Density functional theory/B3LYP study of nanometric 4-(2,4-dihydroxy-5-formylphen-1-ylazo)-N-(4-methylpyrimidin-2-yl)benzenesulfonamide complexes: Quantitative structure–activity relationship, docking, spectral and biological investigations

Received: 17 October 2016

DOI 10.1002/aoc.3721

Revised: 4 November 2016

Accepted: 25 November 2016

F U L L PA P E R

Density functional theory/B3LYP study of nanometric 4‐(2,4‐

dihydroxy‐5‐formylphen‐1‐ylazo)‐N‐(4‐methylpyrimidin‐2‐yl)

benzenesulfonamide complexes: Quantitative structure–activity

relationship, docking, spectral and biological investigations

Fawaz A. Saad¹| Marwa G. Elghalban^1,2| Nashwa M. El‐Metwaly^1,2| Hoda El‐Ghamry^1,3

|

Abdalla M. Khedr^1,3

¹Department of Chemistry, Faculty of Applied

New metal ion complexes were isolated after coupling with 4‐(2,4‐dihydroxy‐5‐

formylphen‐1‐ylazo)‐N‐(4‐methylpyrimidin‐2‐yl)benzenesulfonamide (H₂L) drug

ligand. The structural and molecular formulae of drug derivative and its complexes

were elucidated using spectral, analytical and theoretical tools. Vibrational spectral

data proved that H₂L behaves as a monobasic bidentate ligand through one nitrogen

from azo group and ionized hydroxyl oxygen towards all metal ions. UV–visible and

magnetic moment measurements indicated that Fe(III), Cr(III), Mn(II) and Ni(II)

Science, Umm Al‐Qura University, Makkah, Saudi

Arabia

²Chemistry Department, Faculty of Science,

Mansoura University, Mansoura, Egypt

³Chemistry Department, Faculty of Science, Tanta

University, Tanta, Egypt

Correspondence

Fawaz A. Saad, Department of Chemistry, Faculty

of Applied Science, Umm Al‐Qura University,

Makkah, Saudi Arabia.

complexes have octahedral configuration whereas Cd(II), Zn(II) and Co(II)

complexes are in tetrahedral form. The Cu(II)complex has square planar geometry

as verified through electron spin resonance essential parameters. X‐ray diffraction

data indicated the amorphous nature of all compounds with no regular arrangement

for the solid constituents during the precipitation process. Transmission electron

microscopy images showed homogeneous metal ion distribution on the surface of

the complexes with nanometric particles. Coats–Redfern equations were applied

for calculating thermo‐kinetic parameters for suitable thermal decomposition stages.

Gaussian09 and quantitative structure–activity relationship modelling studies were

used to verify the structural and biological features. Docking study using

microorganism protein receptors was implemented to throw light on the biological

behaviour of the proposed drug. The investigated ligand and metal complexes were

screened for their in vitro antimicrobial activities against fungal and bacterial strains.

The resulting data indicated that the investigated compounds are highly promising

bactericides and fungicides. The antitumour activities of all compounds were

evaluated towards human liver carcinoma (HEPG2) cell line.

Email: fasaad@uqu.edu.sa

KEYWORDS

antitumour and antimicrobial studies, azodye, docking, nanometre complexes, QSAR,

spectral characterization

1

|

INTRODUCTION

and photoelectronic implementations,^[6]as well as their

involvement in many analytical and biological applica-

tions.^[7,8]Metal complexes of azodyes have also attracted

increasing attention due to their interesting geometrical and

electronic features. Their applications include printing sys-

tems, nonlinear optical elements, molecular memory storages

Diverse research studies have been published related to the

synthesis and spectral properties of azodye compounds.^[1–3]

This reflects their significant applications in distinct fields

such as in colouring fibres,^[4]optical storage technology^[5]

Appl Organometal Chem. 2017;e3721.

wileyonlinelibrary.com/journal/aoc

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https://doi.org/10.1002/aoc.3721

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SAAD ET AL.

and others.^[9,10]Also, sulfonamide derivatives resulting from

the exchanges of diverse functional groups, while retaining

the leading structural feature of sulfonamides, can present a

range of promising pharmacological and medicinal activi-

ties.^[11,12]Additionally, other basic moieties in sulfonamide

compounds, such as aromatic amino groups, represent the

main reason for the chemical multitude of such compounds

because they can act as chelation centres. These can be con-

sidered as the reactive site for chemical modifications of sul-

fonamide ligands to afford a large number of complexes with

great biological importance. Furthermore, sulfonamides and

azodye derivatives of sulfonamides were found to have a vari-

ety of biological properties such as anti‐tubercular, anticancer

and antimalarial activities.^[13]Many sulfonamide azodye

derivatives are usually applied as powerful ligands for a vast

range of transition metal ions.^[14–16]The metal chelates find

many applications in biological systems, dying processes

and analytical detection of various metal ions.^[17,18]Among

sulfonamide derivatives, 4‐amino‐N‐(4‐methylpyrimidin‐2‐

yl)benzenesulfonamide is well known as one of the most

widely clinically applied chemical compounds.^[19]

Based on the above considerations and in continuation of

our research works,^[20–22]the present paper reports the

synthesis and characterization of a novel series of bioactive

nano‐sized and transition metal complexes with 4‐(2,4‐

dihydroxy‐5‐formylphen‐1‐ylazo)‐N‐(4‐methylpyrimidin‐2‐yl)

benzenesulfonamide (H₂L). The choice of azo compounds

leads to a detailed spectral study as well as theoretical

aspects. The nanometre scale of the complexes may serve

excellently in the biological field which was considered

the main goal in the study reported here. The investigated

compounds were screened in vitro for their antitumour

and antimicrobial activities. Computational studies were

used to emphasize the structural and biological features to

deepen the study.

FIGURE

1

Optimized structure of 4‐(2,4‐dihydroxy‐5‐formylphen‐1‐

ylazo)‐N‐(4‐methylpyrimidin‐2‐yl)benzenesulfonamide (H₂L)

and left in a refrigerator for 6 h. The obtained solid product

was filtrated off, washed several times with NaCl solution

(30 ml, 10%), air‐dried and recrystallized several times from

hot ethanol.

2.2 | Synthesis of Metal Ion Complexes

New metal ion complexes were synthesized by addition of

1 mmol of a methanolic solution of each metal salt

(0.4040 g of Fe(NO₃)₃⋅9H₂O, 0.4002 g of Cr(NO₃)₃⋅9H₂O,

0.1833 g of CdCl₂, 0.1979 g of MnCl₂⋅4H₂O, 0.2377 g of

NiCl₂⋅6H₂O, 0.1705 g of CuCl₂⋅2H₂O, 0.2195 g of

Zn(CH₃COO)₂⋅2H₂O and 0.2379 g of CoCl₂⋅6H₂O) to

1 mmol of H₂L) (0.3974 g) dissolved in MeOH–

dimethylformamide (DMF) mixture (20% v/v). The addition

process was carried out dropwise with continuous stirring.

The obtained reaction mixture was allowed to reflux for

12–15 h over a water bath at a suitable temperature. A few

drops of triethylamine were added as basic medium until

the formed coloured metal complexes were precipitated.

The resulting precipitates were filtered off, washed with eth-

anol and then desiccated under anhydrous CaCl₂. The

purities of all studied compounds were checked using TLC

and melting point constancy.

2

| EXPERIMENTAL

All the reagents and solvents utilized in this work were of

reagent‐grade quality and applied as purchased from com-

mercial suppliers without any further purification.

2.1 | Preparation of Azodye Ligand (H₂L)

2.3 | Measurements and Instrumentation

The new azodye ligand H₂L (Figure 1) was prepared as

described previously.^[23]In short, a suspension of 4‐amino‐

N‐(4‐methylpyrimidin‐2‐yl)benzenesulfonamide (0.2643 g,

1 mmol) in water (15 ml) and HCl (15 ml) was warmed to

75 °C until entire dissolution. The obtained pure aqueous

solution was diazotized below 5 °C with aqueous sodium

nitrite (1.5 g in 25 ml of water). To a solution of 2,4‐

dihydroxybenzaldehyde (0.1381 g, 1 mmol) in water contain-

ing 1.6 g of NaOH, the resulting diazonium chloride solution

was added dropwise with continuous stirring in the course of

30 min at least. This mixture was stirred for 1 h at 0–5 °C,

Micro‐analysis (C, H, N) was carried out at the Micro

Analytical Center, Cairo University using a PerkinElmer

2400 CHN elemental analyser. Fourier transform infrared

(FT‐IR) spectra were obtained using a Bruker Tensor 27

FT‐IR spectrophotometer within the range 200–4000 cm⁻¹

as KBr discs. Electronic spectra were obtained using a

Jenway 6405 spectrophotometer in dimethylsulfoxide

(DMSO) as a solvent in the range 200–900 nm. Room tem-

perature electron spin resonance (ESR) spectra were recorded

with a Jeol JES‐RE1X EPR spectrometer applying DPPH as

SAAD ET AL.

3 of 15

TABLE 1 Microanalysis, physical characteristics and molar conductance data of investigated sulfa drug complexes^a

Microanalysis, found (calcd)

H (%) N (%)

Molecular weight,

found (calcd)

Molecular formula; empirical formula

Colour (Λ_m)

C (%)

H₂L (C₁₈H₁₅N₅O₅S)

413.00(413.41)

656.00(656.34)

638.00(638.46)

614.00(614.31)

—(556.84)

Yellowish orange(—)

Deep brown(10.23)

Faint brown(10.55)

Brown(9.88)

52.28(52.30)

36.31(36.60)

35.43(35.74)

35.78(35.19)

38.46(38.82)

38.14(38.57)

40.48(40.84)

38.33(38.29)

40.66(39.83)

3.66(3.66)

3.76(3.38)

3.63(3.16)

3.26(3.28)

3.00(3.62)

3.28(3.60)

3.19(3.05)

3.13(3.45)

3.59(3.34)

16.90 (16.94)

— (14.94)

1) [FeHL(NO₃)₂(CH₃OH)₂]; C₂₀H₂₂FeN₇O₁₃

S

2) [CrHL(NO₃)₂(H₂O)(CH₃OH)]; C₁₉H₂₀CrN₇O₁₃

3) [CdHLCl(H₂O)]2H₂O; C₁₈H₂₀CdClN₅O₈S

4) [MnHLCl(H₂O)₃]; C₁₈H₂₀ClMnN₅O₈S

5) [NiHLCl(H₂O)₃]; C₁₈H₂₀ClN₅NiO₈S

S

— (15.36)

11.54(11.40)

12.13(12.58)

12.14(12.49)

12.59(13.23)

12.60(12.62)

12.46(12.90)

Deep brown(9.36)

Dark green(8.42)

Brown(8.76)

560.00(560.59)

529.00(529.41)

554.00(554.85)

542.00(542.82)

6) [CuHLCl(H₂O)]; C₁₈H₁₆ClCuN₅O₆S

7) [ZnHL(CH₃COO)(H₂O)]; C₂₀H₁₉N₅O₈SZn

8) [CoHLCl(H₂O)]H₂O; C₁₈H₁₈ClCoN₅O₇S

Reddish brown(9.12)

Dark green(8.94)

^aThe yield for the synthesized complexes was found to be 77.35–80.42%; molecular weight was obtained from mass spectra; and Λ_mis the molar conductance

(Ω⁻¹cm²mol⁻¹) at room temperature.

an external standard. The effective magnetic moments were

estimated at ambient temperature using a Johnson Matthey

magnetic susceptibility balance. The molar conductance of

the studied metal chelates was obtained using a Jenway

model 4070 conductance bridge. A Shimadzu GV‐5050 mass

spectrometer was used to measure the electron ionization

mass spectra (EI‐MS) of all compounds using the electron

spray ionization technique. X‐ray diffraction (XRD) patterns

were measured with an X‐ray diffractometer (GNR,

APD2000PRO, Italy) with a graphite monochromator using

Cu Kα₁radiation at 0.03° min⁻¹scanning rate. Using Joel

JSM‐6390 equipment, transmittance electron microscopy

(TEM) images were obtained. Thermogravimetric analysis

(TGA) was performed with a Shimadzu TGA‐50 thermal

analyser under dynamic nitrogen atmosphere with a heating

rate of 10 °C min⁻¹from ambient temperature up to

800 °C. Antibacterial and antifungal activities of the

synthesized compounds were investigated using the agar well

diffusion method.^[24]The anticancer activity of the free

ligand and complexes was studied towards human liver

carcinoma (HEPG2) cell line at the Regional Center for

Microbiology and Biotechnology, Al‐Azhar University as

well as other biological activities.^[25,26]

2.4 | Theoretical Aspects

2.4.1

| Structural optimization

In the gas phase, the best orientations of sulfa drug ligand

structure and its eight complexes were accomplished using

Gaussian09 software.^[27]Density functional theory (DFT)/

B3LYP is the best method for achieving the optimization

using different base sets. The output Gaussian files were

viewed using visualization screen in the program.^[28]Essen-

tial parameters abstracted were on the bases of frontier orbital

energy values. Other essential data were obtained from output

log file: oscillator strength, excitation energy and bond

lengths and charges attributed to coordinating centres. A

quantitative structure–activity relationship (QSAR) study

was accomplished for the organic compound to give a general

overview of its stability and biological activities.

2.4.2

| Docking implementation

Applying Autodock Tools 4.2 was achieved by using

Gasteiger partial charges which were added to sulfa drug

atoms. The docked protein receptor complexes were executed

using integrated non‐polar hydrogen atoms and rotatable

bonds were refined. Running of the program began with the

TABLE 2 Assignments for diagnostic important bands in FT‐IR spectra of H₂L and its complexes

Compound

ν(OH)

ν(NH)

ν(C═N)

ν(N═N)

δ(H₂O)

ν(M─O)

ν(M─N)

ν(M─Cl)

H₂L

1

3421

3423

3444

3413

3419

3446

3418

3416

2925

2939

2937

2929

2931

2933

2920

2929

2947

1478

1476

1477

1452

1486

1491

1472

1469

1456

1407

1389

1385

1411

1412

1365

1380

1410

—

803

797

802

794

805

797

601

577

600

590

612

607

605

611

475

460

452

482

484

453

410

484

2

—

3

369

374

364

317

—

4

5

6

7

8

364

4 of 15

SAAD ET AL.

TABLE 3 Electronic spectral data for metal ion–sulfa drug complexes

Ligand field parameters

Intraligand and charge

transfer (cm⁻¹

Compound

μ_eff(BM)

D–d transition(cm⁻¹

)

10Dq (cm⁻¹

)

B (cm⁻¹

)

β

Z

H₂L

1

—

35 843; 31 824; 28 420; 21 400

34 735; 31 056

—

20 833

14 648

—

2.011

1.292

—

5.62

3.81

dia

27 560; 21 100; 20 833

868.04

606.70

—

0.8552

0.6609

—

2

20 661; 14 648

33 860; 29 239

3

—

18 240; 21 645; 27 473

25 727; 15 949

20 325

34 650; 33 014; 27 472; 21 930

34 000

4

5.93

3.11

1.65

dia

18 240

10 034.5

—

760.00

771.89

—

0.8837

0.7415

—

1.4622

0.8024

—

5

32 679; 27 778

6

33 333; 25 381; 22 321

31 646; 26 042; 22 321; 17 730

32 258; 25 125; 22 624

7

—

8

4.61

16 541

3 723.57

789.81

0.8134

1.0861

addition of fundamental hydrogen atoms and Kollman united

atom type charges.^[29]Autogrid program was implemented to

produce the affinity (grid) maps of × × Å grid points and

0.375 Å spacing.^[30]Electrostatic terms and van der Waals

forces were evaluated through distance‐dependent dielectric

functions and Autodock parameter sets, respectively.

Docking simulations were accomplished by the local search

method of Solis and Wets and Lamarckian genetic algo-

rithm.^[31]Occasionally, initial position, orientation and tor-

sions of the drug molecule were set. All rotatable torsions

were released during docking. Ten different runs were used

to achieve each docking experiment, that were set to block

after an ultimate 250 000 energy consideration. The size

was established to be 150. Throughout the study, a transla-

tional step of 0.2 Å, quaternion and torsion steps of five

were used.

spectrum of the free ligand with those of its metal complexes.

The spectrum of the ligand displays a broad band centred at

3421 cm⁻¹attributed to stretching vibrations of intramolecu-

lar hydrogen bonded hydroxyl groups.^[33]Spectra of

complexes show broad bands in the range 3413–3446 cm⁻¹

corresponding to ν_OHof solvent molecules associated with

the complexes. Also, the complexes exhibit weak bands at

794–805 cm⁻¹for δr(H₂O) of coordinated molecules.^[34]

Moreover, fresh bands at 1090, 1275 cm⁻¹and 1090,

1317 cm⁻¹for ν(M─OH) and δ(OH) are good indications

for thw presence of CH₃OH molecules associated with

Fe(III) and Cr(III) complexes, respectively. The behaviour

of OH groups in the drug cannot be detected from their

stretching and bending vibrations in the spectra of the com-

plexes due to their replacement by the same from solvents.

The band appearing at 1407 cm⁻¹assigned to ν_N═Nis shifted

upon chelate formation denoting its coordination towards

3

| RESULTS AND DISCUSSION

The new azodye ligand H₂L and its metal ion complexes

(1–8) are found to be stable towards moisture, light and

air. The coloured ligand is soluble in polar organic

solvents such as ethanol and methanol in the presence of

DMF solvent. The eight coloured complexes are soluble

in DMF and DMSO but are insoluble in other common

organic solvents. The micro‐analyses confirm that the

complexes have a metal‐to‐ligand molar ratio of 1:1. The

obtained results of micro‐analyses are consistent with the

calculated results from empirical formulae of all complexes

(Table 1). The molar conductance values of the complexes

lie within the range 8.42–10.55 Ω⁻¹cm²mol⁻¹which

indicates that these mononuclear complexes are non‐

electrolytes.^[32]

3.1 | FT‐IR Spectra and Mode of Bonding

The FT‐IR spectral bands of diagnostic importance for the

drug derivative and its metal chelates are presented in

Table 2. The binding coordination modes for the ligand

towards metal ions were scrutinized by comparing the FT‐IR

FIGURE 2 Optimized structural formulae for Fe(III) and Cr(III) complexes

SAAD ET AL.

5 of 15

metal centres. In most cases, ν_NH, ν_C═Oand ν_C═Nof pyrimi-

dine ring and ν_SO2(sym) bands appearing at 2925, 1625, 1478

and 1148 cm⁻¹in the drug spectrum manifest slight shifts in

spectra of the complexes. This rules out such groups from

participation in chelation with metal centres. The spectra

include the occurrence of new bands at 577–612 and

410–484 cm⁻¹assigned to M─O and M─N stretching,

respectively.^[35]This confirms the coordination of one nitro-

gen atom from azo group and ionized o‐hydroxyl group

towards all central metal atoms. The ν(M─Cl) band appears

in the lower frequency range up to 374 cm⁻¹in the spectra

of the complexes.^[36]Furthermore, for Fe(III) and Cr(III)

chelates (1 and 2), the appearance of two bands at 1436,

1234 cm⁻¹and 1432, 1236 cm⁻¹, respectively, with a

difference Δ = 202 and 196 cm⁻¹indicates the coordination

of nitrato group in monodentate mode.^[34]Also, for Zn(II)

complex (7), the appearance of ν_as(OCO) and ν_s(OCO) bands

at 1660 and 1432 cm⁻¹, respectively, confirms the unidentate

mode of acetate group.^[34]

3.2 | Electronic Spectral Analysis

Essential spectral analysis data are summarized in Table 3,

obtained after the exposure of solvated compounds to a wide

range of wavelengths (200–900 nm). Magnetic moment

values (Table 3) were also calculated to establish a detailed

view on the structural formulae. Free drug spectrum displays

observable intraligand transition bands at 35 843 and 31

824 cm⁻¹for π → π* and 28 420 and 21 400 cm⁻¹for

n → π* transitions. The value of molar absorptivity (for

1.05 mmol l⁻¹) assigned to n → π* transition is

ε₁= 214 mol⁻¹dm³cm⁻¹which is applicable for the first

transition (HOMO → LUMO). A distinct conjugation for

enriched chromophor groups spread along the drug structure

is the main cause for redshift of charge transfer (CT) bands.

The spectrum of the [FeHL(NO₃)₂(CH₃OH)₂] complex (1)

exhibits three significant d–d transition bands at 27 560, 21

6

4

100 and 20 833 cm⁻¹. Such bands belong to A_1g→ E_g,

6

4

6

4

⁴A_1g(G, ν₃), A_1g→ T_2g(G, ν₂) and A_1g→ T_1g(G, ν₁)

transitions, respectively, inside an octahedral configuration

(Figure 2). Its magnetic susceptibility value (5.62 BM) agrees

comfortably with high‐spin octahedral feature. Values of

10Dq, Racah and nephelauxetic parameters (20 833 cm⁻¹

,

868.04 cm⁻¹and 0.8552) were computed. Nephelauxetic

parameter reflects highly ionic nature of Fe─L bonds. The

spectrum of the [CrHL(NO₃)₂(H₂O)(CH₃OH)] complex (2)

exhibits two significant transition bands at 20 661 and 14

648 cm⁻¹. Such bands belong to A_2g(F) → T_1g(F)(ν₂) and

⁴A_2g→ ⁴T_2g(F)(ν₁) transitions, respectively, inside an octahe-

dral configuration (Figure 2). Its magnetic moment value

(3.81 BM) coincides well with spin‐only moment, which

rules out the orbital contribution for d³systems. Racah

parameter value (606.70 cm⁻¹) was calculated using the

standard equation.^[37]Nephelauxetic parameter value

(0.6609) obtained by applying the relation β = B(complex)/

4

FIGURE

3

Coats–Redfern plots for [CoLCl(H₂O)]H₂O (8).

Y = log[−log(1 − α)/T²], where α is the fraction decomposed and T is the

absolute temperature; n = 1 for the distinct thermal degradation steps

6 of 15

SAAD ET AL.

TABLE 4 Coats–Redfern thermodynamic parameters for some metal complexes^a

Compound

1

n

Step

r

T (K)

E* (kJ mol⁻¹

)

H* (kJ mol⁻¹

)

ln A

S* (kJ mol⁻¹K⁻¹

)

G* (kJ mol⁻¹

)

1

1st

2nd

3rd

0.9509

0.9970

0.9941

410

574

735

0.0108

0.0306

0.1081

−3.3980

−4.7417

−6.0027

−8.3014

2.1950

−8.9623

−0.3249

−0.2404

−0.3352

129.8086

133.2619

240.4002

2

4

5

7

8

1

1st

2nd

3rd

0.9915

0.9306

0.9887

339

396

561

0.0566

0.0300

0.0330

−2.7619

−3.2623

−4.6312

−8.3014

2.1950

−8.9623

−0.3233

−0.2373

−0.3330

106.8413

90.7236

182.1795

0

1

0

1st

2nd

3rd

0.9702

0.9615

0.9918

406

473

605

0.0169

0.2223

0.0055

−3.3586

−3.7102

−5.0245

−8.3014

2.1950

−8.9623

−0.3248

−0.2388

−0.3336

128.5153

109.2494

196.8178

0

1

1st

2nd

3rd

0.9304

0.9677

0.9941

498

580

832

0.0204

0.2066

0.0432

−4.1200

−4.6155

−6.8741

−8.3014

2.195013

−8.9623

−0.3265

−0.2405

−0.3363

158.4823

134.8808

272.9047

1

0

1st

2nd

3rd

0.9773

0.9835

0.9565

500

575

741

0.0112

0.1647

0.0261

−4.1458

−4.6158

−6.1346

−8.3014

2.1950

−8.9623

−0.3265

−0.2404

−0.3353

159.1263

133.6365

242.3298

1

1st

0.9914

0.9738

0.9765

0.9603

335

367

406

518

0.0453

0.0679

0.0724

0.0281

−2.7399

−2.9834

−3.3031

−4.2786

−8.3014

2.1950

−8.9623

−9.5646

−0.3232

−0.2367

−0.3303

−0.3373

105.5369

83.8877

130.8018

170.4637

2nd

3rd

4th

^aA is the frequency factor, E is the activation energy, ΔH* is the activation enthalpy, ΔS* is the activation entropy and ΔG* is the Gibbs free energy.

B⁰(free ion) is attributed to low‐energy quartet–doublet

transitions. This value reflects the relative covalent character

for new σ bonds coincident with Cr─O and Cr─N interac-

tions.^[38]Spectra of [CdHLCl(H₂O)]2H₂O (3) and

[ZnHL(CH₃COO)(H₂O)] (7) exhibit CT bands attributed to

diamagnetic complexes with tetrahedral configuration. The

deep colour of the two complexes, although the absence of

d–d electronic transitions, reflects the dominant ligand‐to‐

metal CT. The spectrum of [MnHLCl(H₂O)₃] (4) exhibits

parameters (10 034.5 cm⁻¹, 771.89 cm⁻¹and 0.7415) were

computed and represent also the ionic nature for new σ

bonds. The spectrum of [CuHLCl(H₂O)] (6) exhibits a signif-

icant band at 20 325 cm⁻¹assigned to ²B_1g→ ²E_gtransition

inside a square planar configuration. Its magnetic moment

value (1.65 BM) coincides with spin of free electron with a

relative metal–metal interaction inside the crystal. Also, the

band at 22 321 cm⁻¹is attributed to ligand‐to‐metal CT.

The spectrum of [CoHLCl(H₂O)]H₂O (8) exhibits one signif-

icant band at 16 541 cm⁻¹assigned to ⁴A₂(F) → ⁴T₁(P) tran-

sition inside a tetrahedral configuration (Figure 1S). Its

magnetic moment value (4.61 BM) is in the range suitable

for the appearance of orbital contribution inside a tetrahedral

configuration. Values of 10Dq, Racah and nephelauxetic

parameters (3723.57 cm⁻¹, 789.81 cm⁻¹and 0.8134) were

computed^[40]and indicate a considerable ionic character for

new σ bonds. Values of Racah inter‐electronic repulsion

parameter are changed with 3d transition metal complexes

by changing Z and q values, where Z is the cation charge

efficiency and q is the number of existing d‐shell as d^q. The

effective metallic charges are computed using a known

relation^[40]and found as +2.011, +1.292, +1.4622,

+0.8024 and +1.0861 for Fe(III), Cr(II), Mn(II), Ni(II) and

Co(II) ions, respectively.^[40]These values are frequently

three transition bands at 27 473, 21 645 and 18 240 cm⁻¹

.

6

Such bands are assigned to A_1g

→

⁴Eg,⁴A_1g(G,ν₃),

⁶A_1g→ ⁴T_2g(G,ν₂) and ⁶A_1g→ ⁴T_1g(G,ν₁) transitions, respec-

tively, inside an octahedral configuration. Its magnetic

moment value (5.93 BM) coincides well with spin‐only

moment expected for low‐field d⁵complexes. Values of

10Dq, Racah and nephelauxetic parameters (18 240 cm⁻¹

,

760 cm⁻¹and 0.8837) were computed and indicate the

absence of elemental feature with considerable ionic charac-

ter for new σ bonds. The spectrum of [NiHLCl(H₂O)₃] (5)

exhibits two significant d–d transition bands at 25 727 and

3

15 949 cm⁻¹assigned to A_2g

→

³T_1g(p)(ν₃) and

³A_2g→ T_1g(F)(ν₂) transitions, respectively.^[39]Its magnetic

moment value (3.11 BM) agrees with spin‐only moment for

d⁸system. Values of 10Dq, Racah and nephelauxetic

3

FIGURE 4 Mass spectrum of [FeHL(NO₃)₂(CH₃OH)₂] (1)

SCHEME 1 Fragmentation pathways of [CrHL(NO₃)₂(H₂O)(CH₃OH)] (2)

SAAD ET AL.

7 of 15

release of two nitrate groups with 18.87% (calcd 18.89%)

mass loss. The last degradation stage happens at

372–1000 °C involving complete decomposition of the com-

plex and formation of Fe₂O₃(12.59%; calcd 12.17%) as the

residue. For [CrHL(NO₃)₂(H₂O)(CH₃OH)] (2), the first step

appears at 48–78 °C attributed to the volatilization of coordi-

nated solvent molecules (H₂O + CH₃OH) with 7.69% (calcd

7.84%) mass loss. The second step occurs at 80–154 °C

attributed to removal of two coordinated nitrate groups with

19.23% (calcd 19.42%) mass loss. The composition of the

final residue is Cr₂O₃+ 5C, and the experimental result

(21.54%) is in good agreement with the result of theoretical

calculation (21.30%). [CuHLCl(H₂O)] (6) shows a first

decomposition stage at 272–302 °C assignable to the removal

of coordinated water with 3.33% (calcd 3.40%) mass loss.

The next thermal decomposition step at 304–322 °C is attrib-

uted to elimination of 0.5Cl₂with 6.82% (calcd 6.70%) mass

loss. The final step at 324–984 °C involves thermal degrada-

tion of the complex leaving Cu metal as final residual compo-

nent with 11.96% (calcd 12.00%). [ZnHL(CH₃COO)(H₂O)]

(7) displays three successive thermal degradation stages.

The first one at 148–276 °C is assigned to the liberation of

one coordinated water molecule with 3.34% (calcd 3.25%)

mass loss. The second step at 278–316 °C corresponds to

the elimination of coordinated acetate with 10.83% (calcd

10.64%) mass loss. The third one at 318–598 °C corresponds

to the thermal decomposition of the complex and formation

of Zn as a metallic residue,^[44]amounting to 10.05% (calcd

11.79%). [CoHLCl(H₂O)]H₂O (8) degrades in four consecu-

tive thermal decomposition steps in the following

mechanism:

42−76°C

−3:10%ðcalcd 3:32%Þ

½CoHLClðH₂OÞꢀ:H₂O

→½CoHLClðH₂OÞꢀ

FIGURE 5 XRD patterns for H₂L and Fe(III) complex

78−106°C

−3:44%ðcalcd 3:32%Þ

½CoHLClðH₂OÞꢀ

½CoHLClꢀ

→½CoHLClꢀ

below that of the formal charges. This reduction for oxidation

states is indicative of the effective ionic nature for new σ

bonds covered with high ligand‐to‐metal CT.^[41]

108−152°C

−6:90%ðcalcd 6:53%Þ

→½CoHLꢀ

3.3 | TGA and Thermo‐kinetic Parameters

Most of the investigated metal complexes were subjected to

TGA in order to understand their coordination structure.^[42,43]

The TGA curve of Fe(III) complex (1) exhibits three pyrol-

ysis processes. The first mass loss occurs in the range

53–200 °C, corresponding to the removal of two coordinated

methanol molecules. The found mass loss (10.00%) is close

to the calculated value (9.76%). The second pyrolysis step

takes place within the range 204–370 °C attributed to the

154−590°C

½CoHLꢀ

→½CoHLꢀ−16:21%ðcalcd 16:01%Þ

TGA curves were applied to calculate the kinetic param-

eters applying the Coats–Redfern method^[45](Figure 3).

Also, the thermodynamic parameters of the thermal decom-

position stages were determined^[46](Table 4). The negative

TABLE 5 Spin Hamiltonian parameters for Cu(II) complex (A and p × 10⁻⁴

)

Complex

3

g_||

g_⊥

g₀

A_||

f

A_⊥

A₀

G

p

k

²K_||

²K_⊥

α²

β²

2.1606

2.0935

2.116

163.12

132.45

63.31

96.58

1.74

25.55

3.894

−0.484

−1.114

0.691

0.703

8 of 15

SAAD ET AL.

complexes degrade through the elimination of drug ligand

which gives rise to the occurrence of molecular ion peaks

assignable to [L]⁺besides other peaks due to successive frag-

mentation processes of the complexes. This is a very wide-

spread behaviour for metal ion complexes containing

distinct ligands (ML) which decompose during spray ioniza-

tion processes via cleavage of the metal–ligand bonds.^[50,51]

As example, the mass spectrum of complex 2 displays molec-

ular ion peaks at m/z 638, 609, 617, 587, 525, 465 and 411

FIGURE 6 ESR spectrum of solid Cu(II) complex

sign of all ΔH* values reveals that all thermal decomposition

stages are exothermic. The activation entropies (ΔS*) have

negative values which donate a more ordered activated

complex than the reactants and/or the thermal degradation

processes are slower than normal ones.^[47]ΔG* values

increase in an adequately behavior for the subsequent

thermal decomposition steps as a result of increasing TΔS*

values from one step to upcoming ones overriding ΔH*

values.^[48]ΔS* of the dehydration step has small negative

values because this step includes two simultaneous processes.

The first is release of water molecules from the solid complex

with positive ΔS* and the second is the formation of anhy-

drous complexes (more ordered) with negative ΔS*. The

obtained values are the resultant of both processes.^[49]

3.4 | Mass Spectral Analysis

EI‐MS analysis was applied in order to support the

constituents and purities of the prepared ligand and metal

complexes (Figure 2S). Mass spectra of free drug (H₂L),

[FeHL(NO₃)₂(CH₃OH)₂] (Figure 4), [CrHL(NO₃)₂(H₂O)

(CH₃OH)],

[CuHLCl(H₂O)],

[CdHLCl(H₂O)]2H₂O,

[NiHLCl(H₂O)₃],

and

[ZnHL(CH₃COO)(H₂O)]

[CoHLCl(H₂O)]H₂O display peaks at m/z 413, 656, 638,

614, 560, 529, 554 and 542, respectively, consistent with

their molecular weights. Furthermore, most of the studied

FIGURE 8 Frontier molecular orbitals of (A) HOMO and (B) LUMO for

Fe(III), Cr(III), Cd(II), Mn(II), Ni(II), Cu(II), Zn(II) and Co(II) complexes

(1–8, respectively)

FIGURE 7 Frontier molecular orbitals of (A) HOMO and (B) LUMO

SAAD ET AL.

9 of 15

TABLE 6 Gaussian optimized parameters using DFT/B3LYP method

Compound

E_H(eV)

EL (eV)

(EH − EL) (eV)

El − Eh

x (eV)

μ (eV)

η (eV)

S (eV⁻¹

)

ω (eV)

(eV)

H₂L

−0.2430

−0.11654

−0.20994

−0.14533

−0.14656

−0.19226

−0.21992

−0.20011

−0.12787

−0.1950

−0.1265

−0.0220

−0.0623

−0.0914

−0.0403

−0.0159

−0.0363

−0.1061

−0.0420

0.12646

0.02200

0.06234

0.09137

0.04028

0.01585

0.03625

0.10607

0.04201

0.17977

0.22094

0.17650

0.192245

0.21240

0.227845

0.218235

0.180905

0.216005

−0.17977

−0.22094

−0.1765

0.06323

0.0110

0.031615

0.00550

0.255553

2.21884

15.81527756

90.90909091

32.08213025

21.88902266

49.65243297

126.1829653

55.17241379

18.8554728

Fe(III)–HL

Cr(III)–HL

Cd(II)–HL

Mn(II)–HL

Ni(II)–HL

Cu(II)–HL

Zn(II)–HL

Co(II)–HL

−0.23194

−0.20767

−0.23793

−0.23254

−0.23577

−0.23636

−0.23394

−0.23701

0.03117

0.045685

0.02014

0.007925

0.018125

0.053035

0.021005

0.015585

0.022843

0.010070

0.003963

0.009062

0.026518

0.010503

0.499715

0.404489

1.120004

3.27529

−0.19225

−0.2124

−0.22785

−0.21824

−0.18091

−0.21601

1.313835

0.308538

1.110644

47.60771245

corresponding to [CrHL(NO₃)₂(H₂O)(CH₃OH)] (molecular

weight of complex), [CrHL(NO₃)₂(H₂O)]³⁻(loss of coordi-

nated methanol), [CrHL(NO₃)₂(CH₃OH)]³⁺(loss of coordi-

nated water), [CrL(NO₃)₂]⁺(loss of methanol and water),

implemented method used to investigate the particle shape

and size for a solid matrix. High‐resolution images were

obtained (Figure 4S). The micrographs indicate diverse parti-

cle shapes in nanocrystalline matrices. A rocky shape is the

main feature for free drug and Zn(II) complex (7). This

suggets the adaptable accumulation for the particles. Micro-

graphs of Cd(II), Mn(II) and Cu(II) complexes (3, 4 and 6)

represent their nanometric features by clear cubic‐like crystal

shapes. Micrographs of Fe(III), Cr(III), Ni(II) and Co(II)

complexes (1, 2, 5 and 8) display clear homogeneous matri-

ces with a distinct isolation for spherical particles in the

nanometre range. This points to essential rule for the pres-

ence of metal ions on yielding nanometre particles.^[53]The

highly symmetric spherical anions occluded in complexation

sphere may lead to the spherical feature appearing in images.

Also, this may be the result of the distinct accumulation of

several individual particles of polycrystalline nature. The

dark areas in the micrographs may point to the aggregation

of condensed fine particles. The nanometre sizes may

enhance the biological activity with regard to bulk analogue.

This property may simplify the permeability through infected

cell membranes.

[CrHL(NO₃)]⁺, [CrHL]⁻and [HL]²⁺

,

respectively

(Scheme 1). The results of EI‐MS are in good agreement with

elemental analyses (Table 1) which confirm the proposed

molecular formulae of all investigated compounds.

3.5 | XRD and TEM

XRD patterns for all prepared compounds were obtained in

the range 10° < 2θ < 80° (Figure 3S). This analysis is used

to give a clear view about the lattice dynamics of solid com-

pounds.^[52]All the patterns obtained reflect the amorphous

appearance of the drug (Figure 5) and its complexes. This

may be due to there being no regular arrangement for the

solid constituents during the precipitation process. Almost

any compound may solidify in an amorphous state if the

reaction is fast or the solution is cooled rapidly enough.

Some solids are intrinsically amorphous, due to their constit-

uents not being able to give a good fit inside a crystalline

lattice. This prohibits the chance for computing the crystallite

sizes or d‐spacing inside the lattice to give a distinct view

about the investigated compounds. The amorphous nature

reflects the infinitely small size for the aggregates which

may be found comfortably in the nanometre range which is

3.6 | ESR Spectrum of Cu(II) Complex

Spin Hamiltonian operators and interaction exchange vector

(G) for solid Cu(II) complex were estimated (Table 5) from

its spectrum (Figure 6). The axially symmetric g tensor

verified through TEM analysis. TEM is

a broadly

TABLE 7 Significant charges, bond lengths, dipole moments (D), oscillator strengths (f) and excitation energies (E)

Compound

N(18)

O(26)

M

C(24)═O(26)

N(19)═N(18)

D (D)

f

E (nm)

H₂L

−0.370013

−0.313167

−0.347690

0.243615

−0.209119

−0.617981

−0.656333

0.252231

—

1.363869

—

1.263122

—

5.7941

6.5640

5.8226

5.6894

1.7069

2.5207

2.1669

3.8270

2.5142

0.0019

0.0002

0.0000

0.0020

0.0005

0.0001

0.0011

0.002

503.36

Fe(III)–HL

Cr(III)–HL

Cd(II)–HL

Mn(II)–HL

Ni(II)–HL

Cu(ii)–HL

Zn(II)–HL

Co(II)–HL

0.551849

0.826656

−0.040645

0.372640

0.239724

0.492258

0.051785

1.768644

8044.21

2725.64

3442.12

2487.27

8338.81

3868.66

2407.69

2316.63

—

1.368357

—

1.263575

—

−0.348911

−0.317903

−0.314589

0.139718

−0.555945

−0.536607

−0.586842

0.202435

—

1.369257

—

1.263504

—

−0.087261

−0.164942

1.369257

1.263448

0.0041

10 of 15

SAAD ET AL.

TABLE 8 QSAR data for sulfa drug ligand (H₂L)

Function

Surface area (approx) (Å²)

Surface area (grid) (Å²)

Volume (Å³)

470.12

632.91

1058.46

−3.89

Total energy (kcal mol⁻¹

Total energy (a.u.)

)

−123034.8147206

−196.068433399

−4734.1908206

−118300.6239000

−866861.4656579

743826.6509373

52.5541794

Binding energy (kcal mol⁻¹

Isolated atomic energy (kcal mol⁻¹

Electronic energy (kcal mol⁻¹

Core–core interaction (kcal mol⁻¹

Heat of formation (kcal mol⁻¹

Gradient (kcal mol⁻¹Å⁻¹

)

Hydration energy (kcal mol⁻¹

)

Log P

−1.52

)

Reactivity (Å³)

Polarizability (Å³)

Mass (amu)

117.29

37.92

)

413.41

)

0.0919706

2

parameters are g_||> g_⊥> 2.0023, which indicate that d_{x −y}is

the ground orbital.^[54]The G factor is determined from

G = (g_||− 2.0023)/(g_⊥− 2.0023) = 4. In conformity with

Hathaway and Billing,^[55]G > 4 represents a negligible inter-

change interaction between copper(II) centres. G < 4 means a

significant metal–metal interaction and coincides directly

with magnetic moment value. Here, the highly reduced value

(1.74) indicates a strong interference between copper cen-

tres.^[56,57]The g_||(2.1606) value matches with relatively

covalent M─O and M─N bonds.^[58]The reduction tendency

of A_||towards the increase of g_||points to tetrahedral distor-

tion (f = g_||/A_||).^[59]In any case, the calculated value is in

the range for square planar configuration. Values of σ²(cova-

lence of in‐plane σ‐bonding) and β²(covalence of in‐plane

π‐bonding) were determined using: α²= (A_∥/0.036) +(g_∥

− 2.0023) + 3/7(g_⊥− 2.0023) + 0.04 and β²= (g_∥− 2.0023)

E/− 8λα², where λ (spin–orbital coupling) = −828 cm⁻¹for

free copper ion and E (20 325 cm⁻¹) is the electronic

transition energy. The β²value indicates that the in‐plane

π‐bonding is highly ionic, while the α²value indicates that

the in‐plane σ‐bonding is relatively covalent. Dipolar term

as a displacement vector between charges inside the complex

can be deducted from: p = 2γ_Cuβ₀β_N(r⁻³), where γ_Cuis the

magnetic moment of copper, β₀is the Bohr magneton, β_Nis

the nuclear magneton and r is the distance from nucleus to

outer electron shells. The p value (25.55 × 10⁻⁴) does not

deviate a lot from known values. The orbital reduction fac-

tors, K_||and K_⊥, were also calculated using the following

3.6.1 | Molecular orbital coefficients and bonding parameter

calculations

The deduced g values are completely different from the elec-

tronic value (2.0023). This is attributed to spin–orbit interac-

tion with ground state level. Isotropic and anisotropic g and A

parameters were calculated from A₀= (A_||+ 2A_⊥)/3 and

g₀= (g_||+ 2 g_⊥)/3. Taking A_||and A_⊥as negative values,

the K expression is K = −(A₀/p) − (g_e− g₀). Thus K (Fermi

contact term) can be evaluated. The Fermi contact term is an

indication of polarization exerted by the uneven apportion-

ment of d‐electron density on the inner core s‐electrons.

3.7 | Molecular Modelling, DFT and QSAR Methods

The Gaussian09 program is a theoretical tool implemented to

optimize the molecular modelling of the investigated com-

pounds. Significant parameters were abstracted from the out-

put files based on the numbering schemes.^[61]Moreover,

using the E_HOMOand E_LUMOenergy gap, essential biological

parameters are abstracted.^[61]Figure 7 shows molecular

orbital images for the free drug HOMO and LUMO levels.

HOMO level is centred mainly at the methylpyrimidin‐2‐

ylbenzenesulfonamide part enriched with heavy donor atoms

although the LUMO levels are spread over the other side

donor atoms. This may suggest that the lower energy levels

of such atoms participate in a widespread resonance. This

may give such atoms a great opportunity for dual nature in

charge transfer process of metal to ligand or vice versa.

Images of HOMO and LUMO levels for all complexes are

displayed in Figure 8(A) and (B), respectively. HOMO

images display the approximately unchangeable level posi-

tion for all complexes in comparison with free ligand, except

Fe(III) and Cr(III) complexes, in which the HOMO level is

equations:

²K_∥= (g_∥− 2.00277)E/8λ

and

²K_⊥= (g_⊥

2

− 2.00277)E/2λ, where, K_||= α²β². For pure σ‐ bonding

2

K_||≈ K_⊥≈ −0.77, while K_||(−0.484) < K_⊥(−1.114) sig-

nifies in‐plane π‐bonding, with K_⊥

2

<

K_||accounting for

out‐of‐plane π‐bonding.^[60]

TABLE 9 Docking energies for H₂L–protein receptor complexes

Est. free energy of

binding (kcal mol⁻¹

Est. inhibition

constant, K_i(μM)

vdW + bond + desolve

Electrostatic energy

Total intercooled

Frequency

(%)

Interact

surface

Receptor

)

energy (kcal mol⁻¹

)

(kcal mol⁻¹

)

energy (kcal mol⁻¹

)

5bmm

5htg

−5.60

+202.29

+553.39

−7.14

78.15

−

−7.52

+199.27

+547.12

−6.59

−0.26

+0.24

+0.18

−2.04

−0.70

−7.79

+199.51

+547.30

−8.64

20

10

50

30

915.479

730.722

683.538

812.208

879.134

5j9b

−

5ey0

2b0o

5.81

611.96

−4.38

−6.61

−7.31

SAAD ET AL.

11 of 15

FIGURE 9 Docking complexes for H₂L drug with (A) 5bmm and (B) 5htg

protein receptors

FIGURE 10 HP plots of H₂L drug with (A) 5bmm and (B) 5htg protein

condensed around central atoms, nitrate and sulfonamide

groups, which are considered the electron‐intense environ-

ment in the two complexes. This favours the two atoms

towards ionic character. LUMO images display centring of

the level with the central atoms and their coordinates in all

complexes. This is due to the contribution of metal atom in

the electronic transition environments with the coordinating

atoms. It also reflects the flexibility of transition due to the

presence of central metal atoms. Electronegativity (χ), chem-

ical potential (μ), global hardness (η), global softness (S),

global electrophilicity index (ω) and absolute softness (ϭ)

were estimated according to known equations.^[62,63]Electro-

philicity index is one of the important parameters, which is

extensively used for testing the chemical reactivity of com-

pounds. Electrophilicity is the character of atoms which ben-

efits the energy reduction process on donors. This index

quantifies the stabilization energy when the system achieves

a further electronic charge from the environment. Indicators

η and are measures of the molecular constancy and reactiv-

ity. Also, their characters are belonging to each other. The

softness indicators are the reverse of global hardness.^[64]

receptors

3.7.1

| Computed parameters

Essential quantum parameters were estimated and are pre-

sented in Table 6. The investigation offers the following

points. The free drug has a softness character which reflects

its flexibility towards coordination. Positive electrophilicity

indicator (χ) and negative electronic chemical potential (μ)

may indicate that the drug compound is able to capture elec-

trons from the environment and its energy decreases coher-

ently. Moreover, the two index values increase for the

complexes and lead to their higher stability than the free

drug. The reduction of energy gaps (ΔE) in comparison with

the free drug reflects the high softness of the complexes

which leads to the anticipation of effective biological activity.

The reduction for E_HOMOcompared to the drug may suggest

the strength of metallic bonds. The dipole moment values of

Fe(III), Cr(III), H₂L and Cd(II) are higher than the reference

one (4.80 D for 100 pm distance). This may represent the dis-

tance between charges as ca 120–130 pm and supports the

12 of 15

SAAD ET AL.

TABLE 10 Antibacterial and antifungal activities of H₂L and metal its complexes^a

Inhibition zone diameter (mm per mg sample)

Sample

E. coli (G⁻)

S. aureus (G⁺)

C. albicans (fungus)

A. fumigatus (fungus)

Control: DMSO

Standard

0.0

Ampicillin antibacterial agent

Amphotericin B antifungal agent

22.0

—

18.0

—

19.0

—

17.0

H₂L

16.9 0.58

19.6 0.33

9.7 0.3

18.2 0.44

22.4 0.58

NA

13.8 0.25

16.3 0.25

NA

15.7 0.33

20.2 0.55

NA

Fe(III) complex (1)

Cr(III) complex (2)

Cd(II) complex (3)

Mn(II) complex (4)

Ni(II) complex (5)

Cu(II) complex (6)

Zn(II) complex (7)

Co(II) complex (8)

14.7 0.4

15.9 0.44

17.6 0.58

10.8 0.44

22.3 0.25

16.5 0.25

15.1 0.4

19.6 0.19

22.4 0.36

11.7 0.28

14.6 0.42

15.9 0.53

10.8 0.4

13.4 0.58

16.7 0.33

11.9 0.25

9.9 0.37

10.2 0.41

12.7 0.5

16.8 0.39

20.6 0.58

16.9 0.58

NA

^aTests done using the diffusion agar technique. Each experiment was conducted at least three times. NA means no activity. The data are expressed in the form of

mean standard deviation.

relative ionic character for their bonds and coinciding with

spectral parameter (β). The low values for Zn(II), Ni(II),

Co(II), Cu(II) and Mn(II) complexes indicate a relatively

small distance between charges or lower polarity over all

the compound.

to 1. The calculated values indicate lower electronic transi-

tion efficiency for such electronically condensed metal

atoms.

3.7.3

| QSAR calculations

Log P value is one of the essential results abstracted through

QSAR study of the optimized structure using HyperChem

software. The structure was approximately optimized by

molecular mechanics force field (MM⁺) and followed by full

modulation with semi‐empirical AM1. The structure was

adjusted without confirming any indexes, leading to equilib-

rium state data. An interconnection between anticancer activ-

ity of a drug and its partition coefficient (log P) is by an

inverse relation.^[65]Log P is the measure of lipophilicity for

unionized particles, for which high a log P value means little

absorption or penetration of drug. For compounds to have a

plausible probability of absorption, their values must not be

maximal. Here, the calculated value is very low (log

P = −1.52) which suggests distinct biological behaviour.

Also other essential parameters were calculated for optimized

structure (Table 8) by applying energy minimization protocol

using Polake–Ribiere conjugated gradient algorithm.

3.7.2

| Bond lengths, atomic charges and oscillator strengths

Consistent with numbering scheme and using output files,

essential bond lengths and charge density over concerned

sites were extracted and are summarized in Table 7. Bond

lengths concerning coordinating atoms undergo an observ-

able elongation compared to the original free drug. This elon-

gation is directly related to coordination of such atoms.

Moreover, charge over N(18) atom is generally reduced

which is consistent with its coordination. The charge over

O(26) atom is varied, the charge over the atom increasing

for five of the complexes and reducing for the other three,

Cd(II), Zn(II) and Co(II). The increased values may be due

to the replacement of hydrogen with metal atom which

increases the bond polarity. While, the reduced values may

suggest a strong ligand‐to‐metal CT. Oscillator strength is

an indicator for possible absorption or emission of radiation

by the molecule consumed in electronic transitions. Its value

is between 0 and 1; a strong transition will have a value close

3.7.4

| Docking analysis

Drug design has benefitted recently from various computa-

tional tools using highly sophisticated methods to enhance

the designing field. Autodock tools were implemented to

clarify the biological features for the new drug to comple-

ment the experimental results. This study is interested in

designing a new drug that may serve in the biological field,

such as antibacterial, antifungal and antitumour activities.

The docking process was accomplished using protein recep-

tors of the microorganisms used in the experimental applica-

tion: 5bmm, 5htg, 5j9b, 5ey0 and 2b0o as hosts for

Escherichia coli, Candida albicans, Aspergillus fumigatus,

Staphylococcus aureus and liver carcinoma cell line,

FIGURE 11 In vitro cytotoxicity of organic ligand and complexes 1–8

towards human liver carcinoma cell line (HEPG2), compared with standard

doxorubicin (Dox) with IC₅₀value of 4.73 μg ml⁻¹

SAAD ET AL.

13 of 15

respectively. The computed energies for the complexes were

abstracted and tabulated (Table 9). The binding free energy,

constant of inhibition, electrostatic energy, total intercooled

energy and receptor–inhibitor complex interact surface are

the determined energies. The minimization in binding energy

due to mutation may increase the interaction ability toward

host receptors.^[66]The data display significant inhibition

activity for 5bmm, 5ey0 and 2b0o receptors, with an absence

of this for 5htg and 5j9b. This is based on the instability of

the two complexes through their significantly high energies

calculated with two protein receptors (5htg and 5j9b) as well

as the inhibition constant being completely absent. The

docked complexes are presented in Figures 9 and 5S. In

agreement with computation, HB plot curves (Figures 10

and 6S) clarify the different modes of interaction, in which

the red spots relating to hydrogen‐bonding interaction are

strongly condensed for 5bmm, 5ey0 and 2b0o receptors and

dispersed for 5htg and 5j9b. So, an excellent interaction with

5bmm, 5ey0 and 2b0o protein receptors is expected. Two‐

dimensional plot curves (7S) verify the mode of interaction

inside the docking complexes. The gallery complexes with

protein receptors were abstracted and are displayed in 8S.

Finally the data suggest superior interaction of the sulfa drug

derivative with E. coli, S. aureus and liver carcinoma in com-

parison with C. albicans and A. fumigatus, sufficiently agree-

ing with experimental results discussed below.

bactericide in use (ampicillin) against S. aureus. Zn(III) com-

plex displays higher antibacterial activity than the standard

ampicillin towards E. coli and Fe(III) complex exhibits strong

effectiveness against this bacterium. Fe(III) and Ni(II) com-

plexes present potent activity towards C. albicans. Also,

Fe(III) and Ni(II) complexes show greater efficacy than the

standard drug amphotericin B against A. fumigatus. The

increased antimicrobial activity upon chelate formation can

be attributed to the presence of metal ions which are more

hypersensitive towards the microbial cells compared with

the organic chelating agent.^[68]Furthermore, the strengthened

influence of the metal chelates may be attributed to the grow-

ing lipophilic nature of these compounds upon complexa-

tion.^[69]The coordinating metal ions may block the

enzymatic efficiency of cells and/or they may catalyse toxic

reactions among cellular constituents. The differences in the

activity of distinct complexes across various organisms is a

result of either the impermeability of the cells of the microbes

or differences in ribosomes in microbial cells.^[70]The

screened organisms are classified as follows: E. coli was

selected as a representative of Gram‐negative bacteria and

S. aureus as Gram‐positive bacteria, C. albicans represents

unicellular fungi and A. fumigatus is a higher fungus which

exemplifies multicellular fungi. Consequently, they represent

a broad spectrum of test organisms. Hence, the resulting data

indicate the potential of the tested azodye ligand and its com-

plexes as novel and highly promising broad‐spectrum bacteri-

cides and fungicides.

3.8 | Biological Investigation

3.8.1

| In vitro antibacterial and antifungal activities

3.8.2

| Antitumour evaluation

In vitro antimicrobial activities of H₂L and metal chelates

against E. coli (Gram‐negative bacteria), S. aureus (Gram‐

positive bacteria), C. albicans and A. fumigatus were

screened using the agar well diffusion method.^[24]The stan-

dard drugs ampicillin and amphotericin B were tested for

their antibacterial and antifungal activities at the same con-

centration and conditions as for the investigated compounds.

The results obtained are presented in Table 10. The

nanometric nature of the scrutinized chemical compounds is

predicted to increase their efficiency in the biological field

due to their high surface to volume ratio. They are expected

to be highly active due to their ability interact easily with

other particles which increase their antimicrobial efficacy.^[67]

The mode of action of the drug and its metal chelates may

encompass hydrogen bond formation through N═N and/or

OH groups of the ligand or the metal complex and the active

position of the cell which disturbs the ordinary cell processes.

Also, the compounds may cause turmoil in the respiration

system of the organism cells and block the synthesis of pro-

teins which limits the future growth of the tested organ-

isms.^[68]According to the screening results, in most cases,

the investigated compounds show acceptable antimicrobial

and antifungal activities towards tested pathogenic bacteria

and fungi. H₂L and Fe(III), Mn(II) and Ni(II) complexes

exhibit greater antibacterial activity than the standard

Chemotherapy is considered as the major approach for treat-

ment of both metastasized and localized cancer. Also, novel

synthetic anticancer curing agents are in great demand to

improve the outcome for the great number of patients who

relapse after treatment with the presently available cancer

therapies.^[71]Therefore, the synthesized ligand and metal

complexes were screened for their in vitro cytotoxicity and

growth inhibitory activities against human liver carcinoma

cell line (HEPG2). The cytotoxicity of the examined samples

was measured by median growth inhibitory concentration

(IC₅₀) required for producing 50% cytotoxic effect towards

cancer cells during the tested sample incubation.^[72]IC₅₀is

the concentration of tested compound that reduces cell

growth by 50% under the naturalistic experimental condi-

tions. Each point was determined from the average of three

experiments and specified as the value standard deviation.

The cytotoxicities of doxorubicin (Dox) drug, H₃L and metal

complexes towards HEPG2 cell line, using different concen-

trations of Dox and investigated materials, are presented in

Figure 11. It is clear from the resulting data that the order

of cytotoxic activity (IC₅₀values) against HEPG2 cell line

of the examined compounds is Co(II) complex, Cu(II) com-

plex, Cr(III) complex, Zn(II) complex, Ni(II) complex, H₂L,

Cd(II) complex, Mn(II) complex and Fe(III) complex in

14 of 15

SAAD ET AL.

[17] M. M. Al‐Rufaie, Mod. Chem. Appl. 2016, 4, 1.

[18] V. A. Modhavadiya, Orient. J. Chem. 2012, 28, 921.

descending order. These results indicate that the type of metal

ion plays an important role in determining the anticancer

activity of the tested chemical compounds.^[73]According to

Shier,^[74]compounds displaying IC₅₀less than 5.00 μg ml⁻¹

are strong anticancer agents, compounds with IC₅₀more than

5 and less than 10 μg ml⁻¹are considered moderate antican-

cer agents, while those with IC₅₀within the range 10–25 μg

ml⁻¹are weak anticancer drugs. Accordingly, Co(II) and

Cu(II) complexes can be considered moderate anticancer

agents whereas the other materials investigated are very weak

anticancer agents.

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4

| CONCLUSIONS

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A series of metal ion complexes were prepared using a new

sulfa drug derivative. The structural and molecular formulae

were investigated spectrally and theoretically. Mono‐negative

bidentate is the proposed mode of ligand binding towards all

metal ions. Octahedral structure is the main feature proposed

for most of the complexes. ESR was used to verify the struc-

tural formula of Cu(II) complex. XRD patterns and TEM

images indicated the nanometre sizes of the investigated com-

pounds. Computational implementation confirmed the pro-

posed geometries through use of the Gaussian09 program.

QSAR and docking studies gave a good insight into the

expected biological feature of the organic compound. The

biological results are is the major goal achieved in this study.

The data indicate highly promising bactericidal and fungi-

cidal compounds. Also, the antitumour activity results

against HEPG2 cell line are acceptable.

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How to cite this article: Saad FA, Elghalban MG,

El‐Metwaly NM, El‐Ghamry H, Khedr AM. Density

functional theory/B3LYP study of nanometric 4‐(2,4‐dihy-

droxy‐5‐formylphen‐1‐ylazo)‐N‐(4‐methylpyrimidin‐2‐yl)

benzenesulfonamide complexes: Quantitative struc-

ture–activity relationship, docking, spectral and biolog-

ical investigations. Appl Organometal Chem. 2017;

e3721. https://doi.org/10.1002/aoc.3721

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Article Doi

Density functional theory/B3LYP study of nanometric 4-(2,4-dihydroxy-5-formylphen-1-ylazo)-N-(4-methylpyrimidin-2-yl)benzenesulfonamide complexes: Quantitative structure–activity relationship, docking, spectral and biological investigations

DOI: 10.1002/aoc.3721

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