ν(SO )), 1265 (m,
2
2
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sh, ν(ArꢀO)), 1137 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Im). H NMR (300 MHz, DMSOꢀd6) δ (ppm):
12.55 (s, 1H, OH), 11.06 (s, 1H, SO2NH), 9.31 (s, 1H, NH), 8.93 (s, 1H, HꢀC=N), 7.87ꢀ7.78
(m, 4H, 4 x ArꢀH), 7.53 (dd, J = 8.5, 2.3 Hz, 1H, ArꢀH), 7.46 (d, J = 8.1 Hz, 2H, 2 x ArꢀH),
7.41ꢀ7.35 (m, 2H, 2 x ArꢀH), 7.07 (d, J = 8.5 Hz, 1H, ArꢀH), 6.79 (s, 2H, NH2), 5.40 (s, 2H,
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CH2ꢀAr), 4.18 (t, J = 7.4 Hz, 2H, C
CH2ꢀCH3), 1.26 (h, J = 7.4 Hz, 2H, CH2ꢀCH2ꢀC
CH2ꢀC
3). 13C NMR (151 MHz, DMSOꢀd6) δ (ppm): 190.69, 161.64, 158.24, 151.83,
H
2ꢀCH2ꢀCH2ꢀCH3), 1.78 (p, J = 7.4 Hz, 2H, CH2ꢀC
H2ꢀ
H2ꢀCH3), 0.90 (t, J = 7.3 Hz, 3H, CH2ꢀCH2ꢀ
H
136.96, 136.44, 131.28, 129.15, 127.70, 127.50, 126.09, 123.25, 121.92, 112.78, 111.77,
107.31, 49.15, 40.40, 31.71, 19.27 and 13.74. EIꢀMS, (m/z, Int.%): (473.0, 56.46) [M ‒
H2O]+. Anal. Calcd. for C22H27ClN6O3S (M = 491.02): C, 53.82; H, 5.54; N, 17.12; S, 6.53;
Found: C, 53.98; H, 5.55; N, 16.99; S, 6.23. Conductivity = 29.4 ꢁS/cm.
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Nꢀ(5ꢀ(1,2ꢀdimethylimidazolꢀ3ꢀium chloride)ꢀ3ꢀisopropylsalicylidene)sulfaguanidine (4e):
Yellow crystals, Yield (0.319 g, 63.2 %), mp: 180ꢀ182 °C. FTIR (KBr, cmꢀ1): 3476 (m, br,
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ν(OꢀH)), 3434, 3354 (m, sh, ν(NH )), 3236 (m, br, ν(NꢀH)), 1623 (vs, sh, ν(C=N)Azomethine), 1327 (s,
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sh, ν(SO )), 1270 (m, sh, ν(ArꢀO)), 1137 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Im). H NMR (300 MHz,
2
DMSOꢀd6) δ (ppm): 13.62 (s, 1H, OH), 11.20 (s, 1H, SO2NH), 10.01 (s, 1H, NH), 8.96 (s,
1H, HꢀC=N), 7.83 (d, J = 8.5 Hz, 2H, 2 x ArꢀH), 7.72 (dd, J = 2.1, 1.1 Hz, 1H, ArꢀH), 7.67ꢀ
7.62 (m, 2H, 2 x ArꢀH), 7.58 (d, J = 2.3 Hz, 1H, ArꢀH), 7.54ꢀ7.48 (m, 1H, ArꢀH), 7.44ꢀ7.36
(m, 1H, ArꢀH), 6.74 (s, 2H, NH2), 5.37 (s, 2H, CH2ꢀAr), 3.76 (d, J = 3.2 Hz, 3H, CH3), 3.27
(dd, J = 13.5, 6.8 Hz, 1H, C
H(CH3)2), 2.64 (d, J = 3.6 Hz, 3H, CH3), 1.24 (d, J = 7.0 Hz, 6H,
CH(C
H
3)2). 13C NMR (151 MHz, DMSOꢀd6) δ (ppm): 190.69, 165.88, 155.46, 153.15,
145.01, 142.76, 137.34, 133.96, 130.71, 127.51, 123.13, 122.09, 121.45, 118.98, 115.23,
109.37, 50.73, 40.41, 35.28, 26.41, 22.63 and 9.99. EIꢀMS, (m/z, Int.%): (505.0, 65.00) [M]+.
Anal. Calcd. for C23H29ClN6O3S (M = 505.03): C, 54.70; H, 5.79; N, 16.64; S, 6.35; Found:
C, 54.58; H, 5.99; N, 16.48; S, 5.78. Conductivity = 34.8 ꢁS/cm.
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Nꢀ(5ꢀ(1,2ꢀdimethylimidazolꢀ3ꢀium tetrafluoroborate)ꢀ3ꢀisopropylsalicylidene)sulfaguanidine
(4f): Orange crystals, Yield (0.367 g, 66 %), mp: 230 °C. FTIR (KBr, cmꢀ1): 3475 (m, br, ν(Oꢀ
H)), 3459, 3359 (m, sh, ν(NH )), 3185 (m, br, ν(NꢀH)), 1624 (vs, sh, ν(C=N)Azomethine), 1325 (s, sh,
2
ν(SO )), 1270 (m, sh, ν(ArꢀO)), 1176 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Im). 1H NMR (300 MHz, DMSOꢀ
2
d6) δ (ppm): 13.62 (s, 1H, OH), 11.21 (s, 1H, SO2NH), 10.01 (s, 1H, NH), 8.96 (s, 1H, Hꢀ
C=N), 7.83 (d, J = 8.1 Hz, 2H, 2 x ArꢀH), 7.71 (d, J = 2.1 Hz, 1H, ArꢀH), 7.65 (dd, J = 5.1,
2.4 Hz, 1H, ArꢀH), 7.59ꢀ7.49 (m, 2H, 2 x ArꢀH), 7.45ꢀ7.36 (m, 2H, 2 x ArꢀH), 6.74 (s, 2H,
NH2), 5.37 (s, 2H, , CH2ꢀAr), 3.76 (d, J = 3.5 Hz, 3H, CH3), 3.43ꢀ3.20 (m, 1H, C
H(CH3)2),
2.64 (d, J = 3.6 Hz, 3H, CH3), 1.24 (d, J = 6.9 Hz, 6H, CH(C
H
3)2). 13C NMR (151 MHz,
DMSOꢀd6) δ (ppm): 198, 165.38, 158.09, 149.57, 144.42, 142.79, 136.44, 133.47, 130.25,
127.00, 124.96, 124.95, 122.65, 121.58, 121.58, 120.94, 120.94, 118.29, 50.22, 34.76, 26.22,
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22.11 and 9.48. 19F NMR (282 MHz, DMSOꢀd6):
−
148.22 ppm (singlet). 11B NMR (96 MHz,
DMSOꢀd6):
−
1.29 ppm (singlet). EIꢀMS, (m/z, Int.%): (574.1, 4.97) [M + H2O]+. Anal. Calcd.
for C23H29BF4N6O3S (M = 556.38): C, 49.65; H, 5.25; N, 15.10; S, 5.76; Found: C, 49.46; H,
5.55; N, 14.98; S, 5.73. Conductivity = 30.4 ꢁS/cm.
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Nꢀ(5ꢀ(1,2ꢀdimethylimidazolꢀ3ꢀium hexafluorophosphate)ꢀ3ꢀisopropylsalicylidene) sulfaguaniꢀ
dine (4g): Yellow crystals, Yield (0.529 g, 86.1 %), mp: 150ꢀ152 °C. FTIR (KBr, cmꢀ1):
3479 (m, br, ν(OꢀH)), 3435, 3344 (m, sh, ν(NH )), 3236 (m, br, ν(NꢀH)), 1621 (vs, sh,
2
ν(C=N)Azomethine), 1325 (s, sh, ν(SO )), 1273 (m, sh, ν(ArꢀO)), 1178 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Im). 1H
2
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NMR (300 MHz, DMSOꢀd6) δ (ppm): 13.62 (s, 1H, OH), 11.20 (s, 1H, SO2NH), 10.01 (s,
1H, NH), 8.96 (s, 1H, HꢀC=N), 7.87ꢀ7.80 (m, 2H, 2 x ArꢀH), 7.72 (dd, J = 2.2, 1.1 Hz, 1H,
ArꢀH), 7.67ꢀ7.62 (m, 2H, 2 x ArꢀH), 7.54 (d, J = 2.0 Hz, 1H, ArꢀH), 7.53ꢀ7.48 (m, 1H, ArꢀH),
7.43 (d, J = 2.2 Hz, 1H, ArꢀH), 6.74 (s, 4H, NH2), 5.37 (s, 2H, CH2ꢀAr), 3.76 (d, J = 3.2 Hz,
3H, CH3), 3.32 – 3.25 (m, 1H, C
H(CH3)2), 2.64 (d, J = 3.6 Hz, 3H, CH3), 1.24 (d, J = 6.9 Hz,
6H, CH(C
H
3)2). 13C NMR (151 MHz, DMSOꢀd6) δ (ppm): 197.19, 165.88, 158.59, 150.08,
144.93, 143.31, 136.96, 130.76, 127.51, 125.46, 123.13, 122.09, 121.45, 118.81, 112.78,
50.73, 35.28, 28.20, 26.73, 22.63 and 10.00. 19F NMR (282 MHz, DMSOꢀd6): –70.415 ppm
1
2
(doublet, JFP = 711.4 Hz). 31P NMR (202 MHz, DMSOꢀd6): –144.20 ppm (septet, JPF
=
711.40 Hz). EIꢀMS, (m/z, Int.%): (614.0, 45.74) [M]+. Anal. Calcd. for C23H29PF6N6O3S (M
= 614.54): C, 44.95; H, 4.76; N, 13.68; S, 5.22; Found: C, 45.04; H, 4.89; N, 13.67; S, 5.10.
Conductivity = 28.2 ꢁS/cm.
21
Synthesis of the ionic Pd(II) SalꢀSG Schiff bases complexes (5aꢀg)
22
23
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25
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28
A methanolic solution (5 mL) of palladium(II) Chloride (0.126g, 1 mmole) was added
dropwise to a stirred methanolic solution (10 mL) containing ionic Nꢀ(salicylidene)sulfaꢀ
guanidines (1 mmole) and 1mL of conc HCl. Then the reaction mixture was refluxed for 8
hours. After that, the solution was concentrated to leave an oily residue, which was solidified
by adding of petroleum ether (40ꢀ60) and keeping in a refrigerator overnight. The isolated
solids were filtered off and washed with cold methanol/ diethyl ether mixedꢀsolvent (1:2) (3 x
3mL) to yield (5aꢀg). Samples of the isolated solids were characterized as follows;
29
30
31
32
[PdCl(4a)H2O] (5a): Dark yellow powder, Yield (0.368 g, 68.3 %), mp: 240 °C. FTIR (KBr,
cmꢀ1): 3202 (m, br, ν(NꢀH)), 3121, 1493 (m, sh, ν(NH +)), 1627 (vs, sh, ν(C=N)Azomethine), 1321 (s,
3
1
sh, ν(SO )), 1283 (m, sh, ν(ArꢀO)), 1167 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Py). H NMR (500 MHz,
2
DMSOꢀd6) δ (ppm): 11.03 (s, 1H, SO2NH), 10.28 (s, 1H, NH), 9.09ꢀ9.00 (m, 1H, PyꢀH), 8.94
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(s, 1H, HꢀC=N), 8.54 (s, 1H, PyꢀH), 8.16ꢀ7.97 (m, 3H, PyꢀH + ArꢀH), 7.94ꢀ7.79 (m, 2H, Arꢀ
H), 7.72ꢀ7.60 (m, 2H, ArꢀH), 7.54ꢀ7.44 (m, 2H, ArꢀH), 7.43 (d, J = 8.7 Hz, 1H, ArꢀH), 7.09
(dd, J = 8.6, 1.5 Hz, 2H, NH2), 6.60 (d, J = 8.7 Hz, 3H, +NH3) 5.81 (s, 2H, CH2ꢀAr), 2.79 (s,
3H, CH3). 13C NMR (126 MHz, DMSOꢀd6) δ (ppm): 193.33, 167.17, 161.79, 156.05, 151.11,
146.01, 139.59, 133.92, 133.59, 130.64, 129.01, 127.69, 126.25, 123.14, 121.60, 120.12,
119.09, 118.63, 117.54, 114.81, 56.35, and 23.95. EIꢀMS, (m/z, Int.%): (566.1, 90.82) [M ‒
H2O]+. Anal. Calcd. for C21H23ClN5O4PdS (M = 583.38): C, 43.24; H, 3.97; N, 12.00; S,
5.50; Found: C, 43.11; H, 4.21; N, 11.89; S, 5.24. Conductivity = 35.2 ꢁS/cm.
9
[PdCl(4b)H2O] (5b): Pale brown powder, Yield (0.385 g, 62.1 %), mp: 236 °C. FTIR (KBr,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
cmꢀ1): 3188 (m, br, ν(NꢀH)), 3115, 1492 (m, sh, ν(NH +)), 1647 (vs, sh, ν(C=N)Azomethine), 1321 (s,
3
1
sh, ν(SO )), 1283 (m, sh, ν(ArꢀO)), 1166 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Qn). H NMR (300 MHz,
2
DMSOꢀd6) δ (ppm): 11.09 (s, 1H, SO2NH), 10.36 (s, 1H, NH), 9.9ꢀ9.95 (m, 1H, QnꢀH), 9.13
(dd, J = 6.3, 1.7 Hz, 1H, QnꢀH), 9.11 (d, J = 3.9 Hz, 1H, HꢀC=N), 8.58 (dd, J = 5.8, 0.9 Hz,
1H, QnꢀH), 8.61ꢀ8.58 (m, 1H, QnꢀH), 8.56ꢀ8.49 (m, 2H, 2 x QnꢀH), 8.45ꢀ8.48 (m, 1H, Qnꢀ
H), 8.31 (td, J = 7.5, 1.7 Hz, 1H, ArꢀH), 8.12ꢀ7.97 (m, 1H, ArꢀH), 7.76 (s, 1H, ArꢀH), 7.67
(d, J = 2.2 Hz, 1H, ArꢀH), 7.61 (dd, J = 4.3, 2.5 Hz, 1H, ArꢀH), 7.54ꢀ7.37 (m, 1H, ArꢀH),
7.11 (d, J = 8.6 Hz, 1H, ArꢀH), 7.03ꢀ6.95 (m, 1H, ArꢀH), 6.66 (d, J = 9.6 Hz, 2H, NH2), 5.61
(s, 2H, CH2ꢀAr). 13C NMR (125 MHz, DMSOꢀd6) δ (ppm): 192.24, 161.23, 160.09, 158.65,
157.35, 156.43, 150.15, 148.41, 146.11, 139.09, 136.61, 132.12, 130.72, 128.83, 127.56,
126.31, 124.31, 123.83, 122.97, 121.13, 119.87, 118.63, 117.56 and 58.55. EIꢀ MS, (m/z,
Int.%): (566.1, 16.32) [M ‒ H2O ‒ Cl]+. Anal. Calcd. for C24H23ClN5O4PdS (M = 619.41): C,
46.54; H, 3.74; N, 11.31; S, 5.18; Found: C, 46.36; H, 3.96; N, 11.03; S, 4.86. Conductivity =
28.6 ꢁS/cm.
24
25
26
27
28
29
30
31
32
33
[PdCl(4c)H2O] (5c): Deep orange crystals, Yield (0.387 g, 62.3 %), mp: 200ꢀ202 °C. FTIR
(KBr, cmꢀ1):: 3200 (m, br, ν(NꢀH)), 3119, 1494 (m, sh, ν(NH +)), 1649 (vs, sh, ν(C=N)Azomethine),
3
1
1323 (s, sh, ν(SO )), 1282 (m, sh, ν(ArꢀO)), 1168 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Im). H NMR (500
2
MHz, DMSOꢀd6) δ (ppm): 11.05 (s, 1H, SO2NH), 10.28 (s, 1H, NH), 8.98 (s, 1H, HꢀC=N),
7.82 (d, J = 2.0 Hz, 1H, ArꢀH), 7.70ꢀ7.64 (m, 2H, ArꢀH), 7.62 (s, 2H, ArꢀH), 7.55ꢀ7.46 (m,
2H, ArꢀH), 7.13ꢀ7.07 (m, 1H, ArꢀH), 7.05 (d, J = 8.5 Hz, 1H, ArꢀH), 6.93 (d, J = 8.4 Hz, 2H,
NH2), 5.36 (s, 2H, CH2ꢀAr), 3.76 (s, 3H, CH3), 2.62 (s, 3H, CH3). 13C NMR (125 MHz,
DMSOꢀd6) δ (ppm): 191.02, 163.98, 161.27, 158.48, 156.90, 144.87, 136.42, 128.84, 128.32,
127.41, 125.77, 123.04, 122.82, 121.89, 121.42, 121.36, 118.46, 117.80, 116.49, 50.45, 35.23
and 10.03. EIꢀMS, (m/z, Int.%): (569.0, 16.77) [M ‒ H2O ‒ Cl]+. Anal. Calcd. for
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C20H24Cl2N6O4PdS (M = 621.83): C, 38.63; H, 3.89; N, 13.51; S, 5.16; Found: C, 38.42; H,
4.01; N, 13.37; S, 4.99. Conductivity = 31.3 ꢁS/cm.
3
4
[PdCl(4d)H2O] (5d): Pale brown powder, Yield (0.386 g, 59.4 %), mp: 168ꢀ170 °C. FTIR
(KBr, cmꢀ1): 3199 (m, br, ν(NꢀH)), 3111, 1494 (m, sh, ν(NH +)), 1649 (vs, sh, ν(C=N)Azomethine),
3
1
5
1323 (s, sh, ν(SO )), 1282 (m, sh, ν(ArꢀO)), 1135 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Im). H NMR (600
2
6
MHz, DMSOꢀd6) δ (ppm): 11.06 (s, 1H, SO2NH), 10.30 (s, 1H, NH), 9.30 (s, 1H, d, J = 10.5
Hz, HꢀC=N), 8.94 (s, 1H, ArꢀH), 7.85ꢀ7.79 (m, 3H, ArꢀH), 7.75 (d, J = 2.4 Hz, 1H, ArꢀH),
7.60 (dd, J = 8.7, 2.4 Hz, 1H, ArꢀH), 7.47 (d, J = 8.5 Hz, 1H, ArꢀH), 7.38 (d, J = 8.7 Hz, 2H,
ArꢀH), 7.08 (dd, J = 17.0, 8.6 Hz, 1H, ArꢀH), 6.54 (d, J = 8.7 Hz, NH2, 2H), 5.36 (s, 2H,
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8
9
10
11
12
13
14
15
16
CH2ꢀAr), 4.17 (t, J = 7.0 Hz, 2H, C
CH3), 1.30ꢀ1.21 (m, 2H, CH2ꢀCH2ꢀC
3). 13C NMR (125 MHz, DMSOꢀd6) δ (ppm): 192.45, 161.73, 157.36, 151.80, 136.85,
H
2ꢀCH2ꢀCH2ꢀCH3), 1.81ꢀ1.73 (m, 2H, CH2ꢀC
H2ꢀCH2ꢀ
H2ꢀCH3), 0.90 (td, J = 7.3, 2.3 Hz, 3H, CH2ꢀCH2ꢀCH2ꢀ
C
H
135.78, 131.64, 130.68, 129.15, 127.75, 126.11, 123.25, 121.92, 112.78, 111.80, 107.31,
49.32, 40.58, 31.71, 20.08 and 14.68. EIꢀMS, (m/z, Int.%): (650.0, 65.32) [M]+. Anal. Calcd.
for C22H28Cl2N6O4PdS (M = 649.89): C, 40.66; H, 4.34; N, 12.93; S, 4.93; Found: C, 40.43;
H, 4.61; N, 12.76; S, 4.56. Conductivity = 26.4 ꢁS/cm.
17
18
19
[PdCl(4e)H2O] (5e): Dark yellow powder, Yield (0.453 g, 68.3 %), mp: 240 °C. FTIR (KBr,
cmꢀ1): 3195 (m, br, ν(NꢀH)), 3116, 1493 (m, sh, ν(NH +)), 1645 (vs, sh, ν(C=N)Azomethine), 1318 (s,
3
1
sh, ν(SO )), 1284 (m, sh, ν(ArꢀO)), 1173 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Im). H NMR (300 MHz,
2
20
21
22
23
24
25
26
27
28
29
30
31
DMSOꢀd6) δ (ppm): 11.21 (s, 1H, SO2NH), 10.02 (s, 1H, NH), 8.98 (s, 1H, HꢀC=N), 7.88ꢀ
7.78 (m, 1H, ArꢀH), 7.73 (dd, J = 2.2, 1.4 Hz, 1H, ArꢀH), 7.70ꢀ7.62 (m, 1H, ArꢀH), 7.59 (d, J
= 2.3 Hz, 1H, ArꢀH), 7.55 (d, J = 2.3 Hz, 1H, ArꢀH), 7.54ꢀ7.49 (m, 1H, ArꢀH), 7.49ꢀ7.33 (m,
1H, ArꢀH), 7.02 (d, J = 13.6 Hz, H, ArꢀH), 6.83 (d, J = 8.5 Hz, 2H, NH2), 5.38 (s, 2H, CH2ꢀ
Ar), 3.54 (dd, J = 17.3, 11.1 Hz, 3H, CH3), 3.31 (tq, J = 13.6, 6.9 Hz, 1H, C
H(CH3)2), 2.65
(d, J = 4.0 Hz, 3H, CH3), 1.23 (d, J = 6.9 Hz, 6H, CH(C
H
3)2). 13C NMR (151 MHz, DMSOꢀ
d6) δ (ppm): 196.72, 172.03, 158.07, 149.58, 145.39, 144.50, 142.69, 137.19, 136.41, 133.48,
130.23, 127.02, 125.91, 124.96, 122.66, 121.61, 120.90, 118.29, 109.59, 50.22, 34.81, 25.90,
22.12 and 9.55. EIꢀMS, (m/z, Int.%): (611.2, 27.76) [M ‒ H2O ‒ Cl]+. ESIꢀMS (m/z): (319.2,
100) [C10H12ClNO2Pd]+. Anal. Calcd. for C23H30Cl2N6O4PdS (M = 663.91): C, 41.61; H,
4.55; N, 12.66; S, 4.83; Found: C, 41.28; H, 4.76; N, 12.46; S, 4.49. Conductivity = 29.6
ꢁS/cm.
32
[PdCl(4f)H2O]
(5f): Dark yellow powder, Yield (0.476 g, 66.6 %), mp: 90ꢀ92 °C. FTIR
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(KBr, cmꢀ1): 3201 (m, br, ν(NꢀH)), 3116, 1494 (m, sh, ν(NH +)), 1644 (vs, sh, ν(C=N)Azomethine),
3
1
1320 (s, sh, ν(SO )), 1287 (m, sh, ν(ArꢀO)), 1171 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Im). H NMR (300
2
MHz, DMSOꢀd6) δ (ppm): 11.20 (s, 1H, SO2NH), 10.02 (s, 1H, NH), 8.96 (d, J = 5.0 Hz, 1H,
HꢀC=N), 7.97ꢀ7.91 (m, 1H, ArꢀH), 7.87ꢀ7.80 (m, 1H, ArꢀH), 7.78 (d, J = 2.5 Hz, 1H, ArꢀH),
7.77ꢀ7.73 (m, 1H, ArꢀH), 7.72 (dd, J = 2.1, 1.3 Hz, 1H, ArꢀH), 7.65 (td, J = 3.4, 2.1 Hz, 1H,
ArꢀH), 7.58 (d, J = 2.3 Hz, 1H, ArꢀH), 7.50ꢀ7.49 (m, 1H, ArꢀH), 6.78 (s, 2H, NH2), 5.38 (s,
2H, CH2ꢀAr), 3.55 (dd, J = 17.7, 11.1 Hz, 3H, CH3), 3.31 (tq, J = 13.7, 6.9, 6.2 Hz, 1H,
CH(CH3)2), 2.67 – 2.62 (m, 3H, CH3), 1.22 (dd, J = 9.8, 6.9 Hz, 6H, CH(CH
3)2). 13C NMR
(75 MHz, DMSOꢀd6) δ (ppm): 196.13, 174.88, 167.26, 161.86, 157.87, 152.63, 147.05,
10
11
12
13
14
15
144.01, 141.97, 140.28, 133.46, 127.00, 124.96, 120.90, 116.06, 107.51, 107.00, 56.38,
52.14, 34.79, 26.22, 22.09 and 9.53. 19F NMR (282 MHz, DMSOꢀd6):
11B NMR (96 MHz, DMSOꢀd6):
1.30 ppm (singlet). EIꢀMS, (m/z, Int.%): (662.2, 21.65) [M
−148.28 ppm (singlet).
−
‒ H2O ‒ Cl]+. ESIꢀMS (m/z): (319.2, 100) [C10H12ClNO2Pd]+. Anal. Calcd. for
C23H30BClF4N6O4PdS (M = 715.26): C, 38.62; H, 4.23; N, 11.75; S, 4.48; Found: C, 38.38;
H, 4.51; N, 11.77; S, 4.25. Conductivity = 28.5 ꢁS/cm.
16
17
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[PdCl(4g)H2O] (5g): Orang powder, Yield (0.491 g, 63.5 %), mp: 121ꢀ123 °C. FTIR (KBr,
cmꢀ1): 3185 (m, br, ν(NꢀH)), 3117, 1493 (m, sh, ν(NH +)), 1650 (vs, sh, ν(C=N)Azomethine), 1323 (s,
3
1
sh, ν(SO )), 1280 (m, sh, ν(ArꢀO)), 1173 (s, sh, ν(HꢀC=C + HꢀC=N)bend, Im). H NMR (300 MHz,
2
19
20
21
22
23
24
25
26
27
28
29
30
31
DMSOꢀd6) δ (ppm): 11.21 (s, 1H, SO2NH), 10.02 (s, 1H, NH), 8.98 (s, 1H, HꢀC=N), 7.88ꢀ
7.79 (m, 1H, ArꢀH), 7.73 (t, J = 1.8 Hz, 1H, ArꢀH), 7.70 – 7.62 (m, H, ArꢀH), 7.59 (d, J = 2.4
Hz, 1H, ArꢀH), 7.54 (d, J = 2.0 Hz, 1H, ArꢀH), 7.52 (d, J = 1.8 Hz, 1H, ArꢀH), 7.50 (d, J =
2.2 Hz, 1H, ArꢀH), 7.49ꢀ7.35 (m, 1H, ArꢀH), 7.02 (s, 1H, ArꢀH), 6.81 (s, 2H, NH2), 5.38 (s,
2H, CH2ꢀAr), 3.54 (dd, J = 17.2, 11.1 Hz, 3H, CH3), 3.30 (dp, J = 13.6, 6.8 Hz, 1H,
CH(CH3)2), 2.65 (d, J = 4.0 Hz, 3H, CH3), 1.22 (dd, J = 9.8, 6.9 Hz, 6H, CH(CH
3)2). 13C
NMR (75 MHz, DMSOꢀd6) δ (ppm): 196.72, 165.44, 158.10, 149.60, 144.50, 142.71, 137.21,
133.48, 130.22, 127.02, 125.93, 124.97, 122.66, 121.61, 120.91, 118.30, 53.06, 50.21, 34.80,
19
1
26.22, 22.12 and 9.56. F NMR (282 MHz, DMSOꢀd6): –70.417 ppm (doublet, JFP = 711.5
2
Hz). 31P NMR (202 MHz, DMSOꢀd6): –144.21 ppm (septet, JPF = 711.40 Hz). EIꢀMS (m/z,
Int.%): (721.2, 19.24) [M ‒ H2O ‒ Cl]+. ESIꢀMS (m/z): (319.2, 100) [C10H12ClNO2Pd]+. Anal.
Calcd. for C23H30ClF6N6O4PPdS (M = 773.42): C, 35.72; H, 3.91; N, 10.87; S, 4.15; Found:
C, 35.38; H, 4.03; N, 10.67; S, 4.00. Conductivity = 27.3 ꢁS/cm.
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Microbiological screening
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Antibacterial survey
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Reagents: Dimethylsulphoxide (DMSO), Ampicillin antibiotic (C16H19N3O4S, 349.41
g·mol−1) and Amphotericin B (C47H73NO17, 923.49 g·mol−1), antifungal drug, were obtained
from Sigma Chemical Co. (St. Louis, MO, USA).
5
6
Bacterial cultures: strains used in this study from National Organization for Drug Control
and Research (NODCAR), Cairo, Egypt. The different strains are Staphylococcus aureus (S.
aureus, ATCCꢀ25923 as representatives for the Gramꢀpositive bacteria and Escherichia coli
(E. coli, ATCCꢀ25922) as the most important Gramꢀnegative pathogenic bacteria. Antifungal
species, Aspergillus flavus (A. flavus) and Candida albicans (C. albicans, NCIM No. 3100).
Stock cultures grown aerobically on nutrient broth (NB) agar slants (HiꢀMedia) at 37°C were
maintained at 4°C. Preꢀcultures containing 105 CFU/ml, grown aerobically in Mueller Hinton
(MH) liquid medium (HiꢀMedia) at 37°C for 5 h, were used as inoculum for all experiments.
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Antimicrobial susceptibility: Antimicrobial susceptibility of the bacterial strains was carried
out by agar well diffusion method17 (see supplementary information) for the target
compounds as well as standard drugs, Ampicillin. The diameter of the zones of inhibition
(ZOI, mm) was measured accurately as indicative of antimicrobial activity.
17 Determination of MIC; As parameters of the antibacterial efficacy, the minimal inhibitory
18 concentration (MIC) of the new compounds against infection isolates were determined using
19 the macroꢀdilution broth susceptibility test. Freshly prepared MuellerꢀHinton (MH) broth was
20 used as diluent in the macroꢀdilution method. A serial dilution of each compound was
21 prepared within a desired range (0.25 mM to 20.00 mM). One mL of the stock cultures was
22 then inoculated and tubes were incubated at 37 °C for 24 h, control tubes were assayed
23 simultaneously. MIC was examined visually, by checking the turbidity of the tubes.
24 Results and Discussion
25
Synthesis of the target compounds
26
27
28
29
30
31
Stepꢀbyꢀstep route for the synthesis of ionic SalꢀSG Schiff bases (ILꢀSalꢀSG) (4aꢀg) is
depicted in Schemes 2,3. Where, the key starting materials ILꢀfunctionalized salicylaldehydes
3aꢀg) were synthesized starting from salicylaldehydes (1a,b) via a literature protocol.10a,b,c In
(
which, the salicylaldehydes have been chloromethylated with paraformaldehyde/ HClaq/
ZnCl2 mixture and then aminated with 2ꢀmethylpyridine (αꢀpicoline, Pic), 1,2ꢀ
dimethylimidazole ((Me)2Im), 1ꢀnbutylimidazole (nBuIm) or qunioline (Qn) to generate the
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common precursors SalꢀIL chlorides (3aꢀe). Anion metathesis of 3b with
hexafluorophosphoric acid (HPF6(aq)) and sodium tetrafluoroborate afford the corresponding
hexafluorophosphate and tetrafluoroborate salts (3g,f), respectively (see Schemes 2).
2
3
4
5
6
Scheme 2 Schematic diagram for the synthesis of ionic liquidsꢀbased salicylaldehydes (ILsꢀ
Sal, 3aꢀg).
7
8
Eventually, the desired ILsꢀSalꢀSG (ILSSGH) ligands (4aꢀg), were obtained simply by
Schiff base condensation of ionic salicylaldehydes salts (3aꢀg) with sulfaguanidine (see
Schemes 3). These ligands isolated in high to excellent yields and structurally characterized
by elemental analysis, FTIR, NMR (1H, 13C, 19F, 31P, 11B), ESIꢀMS, as well as conductivity
measurements.
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Scheme 3 Synthesis of ionic sulfaguanidineꢀsalicylaldimine Schiff base architectures
(ILSSGH, 4aꢀf) and their metalation by Pd(II) ion.
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7
Unfortunately all trials to metallate ionic sulfaguanidine Schiff bases, by refluxing a
solution of the corresponding ILSSGH ligands (4aꢀg) with palladium(II) chloride in
methanol, were unsuccessful. Instead, Pd(II) complexes, [Pd(II)(SGSIL)Cl(H2O)] (5aꢀg),
were obtained (cf. Scheme 2). The structures of Pd(II) complexes were proposed based upon
elemental and spectral analysis (FTIR, NMR (1H, 13C, 19F, 31P, 11B), ESIꢀMS) as well as
conductivity measurements and matching with the structure of previously reported Pd(II)
complex analogue (Table S1, supplementary information).
8
Characterizations of ILSSGH ligands and their complexes
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31
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ILSSGH ligands (4aꢀg) and their Pd(II) complexes (5aꢀg) were prepared in high yields,
gave satisfactory elemental analysis data which are consistent with their proposed structures
(see the Experimental section). The molar conductance values of the free ligands and their
Pd(II) complexes are in the range of 28.2ꢀ34.8 and 27.3ꢀ48.6 ꢁS/cm, respectively, in
accordance with their electrolytic nature.
FTIR marker bands and their assignments are given in Table S2 (supplementary
information). The FTIR spectral data of ILSSGH (4a–g) revealed the following highlights: (i)
the absorption peak appeared at the range of 3449±30 cm−1 attributed to the free phenolic OH
stretch. (ii) Strong doublet in ranges of 3397±61 cm−1 and 3331±27 cm−1 are assignable to
NH2 vibration of guanidine moiety (NHꢀC(=NH)ꢀNH2). (iii) The N–H stretches for
guanidine fragment exhibited lowꢀenergy shift, 3236ꢀ3185 cm−1 and 3174ꢀ3135 cm−1, due to
the involvement of amine protons in hydrogen bonding.18 (iv) An intense band around 1621
cm−1 is due to azomethine (H–C=N) stretching vibration. (v) Three main peaks (C=N
stretching vibration: 1543ꢀ1534; X− vibration: 562ꢀ552 cm−1, for Cl−, 845 cm−1, for PF6− and
−
1060 cm−1, for BF4 ; bending vibration: 773ꢀ757 cm−1) which are characteristic for the ionic
liquid terminals. (vi) A mediumꢀintensity band in the range of 1268±
5 cm−1 is attributed to
νArꢀO. Noteworthy, a very weak shoulder at 1578±5 cmꢀ1 which could be assigned as a
perturbed carbonyl stretching with the frequency lowering from a free carbonyl ascribed to
conjugation and hydrogen bonding in ketoenamine forms as shown in Scheme 4. This is
indicative of the central backbone is in the expected Oꢀprotonated enolimine tautomeric form
with minor contribution of ketoenamine form in the solid state.
Comparison of the FTIR spectroscopic data collected for Pd(II) complexes with those
obtained for the free ligands demonstrates marked changes in the IR signatures of ligands
(see Figure 1) arising from the binding of Pd(II) ion by the donor atoms set in ligands.
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Scheme 4 Possible sulfonamideꢀsulfonimide and enolimineꢀketoenamines tautomeric forms
and Hꢀbonding profile ionic in SalꢀSD Schiff bases
4
5
6
Figure 1 Selected IR region (1700ꢀ1200 cm−1), for comparison of the azomethine and
phenolate stretching vibrations and their splitting patterns.
7
8
The phenolic–OH stretches which have been observed in the FTIR spectra of the
ILSSGH, at ca. 3449 cmꢀ1, were lost in the spectra of the Pd(II) complexes, indicating
deprotonation of the phenolic oxygen and replacement of phenolic proton by Pd(II) ion, this
further confirmed by a remarkable shift of the phenolic C–O stretch to higher frequency by
11–36 cmꢀ1 in the spectra of complexes (Table 1). Interestingly, emergence of a new weak
band at 1687±5 cmꢀ1, typical of a carbonyl group, coupled with a redꢀshift of the perturbed
carbonyl stretching peak in the spectra of Pd(II) complexes confirming the participation of
carbonyl oxygen of the ketoenamine tautomer in bonding with Pd(II). Moreover, the
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enolimine/ ketoenamine tautometic equilibrium is slightly shifted toward the ketoꢀenamine
tautomer upon coordination to Pd(II). Also consistent with the complex formation and the
participation of azomethine nitrogen in binding with Pd(II) ion was the observation that, the
strong νC=N(azomethine) stretches in the FTIR spectra of the free ligands were displaced to lower
frequency, by 10–29 cmꢀ1, in complexes (cf. Table 1). Finally, the broad band at ca. 3439ꢀ
3385 cmꢀ1 agrees with the hydrated nature of complexes as suggested by the microanalytical
data. In conclusion, infrared spectroscopic data suggested that, of ILSSGH architectures act
as bidentate NOꢀchelating ligands.
9
Table 1 Comparison of FTIR structural parameters in ILSSGH ligands and their Pd(II)
10
complexes
Nr.
4a
5a
4b
5b
4c
5c
4d
5d
4e
5e
4f
ν(OꢀH) ν(C=N) ꢁν(C=N)
ν(ArꢀO)
ꢁν(ArꢀO)
3425
‒
1617
1627
1622
1645
1620
1649
1623
1645
1625
1647
1624
1644
1621
1650
‒
+10
‒
1263, 681
1283, 706
1267, 679
1280, 705
1265, 683
1282, 707
1270, 682
1284, 718
1272, 680
1283, 715
1270, 684
1287, 719
1273, 682
1280, 716
‒
+20, +25
3419
‒
3419
‒
3476
‒
3436
‒
3475
‒
3479
‒
‒
+23
‒
+29
‒
+22
‒
+22
‒
+23, +26
‒
+17, +24
‒
+14, +36
‒
+11, +35
‒
+17, +35
‒
+17, +34
5f
4g
5g
+20
‒
+29
11
12
13
14
15
16
17
18
19
20
21
22
23
1H NMR spectra of ILSSGH and their Pd(II) complexes are dominated by common
remarkable features: (i) The presence of deshielded resonance at δ = ~13.0 ppm, in the
spectra of ILSSGH, originating from the intramolecularly Hꢀbonded phenolic OH,19 the
1
disappearance of these signals in the H NMR spectra of Pd(II) complexes (see Figure 2)
corroborates the successful deprotonation and formation of phenolate precursors. This is also
likely consequence of engaging the phenolate oxygen into coordination to the Pd(II) ion. (ii)
The sulfonamide NH proton resonates at low field (11.14 ± 0.08 ppm in free ligand) due to
intramolecular hydrogen bonding N–H…O, an amine–imine (cf. Scheme 4) interchange may
be considered the most probable reason for broadening of this signal.20 (iii) The immutability
of guanidine NꢀH signal, δ 9.99 ± 0.68 ppm in free ligand, in 1H NMR spectra of complexes
suggested a nonꢀparticipation of the C NH moiety in coordination to Pd(II) ion. However,
the NH2 signal (δ 9.99 ± 0.68 ppm in free ligand) in the spectra of complexes is flanked by
satellites due to the protonation of the amino group is with HCl to form the corresponding
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guanidinium salts. (iv) Noteworthy, consistent with the participation azomethine nitrogen in
bonding to the Pd(II) ion is the observation that the splitting and a downfield shift in position
2
3
of azomethine proton signal, by 0.05ꢀ0.07 ppm, in the 1H NMR spectra of complexes.
1
4
5
Figure 2 partial H NMR region (8.7ꢀ14.0 ppm), for comparison of the azomethine and
phenolic protons resonance and their splitting patterns in 4f & 4d and there Pd(II) complexes.
6
7
The common spectral peculiarities of the 13C NMR spectra for ILSSGH (4a–g)
represented in the two characteristic signals around δ 164/ 194 ppm and 158 ppm
corresponding to carbon atom attached to the phenolic oxygen (Cꢀ1) and azomethine nitrogen
(Cꢀ7), respectively. These peaks are shifted either downfield or upfield in all Pd(II)
complexes, indicating the coordination of deprotonated Schiff base to Pd(II) via (O) phenolic
attached to Cꢀ1 and (N) azomethine attached to Cꢀ7 as shown in Scheme 3.
8
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12 Pharmacology
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16
Many clinical trials of new active pharmaceutical ingredients (API) end in failure due to
the low efficacy of the drug because of limited bioavailability or solubility. Anchoring of
ionic liquid terminals to sulfaguanidine (SG) could provide a synergetic effect of improving
water solubility and at the same time enhancing the pharmacological effect.
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Antimicrobial activity profile
The target imidazolium/ pyridinium/ quinolinium ILꢀsupported SalꢀSG ligands, their
complexes, and standards drugs were in vitro assessed separately for their capacity to inhibit
the growth of a range of clinically significant pathogenic bacterial strains including
Staphylococcus aureus (S. aureus) as gramꢀpositive bacterium, Escherichia coli (E. coli), as
gramꢀnegative one, and Aspergillus flavus (A. flavus) as well Candida albicans (C. albicans,
NCIM No. 3100), as fungal pathogens. In general, our data (ZOIs, Figure 3) demonstrate that
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the incorporation ionic liquid terminals exerts an overall additive effect with respect to
microbiological toxicity, where ionic compartments: (i) ameliorate the waterꢀsolubility of
SalꢀSG and (SalꢀSG)Pd(II);21 (ii) enhance the cytotoxicity of new architectures, SalꢀSG/ (Salꢀ
SG)Pd(II), to microbial strains especially against S. aureus. The effectiveness of the target
compounds in inducing staphylococcalcidal effect higher than E. coliꢀcidal action could be
ascribed to their cell envelope i.e. membrane(s), a complex multilayered structure that serves
to protect these organisms from their unpredictable and often hostile environment, structural
differences. Where, E. coli and most gramꢀnegative bacteria possess an outer membrane
outside the peptidoglycan layer which is lacking in gramꢀpositive organisms, S. aureus. The
essential function of the outer membrane is to serve as a selective permeability barrier,
protecting bacteria from antibacterial agents. The outer membrane of E. coli is predominately
made of patches of Lipopolysaccharide (LPS) each containing hundreds to thousands of LPS
molecules. The packing of the nearest neighbor patches is tight, and as such the LPS layer
provides an effective permeability barrier for the E. coli bacterium.22
3
4
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Figure 3 Graph of zone of inhibition/mm for target compounds against different microbial
species.
17
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21
Among all tested compounds, ligand 4g (Scheme 5), 4ꢀNꢀ(5ꢀ(1,2ꢀdimethylꢀimidazolium
hexafluorophosphate)ꢀ3ꢀisopropylsalicylidene)sulfaguanidine, exhibit remarkable extraꢀ
potent bactericidal activity when compared with standard drug and can be classified as a new
good candidate in fighting staphylococcalcidal infections.
22
23
Scheme 5 significant pharmacological sites in 4g
24
As shown in Figure 3, all ionic Schiff bases are inactive as fungicides. This limited or
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lack of fungicidal activity could be attributed to: (i) the complex structure of fungal cellꢀwall
that composed typically of chitin, 1,3ꢀβꢀ and 1,6ꢀβꢀglucan, mannan and proteins23, which
function as a barrier that limits diffusion of tested compounds through. (ii) Fungal fighting
that proceeds by much more complex mechanisms than bacterial conflict.
2
3
4
5
Noteworthy, Pd(II) complexes are potent than parent ligands and have moderate
fungicidal efficacy compared to the standard antibiotic. The enhanced activity of the ligands
upon complexation can be explained in terms of Overtone’s concept of cell permeability24
and Tweedy’s Chelation theory.25 Considering these theories, chelation considerably reduces
the polarity of the Pd(II) ion because of the partial sharing of its positive charge with the
donor sites and possible π–electron delocalization over the chelate ring. So the lipophilicity of
Pd(II) ion increases as result of chelation, which subsequently favors the diffusion of
complexes through the lipid layer of the bacterial cell membrane.26 Moreover, complexes
may also disturb the respiration process of the microbial cell and thus block the synthesis of
the proteins that restricts further growth of the organism.
6
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Antibacterial efficacy
As a parameter of antibacterial efficacy, the minimal inhibitory concentration (MIC) of
the most potent compounds were determined against S. aureus and E. coli using the macroꢀ
dilution broth susceptibility test using the percentages of inhibition at five different
concentration levels, 0.15ꢀ20 mM. The bacterial growth is inhibited by the target compounds
in a doseꢀdependent profile and the activity is greatly enhanced at the higher concentration.
The observed MIC values (Table 2) demonstrated the strongest biocidal action for 4g (cf.
Scheme 5) against S. aureus (MICS. aureus = 1.18 mM) which is 8ꢀfold lower than that against
E. coli (MICE. coli = 9.85 mM). Consequently, 4g can be classified as a new promosing
candidate in the fight against Staphylococcal infections. Further studies are required to
explore this compound as a new antibiotic.
26
27
Table 2 MIC (mM) assay results for promising antibacterial compounds against different
strainsa
MIC (mM)
Compounds
S. aureus
E. coli
(ATCC 29737)
(ATCC 10536)
6.56 ± 0.88
6.22 ± 0.53
7.23 ± 0.31
8.73 ± 0.25
1.18 ± 0.11
6.45
11.76 ± 0.49
11.39 ± 0.47
12.07 ± 0.30
13.85 ± 0.25
9.85 ± 0.15
10.10
4e
5e
4f
5f
4g
Am
28
aS. aureus representative for G+ Bacteria, E. coli as G− Bacteria
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Am. = Ampicillin (Antibacterial drug)
2
3
Proposed mode of microbial action
Although the exact mechanism by which antimicrobial ionic SalꢀSG/ (SalꢀSG)Pd(II) exert
microbiological toxicity has not fully elucidated, their biocidal mode of action may involve
various targets in microorganisms: (i) Hydrogenꢀbonding interactions of the Hꢀreceptor sites
in a target compound (such as guanidine, azomethine and hydroxyl fragments) with the active
binding sites of components of microbial cells, resulting in interference with the normal cell
process.27 (ii) The planar geometry of these complexes might allow extra coordination of
Pd(II) with electron donating centers of vital molecules of the microbial cells. Moreover, the
variation in the effectiveness of the different compounds against different strains depends on
the impermeability of the cells of microbes or difference in ribosome of the microbial cells.
4
5
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Conclusion
The biocidal activity of newly synthesized Nꢀ(salicylidene)sulfaguanidine bearing ionic
liquids compartments (ILSSGH, 4aꢀf) and their Pd(II) complexes (5aꢀf) has been
investigated against common bacterial and fungal pathogens. Both the ZOIs and MIC values
revealed that ILSSGH have the ability to inhibit the growth of fungal strains < E. coli < S.
aureus. The structure–activity relationship (SAR) study demonstrated that changes of the
ionic liquids fragments exhibited different antimicrobial activities levels. Also, alkyl
substituents on ILꢀSal backbone play a more important role in determining the biocidal
properties of ILSSGH/ Pd(II)ꢀILSSG architectures. Where, exchanging of Hꢀatom on ILꢀSal
by isoPropyl substituent dramatically decrease the minimal inhibitory concentrations.
Acknowledgment
R.F.M.E. would like to thank Prof. Christoph Janiak, Institut für Anorganische Chemie
und Strukturchemie, HeinrichꢀHeine Universität Düsseldorf, for her generous support.
26
Appendix A. Supplementary data
27
28
Supplementary data (experimental and spectral data) associated with this article are available
with the article through the journal Web site, at doi:
29
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Ionic Sal-SG Schiff bases as new synergetic chemotherapeutic candidates:DOI: 10.1039/C5RA11083A
Synthesis, metalation with Pd(II) and in vitro pharmacological evaluation.
Reda F.M. Elshaarawy,a,* Tahia B. Mostafa,b Ayaat A. Refaeeb and Emtithal A. El-
Sawib
a
Faculty of Science, Suez University, Suez, Egypt. Email: reda_elshaarawi@science.suez.edu.eg;
Reda.El-Shaarawy@uni-duesseldorf.de
b
Department of Chemistry, Faculty of Women for Arts, Science and Education, Ain Shams
University, Heliopolis, Cairo, Egypt