Synthesis, characterization, and biological screening of metal complexes of novel sulfonamide derivatives: Experimental and theoretical analysis of sulfonamide crystal

Article abstract of DOI:10.1002/aoc.5623

This study reports the synthesis of sulfonamide-derived Schiff bases as ligands L¹ and L² as well as their transition metal complexes [VO(IV), Fe(II), Co(II), Ni(II), Cu(II), and Zn(II)]. The Schiff bases (4-{E-[(2-hydroxy-3-methoxyp

Full text of DOI:10.1002/aoc.5623

Received: 12 December 2019
DOI: 10.1002/aoc.5623
Revised: 3 February 2020
Accepted: 5 February 2020
F U L L P A P E R
Synthesis, characterization, and biological screening of
metal complexes of novel sulfonamide derivatives:
Experimental and theoretical analysis of sulfonamide
crystal
Sajjad H. Sumrra1 | Abrar U. Hassan1 | Muhammad Imran2
Muhammad Khalid3 | Ehsan U. Mughal1 | Muhammad N. Zafar4
|
|
Muhammad N. Tahir5 | Muhammad A. Raza1 | Ataualpa A.C. Braga6
1Department of Chemistry, University of
This study reports the synthesis of sulfonamide-derived Schiff bases as ligands
L1 and L2 as well as their transition metal complexes [VO(IV), Fe(II),
Co(II), Ni(II), Cu(II), and Zn(II)]. The Schiff bases (4-{E-[(2-hydroxy-3-metho-
xyphenyl)methylidene]amino}benzene-1-sulfonamide (L1) and 4-{[(2-hydroxy-
3-methoxyphenyl)methylidene]amino}-N-(5-methyl-1,2-oxazol-3-yl)benzene-
1-sulfonamide (L2) were synthesized by the condensation reaction of 4-amino-
benzene-1-sulfonamide and 4-amino-N-(3-methyl-2,3-dihydro-1,2-oxazol-5-yl)
benzene-1-sulfonamide with 2-hydroxy-3-methoxybenzaldehyde in an equimo-
lar ratio. Sulfonamide core ligands behaved as bidentate ligands and coordi-
nated with transition metals via nitrogen of azomethine and the oxygen of the
hydroxyl group. Ligand L1 was recovered in its crystalline form and was ana-
lyzed by single-crystal X-ray diffraction technique which held monoclinic
crystal system with space group (P21/c). The structures of the ligands L1and L2
and their transition metal complexes were established by their physical (melt-
ing point, color, yields, solubility, magnetic susceptibility, and conductance
measurements), spectral (UV–visible [UV–Vis], Fourier transform infrared
Gujrat, Gujrat, 50700, Pakistan
2Department of Chemistry, Faculty of
Science, King Khalid University, Abha,
61413, Saudi Arabia
3Department of Chemistry, Khwaja
Fareed University of Engineering &
Information Technology, Rahim Yar
Khan, 64200, Pakistan
4Department of Chemistry, Quaid-i-Azam
University, Islamabad, 45320, Pakistan
5Department of Physics, University of
Sargodha, Sargodha, Pakistan
6Departamento de Química Fundamental,
~
Instituto de Química, Universidade de Sao
~
Paulo, Av. Prof.LineuPrestes, 748, Sao
Paulo, 05508-000, Brazil
Correspondence
Sajjad H. Sumrra, Department of
Chemistry, University of Gujrat. Gujrat
50700, Pakistan.
1
spectroscopy, H NMR, 13C NMR, and mass analysis), and analytical (CHN
Email: sajjadchemist@gmail.com
analysis) techniques. Furthermore, computational analysis (vibrational bands,
frontier molecular orbitals (FMOs), and natural bonding orbitals [NBOs]) were
performed for ligands through density functional theory utilizing B3LYP/6-311
+G(d,p) level and UV–Vis analysis was carried out by time-dependent density
functional theory. Theoretical spectroscopic data were in line with the experi-
mental spectroscopic data. NBO analysis confirmed the extraordinary stability
of the ligands in their conjugative interactions. Global reactivity parameters
computed from the FMO energies indicated the ligands were bioactive by
nature. These procedures ensured the charge transfer phenomenon for the
ligands and reasonable relevance was established with experimental results.
The synthesized compounds were screened for antimicrobial activities against
bacterial (Streptococcus aureus, Bacillus subtilis, Eshcheria coli, and Klebsiella
Muhammad Khalid, Department of
Chemistry, Khwaja Fareed University of
Engineering & Information Technology,
Rahim Yar Khan, 64200, Pakistan.
Email: muhammad.khalid@kfueit.edu.pk
Funding information
Higher Education Commission (HEC),
Grant/Award Number: 7800
Appl Organometal Chem. 2020;e5623.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
1 of 19
https://doi.org/10.1002/aoc.5623

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SUMRRA ET AL.
pneomoniae) species and fungal (Aspergillus niger and Aspergillus flavous)
strains. A further assay was designed for screening of their antioxidant activi-
ties (2,2-diphenyl-1-picrylhydrazine radical scavenging activity, total phenolic
contents, and total iron reducing power) and enzyme inhibition properties
(amylase, protease, acetylcholinesterase, and butyrylcholinesterase). The sub-
stantial results of these activities proved the ligands and their transition metal
complexes to be bioactive in their nature.
K E Y W O R D S
biological screening, crystal structure, DFT study, sulfonamide, transition metal complexes
1 | INTRODUCTION
three decades due to their bioactive roles.[21] As a result
of the pharmacological behavior of sulfonamides and
Coordination chemistry is gaining recognition due to
extensive applications in the development of pharmaceu-
ticals, biomedicine, clinical science, and catalysis.[1] Sev-
eral transition metal complexes as metallodrugs are
found to be very effective in their mechanism of action
with fewer side effects compared to their organic counter-
parts.[2] Researchers have studied the structure and
biological properties of metallodrugs[3] and found that
numerous nitrogen and oxygen atoms in their chelates
have a complex role in imparting bioactive characteris-
tics.[4] Interest in developing these metal chelates from
bioactive compounds stems from the fact that ordinary
drugs cannot compete with pathogenic resistance accom-
panied by drug resistance.[5] Such resisting behavior of
pathogens demands modification and diversification of
these bioactive compounds to make them compatible
with current needs.[6] Metal-based drugs are proving to
be potential candidates to replace their traditionally used
counterparts.[7] This may be due to their higher yields[8]
with lower possibilities of isomer generation.[9] Several
bioactive compounds, such as sulfonamides, triazoles,
isatins, and benzothiazines, have been modified structur-
ally to cope with ever-increasing pathogenic resistance as
a result of their drug resistance.[10] Specific biological
roles of transition metals are also noteworthy regarding
this development.[11] Pathogenic resistance coupled with
drug resistance has posed scientists a serious challenge to
design and develop such bioactive compounds.[12] The
synthesis of these compounds has been seen exponen-
tially for the last two decades.[13] Sulfonamide cores as
biologically active candidates are widely employed as
antifungal,[14] antibacterial,[15] antioxidant,[16] and anti-
cancer agents,[17] and as insulin mimics[18] and enzyme
inhibitors.[19] By knowing such unique properties, many
such bioactive derivatives have been designed.[20] Schiff
base compounds derived from sulfonamides have been
an area of interest for synthetic scientists for the last
transition metals, we wished to combine the chemistry of
these moieties to counter drug resistance.
2 | EXPERIMENTAL
All the chemicals used were of analytical grade, purchased
from Sigma Aldrich and used without any further purifica-
tion. Ethanol was doubly distilled before its use. All the
glassware used was washed thoroughly. The melting
points of synthesized compounds were determined on a
Stuart melting point (MP) apparatus (Stone, Staffordshire,
UK). A Nicolet FT-IR spectrophotometer (168, third ave-
nue, Waltham, Massachusetts, USA) was used to record
the IR spectra in their spectral regions using it in its
1
default version. H and 13C NMR spectra (Manning road,
Billerica, Massachusetts, USA) were determined using a
Bruker Advance 300 MHz instrument (Thermo Electron
Corporation, USA). For the mass spectrometric analysis,
synthesized compounds (ligands and complexes) were dis-
solved in dimethyl sulfoxide (DMSO) and injected through
a direct insertion pump into an LTQ XL linear ion trap
mass spectrometer (Thermo Scientific, USA) equipped
with an electrospray ionization (ESI) probe. A high-tech
Shimadzu UV-4000 spectrophotometer (Nakagyo, Kyoto,
Japan) was used to record the UV–visible (UV–Vis)
spectra. Biological activities were evaluated using the
recommended procedures at the Natural Product Research
Laboratory, University of Gujrat, Gujrat.
2.1 | Synthesis of sulfonamide ligands L1
and L2
The ligands were synthesized according to the previously
reported method.[22] For the synthesis of L1, 15 ml of
ethanolic solution of 2-hydroxy-3-methoxybenzaldehyde
(1.52 g, 10 mmol) was refluxed continuously in a 100 ml

SYNTHESIS AND BIOLOGICAL SCREENING OF METAL COMPLEXES
3 of 19
round-bottomed flask. After 10 min, 15 ml of
4-aminobenzene-1-sulfonamide (1.72 g, 10 mmol) was
added in an equimolar ratio and the resulting reaction
mixture was refluxed continuously for 8 hr. Formation of
the product (L1) was continuously monitored with thin-
layer chromatography until a single spot of the product
appeared on TLC. The precipitated product was filtered,
washed with a hot solution of ethanol and ether (1:1),
and recrystallized to obtain fine crystals. The same proce-
dure was used for the synthesis of L2 by refluxing the
ethanolic solution of 2-hydroxy-3-methoxybenzaldehyde
(1.52 g, 10 mmol) with 4-amino-N-(3-methyl-2,3-dihydro-
1,2-oxazol-5-yl)benzene-1-sulfonamide (0.255 g, 10 mmol)
(Scheme 1).
2.1.2 | 4-{[(2-hydroxy-3-methoxyphenyl)
methylidene]amino}-N-(5-methyl-
1,2-oxazol-3-yl)benzene-1-sulfonamide (L2)
Yield 84%; MP (ꢀC): 226; color: brick red; FT-IR (cm−1):
3309 (–OH), 1604 (CH=N), 1345, 978 (SO2N–H), 1162
1
and 1261 (O=S=O). H NMR (300 MHz, DMSO-d6), δ
(ppm): 2.29 (s, 3H, methylisoxazole), 3.85 (SO2–NH), 6.09
(s, 1H, isoxazole), 7.15–7.18 (m, 3H, Ph), 6.18–6.95 (m,
4H, N–Ph), 8.96 (s, 1H, azomethine), 12.51 (s, 1H, OH);
13C NMR (300 MHz, DMSO-d6),
δ (ppm): 12.52
(methylisoxazole), 56.36 (methoxy) 95.1, 95.88, 113.03
(3C-isoxazole), 116.56, 119.37, 119.72, 120.52, 122.71,
124.21 (6C–Ph), 158.41 (C=N, azomethine), 169.6 (C5).
MS (ESI) m/z (%): 387.09 C18H17N3O5S [M+], 361.37
(2.31), 259.28 (21.32), 226.25 (100), 182.19 (8.4),
150 (7.89). Anal. calcd for C18H19N3O5S (389.43): C
(55.52), H (4.92), N (10.79); found: C (55.12), H (4.23), N
(10.19).
2.1.1 | 4-{E-[(2-hydroxy-
3-methoxyphenyl)methylidene]amino}
benzene-1-sulfonamide (L1)
Yield: 84%, 1.26 g; MP (ꢀC): 209; color: light red; FT-
IR (cm−1): 3309 (–OH), 3205 (–NH2), 1607 (CH=N),
1312, 889 (SO2N–H), 1155 and 1262 (O=S=O). 1H
NMR (300 MHz, DMSO-d6), δ (ppm): 3.83 (m, 3H,
CH3O–Ph), 3.85 (SO2–NH2), 6.91–7.16 (m, 4H, N–Ph),
7.18–7.29 (m, 4H, SO2–Ph), 8.99 (s, 1H, azomethine),
12.72 (s, 1H, OH); 13C NMR (300 MHz, DMSO-d6), δ
(ppm): 56.36 (methoxy) 116.42, 119.33, 119.71, 122.27,
124.26 127.56 (6C–Ph), 151.50 (C=N, azomethine),
165.61 (C5). MS (ESI) m/z (%): 306.33 C14H14N2O4S [M
+], 123 (2.31), 136.14 (11.45), 183.08 (18.22), 226 (100),
252 (30.12), 275 (21.44). Anal. calcd for C14H14N2O4S
(306.34): C (54.89), H (4.61), N (9.14); found: C,
(54.63), H (4.21), N (9.24).
2.2 | Synthesis of coordination
complexes 1–12
Metal complexes were synthesized by taking the ligand to
metal ratio as 2:1, adopting the previously reported proce-
dure.[23] The respective metallic salt (50 mmol) was
added to a magnetically refluxing (100 mmol) ethanolic
solution of the ligand. The reaction mixture was refluxed
for 4–6 hr until the product precipitate formed. The pre-
cipitated product was filtered and washed with hot etha-
nol. The recrystallization of product was carried out
using a mixture of ethanol and ether to obtain pure
product.
SCHEME 1 Synthesis of
sulfonamide ligands L1 and L2 and their
transition metal complexes 1–12

4 of 19
SUMRRA ET AL.
2.2.1 | SC-XRD studies
sample was inoculated on discs. The medium was placed
in an incubator for 48 hr and after completion of the
incubation the process zone of inhibition was measured.
Fluconazole was used as the standard antifungal drug.
Single-crystal X-ray diffraction technique (SC-XRD)
results were gathered by operating an APEX II CCD
Bruker Kappa diffractometer at 296 K equipped with a
graphite monochromator. PLATON software was used to
calculate the geometric parameters (bond angles, bond
distance, hydrogen bonds, and torsion angles).[24] Crystal
constructions, figures, and other mechanical information
were found using Mercury 3.7 software.[25]
2.2.4 | Antioxidant bioassay
DPPH radical scavenging assay
The antioxidant activity of the newly reported com-
pounds was studied using
a previously reported
method.[31] A sample of 1.0 mg/ml was dissolved in
4.0 ml of pure methanol, then 1 ml of methanolic solu-
tion (1.0 mM) in 2,2-diphenyl-1-picrylhydrazine (DPPH)
was added. The resulting mixture was kept for 30 min
under ambient conditions before measuring the absor-
bance at 515 nm in a UV–Vis spectrophotometer. Butyl-
ated hydroxytoluene (BHT) was used as the reference
standard to compare the sample results. Percentage inhi-
bition of DPPH was calculated as follows:
2.2.2 | Computational procedures
Computational studies were performed using Gaussian
09 software.[26] UV–Vis analysis was done by
B3LYP/6-311+G(d,p) approximation[27] in the gas phase.
The results of the output files were viewed by the Gauss
view, Chemcraft and Avogadro programs.
percentage of inhibition = A−B=B × 100
2.2.3 | Biological evaluation
Antibacterial bioassay
where A is the absorbance of the blank and B is the
Ligands and their respective transition metal complexes
were evaluated for their antibacterial properties using
previously employed procedures.[28] The prepared com-
pounds were evaluated against two Gram-positive
(Staphylococcus aureus [A] and Klebsiella pneumonia [B])
and two Gram-negative (Escherichia coli [C] and Bacillus
staphylococcus [D]) bacterial strains. Antibacterial activi-
ties were tested against the four pathogenic bacterial spe-
cies by adopting a disc diffusion bioassay method.[29]
Nutrient broth medium was prepared and 2% agar was
added to it before it was autoclaved. The corresponding
bacterial culture was revived from −80ꢀC stock after
overnight growth. Sterilized discs were soaked with
100 μl of sample solution and placed on plates, then the
resulting culture was incubated at 37ꢀC. The streptomy-
cin and ampicillin were used as standard antibacterial
agents in the same concentration (2 mg/ml) and DMSO
solvent (as control) was also used. After overnight
incubation, the zone of inhibition was measured in
millimeters.
absorbance of the sample.
Total phenolic contents
Total phenolic contents were evaluated by adopting a
previously reported method.[32] A 0.1 ml sample of solu-
tion (1.0 mg/ml) was transferred to a test-tube and 2 ml
of sodium carbonate (7.5%) was added. After vortexing,
1.0 ml of Follin–Ciacatleu reagent (10%) was added and
the volume was made up to 10 ml with distilled water.
The resulting mixture was allowed to stand for 30 min
and then the absorbance was measured at 760 nm using
a UV–Vis spectrophotometer. Gallic acid was used as the
standard in this procedure. Measurements were made for
each compound in triplicate.
Reducing power
The reducing power for all the synthesized products was
evaluated using a previously reported method.[33] A sam-
ple solution of 2.4 ml of 1.0 mg/ml sodium phosphate
buffer (2 M, pH 6.6) and 5.0 ml of potassium ferricyanide
(1%) were added in sequence to incubate the resulting
mixture for 30 min at 50ꢀC followed by the addition of
5.0 ml of trichloroacetic acid (10%). Centrifugation was
done at 10,000 ×g for almost 10 min. Then 5.0 ml of a
solution of the supernatant layer was separated to add
the 1.0 ml of 1.0% ferric chloride and the absorbance
recorded at 700 nm using a UV–Vis spectrophotometer.
To compare the results of the samples, a reference
standard solution of BHT was prepared. All the
Antifungal bioassay
The antifungal activity of the synthesized compounds
was tested against two fungal strains (Aspergillus niger
[E] and Aspergillus flavous [F]) according to the rec-
ommended disc diffusion procedure.[30] For antifungal
bioassay, fungal cultures were revived in potato dextrose
medium. Sterilized medium was transferred into Petri
dishes, allowed to cool at room temperature, and then

SYNTHESIS AND BIOLOGICAL SCREENING OF METAL COMPLEXES
5 of 19
measurements were made in triplicate and the results
were averaged.
3 | RESULTS AND DISCUSSION
Novel sulfonamide-derived Schiff bases L1 and L2 were
air and moisture stable compounds with brick red
color. Ligands were in crystalline form and melted at
209–226ꢀC. All new sulfonamide-derived compounds
were only soluble in ethanol, methanol, dioxane, N,N-
dimethylformamide (DMF), acetonitrile, and DMSO.
The ligands were coordinated with transition metals
[VO(IV), Fe(II), Co(II), Ni(II), Cu(II), and Zn(II)] to
prepare their metal complexes (Scheme 1) in a stoi-
chiometric ratio of moles of 1:2 (metal:ligand). All the
synthesized metal complexes were intensely colored
and microcrystalline in nature. Cobalt, iron, nickel,
and zinc were used as their chloride salts while vana-
dium and copper were used as their sulfates. Ligands
and their coordination complexes 1–12 were character-
ized by their crystal, elemental, physical, spectral, and
computational data. The physical properties of all the
compounds are given in Table 1. The spectral and ana-
lytical data verified the composition and structures of
the products.
Enzyme inhibition studies
An enzyme inhibition procedure was performed by spec-
trophotometry.[34] Protease, amylase, acetylcholine ester-
ase (AChE), and butyrylcholinesterase (BChE) were used
as substrates. A mixture containing 0.5 ml of Tris buffer
0
(pH 7.8), 50 μl of 5,5 -dithiobis-(2-nitrobenzoic acid),
100 μl (5 mg/ml) of test compound solution, and 100 μl of
the specific enzyme was incubated at 37ꢀC for 20 min.
The reaction was initiated by the addition of 50 μl of sub-
strate. The sample was removed from the incubator and
its activity measured using a UV–Vis spectrophotometer
at 412 nm.
The percentage of enzyme inhibition was calculated
as:
percentage of inhibition = K −L=L × 100
where K is the absorbance of the blank and L is the
absorbance of the sample.
TABLE 1 Physical and analytical measurements for complexes 1–12
Elemental composition (%) found (calculated)
MW (g/mole)
(yield %)
Color
(MP, ꢀC)
Complex Formula
C
N
H
M
1
VO(L1)2
(C28H26N4O9S2V)
Fe(L1)2(H2O)2
(C28H30FeN4O10S2)
Co(L1)2(H2O)2
(C28H30CoN4O10S2)
Ni(L1)2(H2O)2
(C28H30N4NiO10S2)
Cu(L1)2(H2O)2
(C28H30CuN4O10S2)
Zn(L1)2(H2O)2
(C28H30N4O10S2Zn)
VO(L2)2
(C36H32N6O11S2V)
Fe(L2)2(H2O)2
(C36H36FeN6O12S2)
Co(L2)2(H2O)2
677.60 (71)
702.53 (74)
705.62 (67)
705.38 (65)
710.24 (78)
712.10 (61)
839.00 (81)
864.68 (73)
867.77 (69)
705.38 (65)
836.35 (76)
838.22 (64)
Light brown
(281–283)
49.63 (48.89) 8.27 (8.32) 3.87 (3.12) 7.52 (7.34)
47.87 (47.49) 7.97 (8.27) 4.30 (4.21) 7.95 (8.21)
47.66 (47.81) 7.94 (8.11) 4.29 (3.81) 8.35 (8.29)
49.68 (48.97) 8.25 (8.21) 3.71 (3.11) 7.61 (8.21)
47.35 (48.41) 7.89 (7.13) 4.26 (4.53) 8.95 (9.32)
47.23 (47.19) 7.87 (8.10) 4.25 (4.29) 9.19 (9.65)
51.24 (51.31) 9.96 (9.87) 4.30 (4.24) 6.04 (6.45)
49.77 (48.99) 9.67 (9.42) 4.64 (4.54) 7.38 (7.43)
49.60 (48.89) 9.64 (9.29) 4.62 (4.56) 6.76 (6.29)
49.61 (49.36) 9.64 (9.87) 4.63 (5.21) 6.73 (6.32)
2
Faded green
(279–281)
3
Light orange
(273–275)
4
Green (261–263)
5
Dark green
(268–270)
6
Off-white
(293–295)
7
Light green
(282–284)
8
Yellow green
(279–281)
9
Light orange
(273–276)
(C36H36CoN6O12S2)
(Ni(L2)2(H2O)2
(C28H30N4NiO10S2)
(Cu(L2)2(H2O)2
(C36H36CuN6O12S2)
(Zn(L2)2(H2O)2
10
11
12
Green (261–263)
Green (268–272)
49.34 (49.19)
9.5 (9.33)
4.6 (4.42) 7.25 (6.89)
7.4 (7.21)
Off white (300
+)
49.46 (49.11) 9.61 (8.98) 4.59 (4.32)
(C36H36ZnN6O12S2)
Note. MP, melting point; MW, molecular weight.

6 of 19
SUMRRA ET AL.
3.1 | FT-IR spectra
confirmed the incorporation of the V=O group in the
prepared coordination compounds.[30] All these indica-
tions confirm the coordination of the transition metal
ions with the synthesized Schiff bases.
The significant Fourier transform infrared (FT-IR) bands
for the ligands and their transition metal complexes are
given in the experimental section as well as in Table 2,
and FT-IR spectra are shown in Supporting Information
Figures S1–S8. Sulfonamide ligands have many donor
sites: C=N, C–O, S–N, C–S, N–H, and SO2. In the FT-IR
spectra of the ligands, the sulfonamide NH2 group and
the aldehyde C=O group disappeared and a new band for
azomethine (HC=N) linkage was observed at
1604–1607 cm−1.[35] Both ligands displayed a broad band
at 3309 cm−1 for ν(OH). The appearance of two bands at
1345 and 1110 cm−1 were assigned to the νasymm(SO2)
and νsymm(SO2) groups, respectively. Furthermore, the
ligands also displayed characteristic bands at 1386 and
1282 cm−1 due to C–O and C=C linkages, respectively.[36]
The bonding of azomethine with metal ions was
evidenced via a shift to a lower frequency at 12–20 cm−1
(1587–1592 cm−1) in all metal complexes.[37] The disap-
pearance of the v(OH) band at 3309 cm−1 in both ligands
and the presence of new bands at 1385–1395 cm−1 in all
metal complexes due to v(C–O) vibrations indicated the
deprotonation of the OH group found in the ligand and
complexation of the phenolic-O group of the ligand with
the metal atoms.[38] All the metal complexes possessed
new broad peaks at 3195–3205 cm−1 which were attrib-
uted to water molecules.[8] The bands for ν(SO2) and
ν(SO2) for the ligands at around 1345 and 1110 cm−1
remained unchanged, indicating their noninvolvement
during coordination. The emergence of new bands in the
spectra of compounds 1 and 7 in the 978–982 cm−1 region
3.2 | 1H NMR spectra
1
The H NMR spectra for the ligands were determined in
DMSO-d6. The possible 1H NMR spectral assignments are
1
given in the experimental section. The H NMR spectra
of both ligands exhibited the singlet peak of azomethine
at 8.96 ppm[39] while the protons of the hydroxyl groups
had singlet peaks at 12.51–12.72 ppm. The pyrimidine
C5–H protons of the ligands had peaks at 7.54–7.58 ppm
as multiplets while their C6–H protons had peaks at
7.88–7.94 ppm. The methoxy protons of both ligands
appeared as singlets at 2.92–3.32 ppm. The –SO2NH– pro-
tons in L1 had a singlet peak at 3.85 ppm (Supporting
Information Figures S9 and S10). All the protons were
found in their expected regions, supporting the binding
mode evidence through their IR spectral studies.
3.3 | 13C NMR spectra
The 13C NMR spectra for the ligands were also obtained
in DMSO-d6. The possible spectral assignments for both
ligands are given in the experimental section. The carbon
atoms were found to be in their expected region,
supporting the binding possibilities evidenced by the FT-
1
IR and H NMR spectral data. The carbon of azomethine
TABLE 2 Conductance, magnetic moments, UV–Vis, and FT-IR spectral data for complexes 1–12
Complex
1
ΩM (Ω−1 cm2 mol−1
)
μeff, BM
λ max (cm−1
)
FT-IR (cm−1
)
12.1
2.30
13450, 18160, 26420
1587 (HC=N), 1388 (C–O), 978 (V=O), 956 (S–N), 841
(C–S)
2
3
4
5
6
7
12.4
17.2
12.5
12.0
21.0
12.5
3.10
1.40
2.10
2.30
Dia.
2.30
10160, 10354
1592 (HC=N), 1395 (C–O), 956 (S–N), 841 (C–S)
1592 (HC=N), 1390 (C–O), 956 (S–N), 841 (C–S)
1590 (HC=N), 1393 (C–O),956 (S–N), 841 (C–S)
1587 (HC=N), 1386 (C–O), 956 (S–N), 840 (C–S)
1592 (HC=N), 1395 (C–O), 958 (S–N), 841 (C–S)
7572,17440, 29123
10116,15850, 24875
14995, 19441, 30367
29405
13435, 18269, 26427
1587 (HC=N), 1388 (C–O),956 (S–N), 841 (C–S), 982
(V=O)
8
13.2
12.4
16.2
12.5
19.0
4.10
2.40
10197, 10287
1592 (HC=N), 1385 (C–O), 955 (S–N), 841 (C–S)
1592 (HC=N), 1389 (C–O), 956 (S–N), 841 (C–S)
1583 (HC=N), 1392 (C–O), 959 (S–N), 841 (C–S
1587 (HC=N), 1388 (C–O), 958 (S–N), 841 (C–S)
1589 (HC=N), 1395 (C–O), 956 (S–N), 841 (C–S)
9
7520, 17950, 29321
9889, 15788, 25003
15246, 19322, 30335
29971
10
11
12
1.87
2.43
Dia.
Note. Dia, Diamagnetic.

SYNTHESIS AND BIOLOGICAL SCREENING OF METAL COMPLEXES
7 of 19
(–HC=N)[40] in both ligands was observed at 158.1–
160.9 ppm. The carbon C2 of the pyrimidine moiety
showed a very minor shift (150.8 to 150.9 ppm), probably
due to the absence of an electron-withdrawing group at
C5, C3, and C4. However, the C5 of the same moiety expe-
rienced a downwards shift, that is, 123.6 ppm to
115.0 ppm, attributed to the conjugation of the
azomethine group. The C1 of the methoxyphenyl group
of ligand L1 showed a downward shift from 121.6 ppm to
119.37 ppm owing to the presence of the hydroxyl group
at the C2 position. The peak at 56.10 ppm indicated the
presence of methoxy groups (Supporting Information Fig-
ures S11 and S12).
other fragmental peaks at 425 (60%), 452.08 (78%),
502 (59%), and 721 (82%) (Supporting Information
Figure S18). The base peaks for all the metal complexes
were found to have different m/z concerning their
metal complexes.[41] The features of the sulfonamide
Schiff bases determined by the mass spectra strongly
confirmed that the synthesis of the ligands produced
their proposed structures and bonding patterns.
3.5 | Molar conductivity measurements
The molar conductivities of 1 × 10−3 M solutions of com-
plexes 1–12 were measured in DMF at room temperature
and are listed in Table 2. All the values for these metal
complexes fell in the range 12–19 Ω−1ꢁcm2ꢁmol−1, indicat-
ing that these chelates are nonelectrolytic[42] in their
nature and ruling out the presence of any counterions in
the proposed structures.[43]
3.4 | Mass spectra
The mass spectra for the main fragments of ligand L1
along with its molecular ion peaks are given in
Supporting Information Figure S13. Mass spectral stud-
ies indicated that the ligands and their corresponding
complexes are coherent with their designs. The molecu-
lar mass of L1 was observed to be 306.0 (C14H14N2O4S)
and the most stable fragment[41] was found at m/
z = 226 for the [C14H12NO2]ꢁ+fragment. Other peaks in
order of increasing abundance were 123 (2.31%), 136.14
(11.45%), 183.08 (18.22%), 226 (100%), 252 (30.12%), and
275 (21.44%). The mass spectra of the metal complexes
were also consistent with the computed masses of their
intended formulae. The molecular mass of the vanadyl
complex (C28H26N4O9S2V) was observed to be m/z
677 (calcd 677.6), with the most stable fragment,
C28H24N3O7SV, at m/z 597.5 along with other mass
fragments in increasing abundances of 486.08 (12%),
517 (51%), 662.22 (23%), and 597.51 (100%) (Supporting
Information Figure S14). The molecular mass of the
copper complex (C28H30CuN4O10S2) was observed at m/
3.6 | Magnetic susceptibilities
Magnetic susceptibilities are a very useful technique for
determining the stereochemistry of metal ions in com-
plexes.[44] They also provide essential information about
the number of unpaired electrons, leading to the determi-
nation of the geometry of complexes.[45] The magnetic
moment readings were the range 4.67–4.79 BM, specify-
ing their paramagnetic nature owing to the presence of
three unpaired electrons, which also implies octahedral
geometry for Co(II) complexes.[46] The magnetic
moments for Ni(II) complexes were found in the
3.13–3.22 BM range, confirming the partial covalent char-
acter for metal–ligand bonds and also the octahedral
geometry around Ni(II) foci.[47] The experiential mag-
netic moment values of Cu(II) complexes were found in
the 1.41–1.72 BM range, suggesting octahedral geometry
for them.[48] The magnetic moment for Zn(II) complexes
was found to be zero, confirming its diamagnetic
nature.[49]
−
z 710 (calcd 710.1), with the C13H12CuN4O6S2 frag-
ment the most stable one (base peak) at m/z 447.9
along with other fragmental peaks with percentages of
305 (34%), 306 (51%), 662.22 (23%), 399 (71%), and
446 (100%) (Supporting Information Figure S15). The
molecular ionic peak [M + 1]+ for ligand L2 was found
at m/z 387, which agrees with the theoretically calcu-
lated m/z value of 387 (Supporting Information
Figure S16). The base peak for the most stable fragment
was confirmed at m/z 226.25, with other fragments at
361.37 (2.31%), 259.28 (21.32%), 226.25 (100%), 182.19
(8.4%), and 150 (7.89%). The vanadyl complex had a
base peak of m/z at 254.08 and there were other frag-
ments at 388.17 (68%), 517 (12%), 295 (64%), and 484
(69%) (Supporting Information Figure S17). The zinc
complex had a base peak of m/z 518.17 (100%) with
3.7 | Single crystal X-ray analysis
The synthesized Schiff base of sulfonamide (L1) was
analyzed by SC-XRD.[50] Crystallographic data are listed
in Table 3 and information on hydrogen bonds with
co-crystals is given in Table 3. A view of the structure of
L1 showing the atom labeling scheme is shown in
Figure 1. Displacement ellipsoids were drawn at the 50%
probability level. Crystal structure data were deposited at
the Cambridge Crystallographic Data Centre.

8 of 19
SUMRRA ET AL.
TABLE 3 Experimental details for crystal of ligand L1
corresponding closely with the values of 1.401, 1.376,
1.376, 1.379, 1.384, and 1.377 Å found by SC-XRD. The
related value obtained with a bond length of carbonyl
group C=O in L1 was determined to be 1.337 Å by DFT,
which is in good agreement with the SC-XRD value of
1.35 Å. The C(12)–S(1) and S(1)–N(2) bond lengths in L1
were determined to be 1.793 and 1.696 Å by DFT
and.1.766 and 1.603 Å by SC-XRD. The S(1) = O (4) and
S(1) = O (5) bond lengths were determined to be 1.461
and 1.461 Å by DFT, and 1.427 and 1.433 Å by SC-XRD.
The N(1)–C(8) and N(1)–C(9) bond lengths were deter-
mined to be 1.29 and 1.404 Å by DFT, which agree with
the values estimated by SC-XRD of 1.27 and 1.422 Å,
respectively (Supporting Information Table S1 and
Figure 2). DFT gave values of 119.5ꢀ, 122.6ꢀ, 125.3ꢀ,
120.4ꢀ, 119.6ꢀ, 120.5ꢀ and 119.3ꢀ for the bond angles S
(1)–C(12)–C(11), O(1)–C(2)–C(1), O(2)–C(3)–C(4), C(1)–
C(6)–C(5), C(2)–C(3)–C(4), C(9)–C(10)–C(11), and C(10)–
C(11)–C(12), respectively. The values for these angles
obtained by SC-XRD were 119.4ꢀ, 122.4ꢀ, 125.6ꢀ, 120.3ꢀ,
119.7ꢀ, 120.4ꢀ, and 119.4ꢀ, respectively (Supporting Infor-
mation Table S1 and Figure 3). In summary, DFT-based
parameters for the chemical structure were found to
agree with SC-XRD data.
Cambridge Crystallographic Data
Centre (CCDC) number
Chemical formula
Mr
1903654
C14H14N2O4S
306.33
Crystal system, space group
Temperature (K)
a, b, c (Å)
Monoclinic, P21/c
296
9.1828 (11), 10.9199
(12), 14.621 (2)
β (ꢀ)
V (Å3)
102.860 (6)
1429.4 (3)
4
Z
Radiation type
Mo Kα
μ (mm−1
)
0.24
Crystal size (mm)
Data collection
Diffractometer
0.42 × 0.32 × 0.28
Bruker Kappa APEXII
CCD
Absorption correction
Multi-scan (SADABS;
Bruker, 2005)
Tmin, Tmax
0.880, 0.955
No. of measured, independent, and
8995, 3269, 2570
observed I > 2σ(I) reflections
Rint
0.044
0.651
3.9 | Hirshfeld surface analysis
(sin θ/λ)max (Å−1
)
Refinement
R[F2 > 2σ(F2)], wR(F2), S
Hirshfeld surfaces at two configurational modes for ligand
L1 are shown in a Hirshfeld surface plot (Figure 4) in
which red indicates the strongest interactions, intermedi-
ate interactions are shown in white, and almost negligible
intermolecular interactions are shown in blue. Possible
hydrogen bond parameters are given in Table 4. Interac-
tions at the molecular level were also computed using
two-dimensional plots at a two-dimensional level, having
the decomposition quantifying the individual contribu-
tions for each intermolecular interaction included in the
structure. In the crystal packing for L1, the O… H contacts
appeared to be the major contributor (33.3%). The percent-
ages of intermolecular contributions for different inter-
atomic contacts to the Hirshfeld surface of molecule are
shown in Table 5. It can be seen that O… H, H…H, C…H,
and N…H contacts made large contributions (Figure 5). In
order to classify the hydrogen-bonded donor and acceptor
groups of L1, the electrostatically mapped Hirshfeld
surfaces were computed using TONTO software[51] at
standard settings of STO-3G basis set at Hartree–Fock
theory.[52] The blue and red shading indicates the positive
and negative electrostatic potentials for the two surfaces
(Figure 6). The unprotonated oxygen atoms of the
hydroxyl group, the ether group, and the unprotonated
nitrogen atom act as hydrogen bond acceptors.
0.046, 0.129, 1.04
No. of reflections
3269
200
No. of parameters
Hydrogen atom treatment
Hydrogen atoms
treated by a mixture
of independent and
constrained
refinement
Δimax, Δimin (e Å−3
)
0.30, −0.36
3.8 | Structural optimization
Density functional theory (DFT) at the B3LYP level of
approximation with 6-311+G(d,p) as the basis set was
used to obtain the structural parameters of L1. The DFT-
based optimized structure with the experimental struc-
tural parameters of the entitled compound is shown in
Supporting Information Table S1. The values of the struc-
tural parameters that were obtained in same amplitudes
of DFT and SC-XRD were R(C13–C14), N(1)–C(9)–C(10)
and C(2)–C(1)–C(8) (Supporting Information Table S1).
The C–C bond lengths in the benzene ring were found to
be 1.413, 1.389, 1.378, 1.388, 1.394, and 1.392 Å by DFT,

SYNTHESIS AND BIOLOGICAL SCREENING OF METAL COMPLEXES
9 of 19
FIGURE 1 The structure of L1
showing the atom labeling scheme.
Displacement ellipsoids are drawn at the
50% probability level
FIGURE 2 Comparative bond lengths at SC-XRD and DFT levels for L1
FIGURE 3 Comparative of bond angles of SC-XRD and DFT for L1

10 of 19
SUMRRA ET AL.
FIGURE 4 Hirshfeld
surfaces mapped at two views
over dnorm for L1 ranging from –
0.4855 to 1.4354 a.u. (1 a.u. of
electron density = 6.748 eÅ−3
)
TABLE 4 Selected hydrogen-bond parameters of ligand L1
D–HꢁꢁꢁA
D–H (Å)
0.82
HꢁꢁꢁA (Å)
1.88
DꢁꢁꢁA (Å)
2.5997 (19)
2.984 (2)
2.976 (2)
3.086 (2)
3.480 (3)
3.468 (3)
D–HꢁꢁꢁA (ꢀ)
146.3
O1–H1ꢁꢁꢁN1
N2–H2AꢁꢁꢁO4
N2–H2BꢁꢁꢁO1
N2–H2BꢁꢁꢁO2
C10–H10ꢁꢁꢁO2
C14–H14ꢁꢁꢁO3
0.80 (3)
0.84 (3)
0.84 (3)
0.93
2.18 (3)
2.20 (3)
2.42 (3)
2.61
175 (3)
153 (3)
137 (3)
155.8
0.93
2.60
155.4
Note. A, acceptor; D, donor.
TABLE 5 Contributions (%) of interatomic contacts to the
Hirshfeld surface for L1
be used as the degree of delocalization. The second-order
perturbation interaction energy (E(2)) can be used to
explain the noncovalent bonding quantitatively as well as
antibonding charge-transfer interactions.[53] The stabili-
zation energy equation as per the second-order perturba-
tion theory is:
Contact
Contribution (%)
O. .. H / H. .. O
H. .. H
H. .. C/ C.. . H
H. .. N/ N.. . H
O. .. C/ C.. . O
N. .. N
33.3
32.1
30.2
2.4
ꢀ
ꢁ
2
Fi,j
E
ð2Þ = qi
ð1Þ
1.2
εj −εi
0.4
where qi denotes the occupancy of the donor orbital, sj
and si are the off-diagonal NBO Fock matrix elements,
E(2) is the stabilization energy, and Fi,j is the diagonal
energy. (The better degree for the bonding and antibond-
ing orbitals interaction was apparent from the degree of
perturbation stabilization energy (E(2)).
C …
N. .. C/ C.. . N
C
0.2
0.1
3.10 | NBO analysis
Natural bonding orbital (NBO) analysis was performed
using the Gaussian 09 program with DFT and transfig-
ured the molecular orbitals into a new molecular orbitals
set that which could be carefully trussed to chemical
bonding principles. This technique involved the success-
ful conversion of nonorthogonal atomic orbitals to units
of natural atomic orbitals, natural hybrid orbitals, and
NBOs. The localized basis set described the wave capabil-
ities within the maximum economic approach, as elec-
tron density and different characters are defined via the
slightest amount of filled NBOs, which delineated the
hypothetical, strictly localized Lewis shape which might
The NBO numbering scheme for ligand L1 is given in
Figure 7. The Ligand, L1 contained σ ! σ*, π ! π*, lone
pair (LP) ! σ*, and LP ! π* transitions, as can be seen
in Supporting Information Table S2. Here we discuss
some hyperconjugative interactions as representative
values. The maximum conceivable electronic transitions
were found to be LP(O2)
!
π*(C11–C12) and
LP(O4) ! π*(C13–C14) with stabilization energy values of
37.65 and 30.39 kcal/mol, respectively. Moreover, some
(π ! π*) transitions were seen, namely, π(C26–C34) ! π*
(C31–C32), π(C11–C12) ! π*(N7–C24), π(C27–C29) ! π*
(C26–C34), π(C31–C32)
!
π*(C27–C29), π(C11–

SYNTHESIS AND BIOLOGICAL SCREENING OF METAL COMPLEXES
11 of 19
FIGURE 5 Fingerprint plot contacts of (a) O . . . H, (b) H . . . H, (c) C . . . H, (d) N . . . H, (e) C. . . O, (f) N. . . N, (g) C. . . C, and (h) C. . .
N

12 of 19
SUMRRA ET AL.
FIGURE 6 Electrostatically mapped
Hirshfeld surfaces of L1 in the range −0.1111 to
0.1257 a.u. using the STO-3G basis set at the
Hartree–Fock level. The hydrogen bonding
interactions for the acceptor/donor atoms of O–
H … O and N–H … O are shown as blue and red
shading around the atoms, depicting positive
and negative potentials, respectively
FIGURE 7 NBO numbering scheme for L1
C12) ! π*(C16–C18), π(C13–C14) ! π*(C11–C12),
π(C16–C18) ! π*(C13–C14), π(C13–C14) ! π*(C16–C18),
and π(N7–C24) ! π*(C26–C34) with stabilization energies
of 25.18, 22.66, 21.96, 20.94, 19.74, 18.86, 18,24, 17.59, and
10.70 kcal/mol, respectively, which revealed the degree of
conjugation in L1. The intramolecular charge transfer,
hyperconjugative interactions, and expanded conjugation
were the main reasons for the stability of L1. These inter-
actions were found to be in excellent agreement with the
SC-XRD data.
system.[54] The Mulliken population examination of L1
was found to use the B3LYP level with a 6-311+G(d,p)
basis set. The Mulliken charge distribution of L1 is shown
in Figure 8. The charge dissemination of L1 shows that all
oxygen atoms linked with sulfur, nitrogen, and hydrogen
atoms (S1, C12, and C13) are negatively charged, whereas
the nitrogen atoms connected with oxygen atoms such as
O5 and O6 are slightly positively charged. Moreover, the
nitrogen atoms attached to hydrogen and carbon atoms
adjacent to the nitrogen atoms are also positively charged.
Some carbon atoms coupled with carbon and nitrogen
atoms were found to have significant negative charges.
3.11 | Mulliken atomic charge analysis
In quantum chemical analysis, Mulliken atomic charge
investigation of any molecular system has a vital role to
play in obtaining the dipole moment, electronic proper-
ties, and molecular polarizability of the chemical
3.12 | FT-IR analysis
Ligand L1 having 35 atoms involving nitrogen, oxygen
and sulfur atoms contained 99 vibration modes having
FIGURE 8 Mulliken charge
distribution of L1

SYNTHESIS AND BIOLOGICAL SCREENING OF METAL COMPLEXES
13 of 19
point group symmetry of C1. The FT-IR frequencies for
L1 are shown in Supporting Information Table S3. The
stretching vibrational modes for the aromatic C–H were
observed at 3000–3100 cm−1 with the combinational
(overtone) peaks owing out-of-plane bending vibrations
(P) transitions,[42] with ranges of 7520–7572 and
17950–17440 cm−1and a high energy band in the range
of 29123–29321 cm−1, proving their high-spin octahe-
dral geometry. For the Ni(II) complexes, three absorp-
tion bands were seen[29] at 9889–10116, 15788–15850,
and 24875–25003 cm−1 due to 3A2g(F) ! 3T2g(F),
3A2g(F) ! 3T1g(F), and 3T2g(F) ! 3T1g(P) transitions.
The spectra recorded for the Cu(II) complexes con-
seen at 2000–1660 cm−1 [55]
.
The symmetric C–H modes
for methyl and methoxy were seen at 2925–2985 cm−1
.
The FT-IR stretching vibrations of aromatic C=C and C–
C were seen at 1650–1400 cm−1. These FT-IR stretching
vibrations are shown in detail in Supporting Information
Table S3. The significant functional groups are listed here
in detail:S=O vibrations Stretching vibration bands for
SO2were seen at 1130 and 1315 cm−1 (DFT) and 1155 and
1262 cm−1 (experimental).
NH2 vibrations The modes for NH2 were seen at 3512 and
3620 cm−1 (DFT) and 3205 cm−1 (experimental).
O-H vibrations The stretching vibration for O–H was seen
at 3251 cm−1(DFT) and 3309 cm−1 (experimental).
CH=N vibration The vibration for CH=N was seen at
1665 cm−1 (DFT) and 1580 cm−1 (experimental).
N–H vibrations The vibration for N–H was seen at
1337 cm−1 (DFT) and 1312 cm−1 (experimental).
The DFT-based vibrational modes were therefore
found to be in agreement with the experimental ones
(Supporting Information Table S3).
firmed
two
bands
at
14995–15246
and
19441–19322 cm−1, attributed to 2B1g ! 2A1g and
2B1g ! 2Eg transitions and confirming their octahe-
dral geometry, along with a high-intensity band at
30335–30367 cm−1 due to metal ! ligand charge
transfer.[14] No characteristic d–d transition bands were
recorded for the diamagnetic nature of the
corresponding Zn(II) complexes. Only the strong band
of high intensity was recorded at 29405–29971 cm−1
due to metal ! ligand charge transfer.[20]
3.14 | FMO analysis
Frontier molecular orbitals (FMOs) such as the highest
occupied molecular orbital (HOMO) and lowest unoccu-
pied molecular orbital (LUMO) give useful insights into
the estimation of chemical and molecular stability.[57]
Furthermore, the energy difference (ELUMO – EHOMO
)
3.13 | UV–Vis spectra
between the LUMO and HOMO was used to estimate the
most important features of the studied molecules, includ-
ing chemical reactivity, optical polarizability, chemical
softness, and chemical hardness.[58] The energies of the
FMOs were computed using the B3LYP/6-31+G(d,p)
level of theory and the results are shown in Table 6.
Three substantial FMO pairs, HOMO ! LUMO, HOMO-
1 !LUMO+1, and HOMO-2 !LUMO+2 were analyzed
(Figure 9). The intramolecular charge transfer was
confirmed by the FMO phenomenon as can be seen in
the electronic transition between HOMO and LUMO in
Figure 9. It is conspicuous to know that HOMO
represents bonding character while LUMO reflects
Time-dependent density functional theory (TD-DFT)
calculations in the gas phase were carried out at the
B3LYP/6-311+G(d,p) level of approximation[56] on the
absorption spectra of L1. The maximum absorption
wavelength (λmax), transition state, oscillator strength,
and calculated transition energy values are shown in
Supporting Information Table S4. L1 displayed
absorbance in the visible region and the highest
calculated λmax value was seen at 387 nm (Supporting
Information Figure S19). Experimental UV–Vis spectra
for the ligands and their complexes were done in DMF
solvent. Oxovanadium(IV) complexes of both ligands
showed typical bands at 13435–13450, 18160–18269,
and 26420–26427 cm−1 for B2 ! Eπ, B2 ! B1, and
B2 ! A1 transitions.[30] The appearance of a band at
30131–30391 cm−1 confirmed the metal ! ligand
charge transfer phenomenon. All the observed bands
confirmed the square pyramidal geometry of both
vanadium complexes.[20] The Fe(II) complexes showed
two typical electronic transitions at 10160–10197 and
10287–10354 cm−1, implying 5T2g and 5Eg transitions
and confirming their octahedral symmetries. The
Co(II) complexes showed two low energy absorption
bands for to 4T1g(F) ! 4T2g(F) and 4T1g(F) ! 4T1g
antibonding
character.
The
energy gaps for
HOMO !LUMO, HOMO-1 ! LUMO+1, and HOMO-
2 ! LUMO+2 were observed to be 0.138, 0.208, and
0.241 Hartree energy (Eh), respectively. The energy gap is
thought to be inversely related to reactivity and directly
TABLE 6 EHOMO, ELUMO, and the energy band gap
(ELUMO – EHOMO) for the ligands
Transitions
EHOMO
−0.227
−0.249
−0.277
ELUMO
−0.089
−0.041
−0.036
Band gap
0.138
HOMO !LUMO
HOMO-1 !LUMO+1
HOMO-2 !LUMO+2
0.208
0.241

14 of 19
SUMRRA ET AL.
FIGURE 9 HOMOs and LUMOs of L1
associated with the stability/strength of the species. Mole-
cules with a small gap (ELUMO – EHOMO) are soft, chemi-
cally unstable, and reactive molecules. On the contrary,
chemically hard, stable, and less reactive molecules have
larger ELUMO – EHOMO gap values.
The global reactivity descriptors electronegativity
(EA), chemical potential (l), global hardness (η), global
softness (S), and electrophilicity index (ω) were obtained
using ELUMO and EHOMO and equations S1–S5 in the
Supporting Information. The results are shown in
Supporting Information Table S5. The ionization poten-
tial and electron affinity values were obtained to be 0.227
and 0.089 (at HOMO ! LUMO level), respectively. The
ionization potential values were observed larger to some
extent as compared to electron affinity values describing
the better electron-donating capability of the investigated
molecule. The global hardness value was found to be
0.069 and the global softness value was 7.246377
(at HOMO ! LUMO level), which shows that the L1 is
less stable and more reactive. The ligand therefore had a
strong tendency to form complexes with different metals
(Figure 9).
3.15 | NLO properties
The structural diversity of organic compounds gives the
potential to be used in the fields of electronics, photonics,
and nonlinear optics (NLO).[59] The B3LYP level of
theory with a 6-311+G(d,p) basis set was used to observe

SYNTHESIS AND BIOLOGICAL SCREENING OF METAL COMPLEXES
15 of 19
TABLE 7 Antibacterial and antifungal results for ligands L1
and L2 and complexes 1–12
the NLO parameters for the B3LYP. The linear polariz-
ability was determined using equation (2):
Bacterial strains
Fungal strains
ꢀ
ꢁ
< a > = 1=3 axx + ayy + azz
ð2Þ
Complex
A
B
C
D
E
B
L1
L2
23
13
14
11
–*
18
13
14
12
16
16
10
9
13
12
13
11
14
29
15
13
18
–*
11
14
11
15
–*
34
39
21
15
19
17
13
19
11
17
22
13
19
23
11
–*
–*
27
37
29
23
23
19
14
18
13
11
13
22
17
15
16
24
–*
32
39
22
26
–*
11
15
14
17
15
11
14
11
11
28
13
31
12
11
13
12
19
16
13
11
13
13
14
15
11
The first hyperpolarizability (βtot) was determined
using equation (3):
1
2
h
i
1
=
2
ꢀ
ꢁ
ꢀ
ꢁ
ꢀ
ꢁ
2
βtot
=
βxxx + βxyy + βxzz 2 + βyyy + βxxy + βyzz 2 + βzzz + βxxz + βyyz
3
ð3Þ
4
5
The first-order polarizabilities along the αxx, αyy, and
6
αzz directions were observed to be 402.175, 206.76, and
135.89 a.u., respectively, which resulted in an <α> value
of 248.27 a.u. The second-order polarizability (βtot) values
7
8
9
along with their major contributing tensors, that is, βxxx
,
10
βxxy, βxyy, βyyy, βxxz, βyyz, βxzz, βyzz, βzzz, and βtot were
observed to be −1422.11, 243.78, −30.694, 348.579,
83.222, 46.098, 91.483, 89.007, 96.029, and 1538.919 a.u.
Urea is a standard compound commonly used in the
literature to compare dipole moments and first-order
11
12
12
–*
33
37
DMSO
Ampicillin
Streptomycin
Fluconazole
hyperpolarizability data. L1 had
a higher dipole
moment than urea (1.3732 D).[60] Similarly, the βtot value
of L1 was found to be greater than that of urea
(βtot = 43 a.u.).
32
29
*Inactive. Note. A, E. coli; B, K. pneominiae; C, S. aureus; D, B. subtilis; E, A.
niger; F, A. flavous. DMSO, dimethyl sulfoxide.
FIGURE 10 Antibacterial
activities of ligand vs. complexes
FIGURE 11 Antifungal activities of
ligands vs. complexes

16 of 19
SUMRRA ET AL.
3.16 | Biological evaluation
3.16.1 | Antibacterial bioassay
metal complexes were evaluated by comparing them with
the two standard drugs streptomycin and ampicillin. The
activities of each sample were recorded in millimeters
(mm) as their zone of inhibition (Table 7). The data rev-
ealed that all the compounds had different inhibition
degrees compared to tested bacterial strains concerning
their growth not varying significantly from literature.
Both the ligands exhibited moderate to significant
(12–29 mm) activities against the selected bacterial spe-
cies. Similar compounds compared against the same bac-
terial species also had moderate to significant activities
(16–32 mm),[47] while our previously reported similar
compounds had lower activities (12–17 mm) compared to
the different bacterial strains.[30] The metal complexes
also exhibited moderate to significant activity overall
against all the tested bacterial strains. Compounds 3, 8,
and 12 were found to be inactive against the E. coli (A),
K. pneumonia (B), and S. aureus (C), respectively. The
highest antibacterial activity of 29 mm was found for
compound 4 against strain B. The data showed that the
antibacterial activity of both ligands is higher than that of
their corresponding metal complexes (Figure 10).
All the synthesized products were examined in vitro for
their antibacterial features against two Gram-positive
(S. aureus and B. subtilis) and two Gram-negative (E. coli
and K. pneomoniae) bacterial strains. The antibacterial
activities of the Schiff base ligands and their transition
3.16.2 | Antifungal bioassay
The sulfonamide ligands and their metal complexes were
screened against two fungal strains, A. niger (E) and
TABLE 8 Antioxidant results for ligands L1 and L2 and
complexes 1–12
Total
Antiradical
activity
Complex inhibition (%)
Total iron
reducing
power (%)
phenols
(mg
GAE/g)
L1
L2
1
55.0
49.0
46.0
83.0
92.0
94.0
70.4
72.0
59.0
82.0
92.7
94.4
26.0
46.9
95.5
92.3
94.3
88.1
96.3
88.1
96.3
88.1
88.1
96.3
88.1
96.3
88.1
96.3
70.7
86.4
58.3
66.7
29.0
57.7
71.0
69.8
82.6
88.1
77.5
76.1
77.8
72.3
2
3
4
5
6
7
8
9
10
11
12
FIGURE 12 Correlational studies of antioxidant values
Note. GAE, Gallic Acid Equivalent.

SYNTHESIS AND BIOLOGICAL SCREENING OF METAL COMPLEXES
17 of 19
A. flavous (F), as per the literature protocol. The results
showed that most compounds had moderate antifungal
activity against both fungal strains (Table 7). Both the
ligands exhibited good antifungal activities against the
selected fungal strains. However, it was observed that
most of their complexes had moderate to weak bioactiv-
ities. The data further showed that complex 11 demon-
strated excellent activity (above 80%) against E and
complex 4 had the highest activity for F, while previously
reported compounds with same sulfonamide moiety had
the lower activity (75%).[61] It was also noted that most of
the transition metal complexes showed less average activ-
ity than their corresponding ligands. Only the zinc com-
plex of L2 had higher activity than its ligand for both the
fungal strains (Figure 11).
3.16.3 | Antioxidant bioassay
Quantitative relationships for different antioxidant
activities (DPPH, total phenolic contents, and total iron
reducing power) were determined. The relative depen-
dences of antioxidant activities as a result of the com-
parison of any two values (antiradical activity vs. total
iron reducing power, antiradical activity vs. total phe-
nols, and total iron reducing power vs. total phenols)
(Figure 12) were determined by interpreting their corre-
lation coefficient as R2.[34]
The antiradical scavenging activities of all the syn-
thetic compounds were determined by spectrophotome-
try, using DPPH as the free radical with gallic acid as the
standard. The results show that the entire sample to be
quite good at their scavenging ability. The maximum
activity (94.4%) was exhibited by compound 10 while the
lowest activity (46%) was exhibited by compound 1, as
shown in Table 8.
TABLE 9 Enzyme inhibition results for ligands L1 and L2 and
complexes 1–12
Enzyme inhibition (%)
Phenolic compounds are found to be good antioxi-
dants and phenol-containing compounds have been
shown to have good antioxidant properties.[62] Total
phenolic content for the ligands and their complexes
was determined as milligram equivalent of gallic acid
standard. The highest value of 88.1% was found for
compound 8 while the lowest value of just 29% was
observed for compound 3. Total iron reducing power
was observed to be significant values varying from
88.1% (2, 4, 6, 7, 9, and 11) to 96.3% (3, 5, 8, 10, and
12). There was a close relationship between total iron-
reducing power and antioxidant activities as per litera-
ture reports.[63]
Complex
Protease
67
Amylase
68
AChE
56
BChE
49
L1
L2
1
56
47
46
51
67
57
57
68
2
76
71
76
76
3
57
56
76
65
4
76
76
76
76
5
87
87
87
87
6
78
71
68
56
7
69
61
49
74
8
76
73
71
64
9
91
67
56
79
3.16.4 | Enzyme inhibition results
10
11
12
87
82
57
65
85
78
83
68
Enzyme inhibition studies of synthesized products were
performed against protease, α- amylase, AChE, and
BChE enzymes by taking their absorbance at 400 nm,
83
86
86
71
Note. AChE, acetylcholine esterase; BChE, butyrylcholinesterase.
FIGURE 13 Enzyme
inhibition results for the ligands
and their complexes

18 of 19
SUMRRA ET AL.
adopting the standard protocol given in the experimental
section. The results revealed that all the synthesized com-
pounds had good enzyme inhibition properties (Table 9),
as found for many previously synthesized similar types of
compounds.[64] The protease enzyme showed maximum
activity of 91% against compound 9 while α-amylase had
a maximum activity of 87% against compound 5. The
AChE enzyme had maximum activity (86%) for com-
pound 12. The BChE enzyme had maximum activity of
82% against compound 5. The other remaining com-
pounds also had significant values against all four
enzymes (Figure 13).
ORCID
Muhammad Khalid https://orcid.org/0000-0002-1899-
5689
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Sumrra SH, Hassan AU,
Imran M, et al. Synthesis, characterization, and
biological screening of metal complexes of novel
sulfonamide derivatives: Experimental and
theoretical analysis of sulfonamide crystal. Appl
Organometal Chem. 2020;e5623. https://doi.org/10.
1002/aoc.5623
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