Materials Express

Synthesis, spectral, molecular modeling, biological and antitumor studies of new nifuroxazide complexes

Eid H. Alosaimi1, Walaa H. El-Shwiniy1,2,∗, Saad M. Alshahrani1, Ayman A. O. Younes1, Mostafa Y. Nassar3, and Sameh I. El-Desoky4,∗ 1Department of Chemistry, College of Science, University of Bisha, Bisha 61922, Saudi Arabia 2Department of Chemistry, Faculty of Science, Zagazig University, Zagazig 44519, Egypt 3Chemistry Department, Faculty of Science, Benha University, Benha 13518, Egypt 4Regional Joint Laboratory, Directorate of Health Affairs, the Arab Republic of Egypt Zagazig, 44515, Egypt Article

ABSTRACT IP: 192.168.39.211 On: Thu, 30 Sep 2021 22:45:07 Series of Zr(IV), Ce(IV) and U(VI) complexesCopyright: American were synt Scientifichesized with Publishers nifuroxazide ligand. Design and formulae Delivered by Ingenta of the complexes suggested in the light of analytical, spectral, magnetic and thermal analyses (1HNMR, IR, UV-Vis). The calculated values of molar conductance mean that, all isolated complexes were electrolytes. The data revealed the complexes formation and suggested that nifuroxazide binds as a bidentate at NO sites with metal ions. The kinetic parameters evaluated using Coats Redfern (CR) and Horowitz-Metzeger (HM) methods. The thermodynamic data reﬂect the thermal stability for all complexes. The calculated bond length and −1 force constant values for UO2 bond are 1.741 Å and 459.409 Nm . The research investigations were related to quantum chemical calculations conducted at the theory level of DFT/B3LYP/LANL2DZ. The nifuroxazide, inorganic salts and their metal complexes were assayed against different bacterial species as well as the in vitro growth inhibitory activity against human breast carcinoma (MCF-7) and HCT-116 cell lines. Zr(IV) complex was found to have the highest activity against all the tested organisms and a powerful anti-cancer drug. Keywords: Nif, TG, 1H NMR, IR, MCF-7, DFT.

1. INTRODUCTION The mechanism of action requires the elimination of the

Nifuroxazide (Scheme 1) belongs to 5-nitrofuran group of NO2 group associated with the development of toxic free the intestinal anti-infective drugs. It is available as an over radicals [6], capable of inactivating or modifying micro- the counter medication for the treatment of acute diarrhea bial ribosomal as well as other macromolecular proteins. if it is caused by bacteria [1, 2]. Nifuroxazide or Antinal Bacteria reduce nitrofuran drugs more rapidly than do is a chemotherapeutic agent for drug-resistant urinary tract mammalian cells, and this is thought to account for the infections (UTIs) and for the prevention of recurrent UTIs. selective antimicrobial activity of these compounds [4]. It acts as a bacteriostatic, but is also bactericidal at higher The discovery of novel drugs with fully chemical char- concentrations [3–5]. acterization requires long time and very expensive. So, It is capable of oral absorption, and is therefore easily the modiﬁcation in molecular structure is desirable espe- extracted without metabolism of dietary from the organ. cially when the physical and chemical characters are veriﬁed with the enhancement of the solubility, pharma- cokinetics, bactericidal and bioavailability of nifuroxazide. ∗Authors to whom correspondence should be addressed. The synthesis of new metal complexes is the target of

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OH 2. EXPERIMENTAL DETAILS 9 2.1. Materials and Reagents All the reagents and solvents utilized in this work were 6 8 of reagent-grade quality. Nifuroxazide purchased from Egyptian Company for Chemicals and Pharmaceuticals · 5 7 (ADWIA) (99.9%), ZrOCl2 8H2O (99.9%, Aldrich Chem- · ical Co), UO2(NO3)2 6H2O (99.9%, Fluka Chemical Co) and Ce(SO4)2 (99.9%, Fluka Chemical Co) utilized for 4 C the synthesis of the complexes. All glass were soaked 2 HN O overnight in chromic mixture (K Cr O + concentrated 1 2 2 7 3 H2SO4) rinsed thoroughly with bidistiled water and dried HC N in an oven at 100 C. O O2N 2.2. General Procedure for the Synthesis Complexes

New metal ion complexes were synthesized by addition of Scheme 1. hydroxy-N -((5-nitrofuran-2yl)methylene)benzohydrazide (Nifuroxazide (Nif)). 1 mmol of a methanolic solution of each metal salt (0.322 · · gofZrOCl2 8H2O, 0.502 g of UO2(NO3)2 6H2Oand pharmaceutical companies to improve their potency and 0.332 g of Ce(SO4)2) to 2 mmol of Nif (0.55 g) dissolved wide speciﬁcity like antitumor and anticancer properties. in MeOH. The addition process was carried out dropwisely Cancer chemotherapeutics seek to stimulate the host’s with continuous stirring. The obtained reaction mixture anti-tumor immune system, alter the inhibiting tumor was stirred at room temperature for 15 h. The mixture was microenvironment, and, eventually, aid in tumor reduc- left for slow evaporation to concentrate the reaction mix- tion [7, 8]. The antibacterial drug is a bidentate ligand ture. The resulting precipitates were ﬁltered off, washed

coordinatively bound to transition elements via the NO with ethanol and then desiccated under anhydrous CaCl2. atoms of methine (C N) and amideIP: 192.168.39.211 (C O) groups. On: Lit- Thu,The 30 puritiesSep 2021 of all22:45:07 studied compounds were checked using tle work has focused on interactionsCopyright: of transition American metal Scientific Publishers Delivered byTLC Ingenta and melting point constancy. The chemical structures ions with nifuroxazide drug [4–11]. Spectrophotometric of the synthesized metal complexes (Scheme 2) were con- surveys of Nif with Co(II), Ni(II) and Cu(II) have been firmed as follows: quantified in terms of stability constants [11] and spectro- Article scopic analyses of Pd(II), Pt(II) and Ru(II) nifuroxazide 2.2.1. Nifuroxazide Ligand Physical and complexes [4]. Chemical Properties To satisfy our concern in the structural and preparation characteristics of certain transition metal nifuroxazide Color: yellowish; m.p.: 282 C; M.Wt: 275.22; Elemen- complexes. Herein, new Zr(IV), Ce(IV) and U(VI) com- tal analysis: found, C, 51.99; H, 3.20; N, 15.07%. Calc. = plexes of Nif were synthesized in order to certainly pro- for C12H9N3O5, C, 52.37; H, 3.30; N, 15.27%; m 0.00 − duce novel bactericidal and bioavailability compounds. Scm2 mol 1; eff: diam.; IR (KBr, ): 3366vs (O–H), Elemental, thermal (TG and DTG) studies, magnetic mea- 3246br (N–H), 1672vs (C O), 1591s (C N). 1HNMR 1 = surements, melting points, UV-Vis, IR, HNMR, and bio- (DMSO-d6): 6.8–6.9 (d, 2H, 2-furan), 7.2–7.8 (d, 4H, logical experiments are used to classify complexes. To 1-benzene), 8.38 (s, 1H, CH N), 10.19 (s, 1H, Ar–OH) measure the cation effect on theoretical parameters of and 12.01 (s, 1H, –NH). the Zr(IV), Ce(IV) and U(VI) complexes of Nif, density functional theory (DFT) was used. For biochemi- 2.2.2. The Physical and Chemical Properties cal and medicinal research of drugs and their complexes, · [ZrO(C12H9N3O5)2Cl]Cl 3H2O such computational description decreases time-consuming Color: Yellow; m.p.: 290 C; Yield: 89%; M.Wt: 782.61; trials. By adding the GAUSSIAN 09W software pack- Elemental analysis: found, C 36.80%, H 2.99%, N 10.65%, age [12], the profiles of the ideal set and geometry of M 11.06%. Calc. for ZrC H Cl N O , C 36.83%, H these complexes is simulated. Antimicrobial behavior of 24 24 2 6 14 3.09%, N 10.74%, M 11.66%; = 70.00 S cm2 mol−1; the analyzed complexes and free ligand were evaluated m towards some selected microorganisms like S. aureus, B. eff: Diam.; IR (KBr, ): 3364ms (O–H), 3248br (N–H), subtilis (G+), E. coli, S. paratyphi (G−), A. fumiga- 1664vs(C O), 1555vs (C N), 552vs (M–O), 463w (M– 1 = tus,G.Candidum, S. Racemosum. The anticancer effi- N). H NMR (DMSO-d6): 3.33 (s, 2H, H2O), 7.22– cacy of Nif and its complexes was screened towards an 7.89 (d, 2H, 2-furan), 6.68–7.83 (d, 4H, 1-benzene), 8.57 adult breast (MCF-7) and colon (HCT-116) carcinoma cell (s, 1H, CH N), 10.21 (s, 1H, Ar–OH) and 12.04 (s, 1H, cultures. –NH).

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C HN O NO O O 2

HC N Zr N HC C H O O HN O 2 NO 2 O2N Cl O NH O C HC N Ce N HC O O2N H2O O NH C

OH OH

C HN O NO O O 2 HC N U N HC O O O2N O NH Article C

IP: 192.168.39.211 On: Thu, 30 Sep 2021 22:45:07 Copyright: American Scientific Publishers Delivered by Ingenta

Scheme 2. The proposed coordination mode of Zr(IV), Ce(IV) and U(VI) with Nif.

2.2.3. The Physical and Chemical Properties (s, 2H, H2O), 6.86–6.89 (d, 2H, 2-furan), 7.77–7.82 (d, 4H, [Ce(C12H9N3O5)2(H2O)2](SO4)2 1-benzene), 8.37 (s, 1H, CH N), 10.20 (s, 1H, Ar–OH) Color: canary yellow; m.p.: 220 C; Yield: 67%; M.Wt: and 12.01 (s, 1H, –NH). 918.71; Elemental analysis: found, C 31.08%, H 2.36%, N

9.11%, M 15.15%. Calc. for CeC24H22N6O20S2, C 31.38%, 2.3. Instrumentation 2 −1 H 2.41%, N 9.15%, M 15.25%; m = 212.40 S cm mol ; All the used instruments reported in Table I. eff: Diam.; IR (KBr, ): 3364w (O–H), 3232br (N–H), 1664vs (C O), 1555ms (C N), 552s (M–O), 467m (M– 1 = N). H NMR (DMSO-d6): 3.31 (s, 2H, H2O), 6.86– Table I. Type of analysis and its models. 6.89 (d, 2H, 2-furan), 7.22–7.82 (d, 4H, 1-benzene), 8.38 (s, 1H, CH N), 10.20 (s, 1H, Ar–OH) and 12.01 (s, 1H, Type of analysis Models –NH). Elemental analyses Perkin Elmer CHN 2400 Molar conductivities CONSORT K410 FT-IR spectra FT-IR 460 PLUS (KBr discs) in the range from 2.2.4. The Physical and Chemical Properties − · 4000-400 cm 1 [UO2(C12H9N3O5)2](NO3)2 2H2O Absorbance A double beam spectrophotometer (T80 Color: lemon yellow; Yield: 89%; m.p.: 270 C; M.Wt: measurements UV/Vis) with wavelength range 190 1255.72; Elemental analysis: found, C 29.34%, H 2.25%, nm∼1100 nm, spectral bandwidth of 2 nm. Magnetic moment Sherwood scientiﬁc magnetic balance using N 11.12%, M 24.14%. Calc. for UC24H22N8O20,C Gouy balance using Hg[Co(SCN) ]as 29.40%, H 2.26%, N 11.43%, M 24.28%; = 155.20 4 m calibrant 2 −1 Scm mol ; eff: Diam.; IR (KBr, ): 3364ms (O–H), 1H NMR spectra A Varian Mercury VX-300 NMR spectrometer. 3248br (N–H), 1664vs (C O), 1582vw (C N), 552vs TGA-DTG TGA-50H Shimadzu 1 = (M–O), 467s (M–N). H NMR (DMSO-d6): 3.32

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2.4. Theoretical Calculations assessment studies were conducted and analyzed by the Minimized structures of the Nif pharmaceutical and its tissue culture unit at the Regional Center for Mycol- complexes and related energies were calculated utilizing ogy and Biotechnology, Al-Azhar University, Cairo, Egypt GAUSSIAN 09W software [12] and Becke3–Lee–Yang– (RCMB). According to the procedure defined by Saintigny Parr (B3LYP) [13–15] employing DFT coupled with dou- and Monnat Jr [22], the anticancer vitality processes were ble basis sets without any drug and complex geometry carried out. In 100 L of growth medium at a cell concen- − restriction. The default 6-31G+(d,p) basis package was tration of 1 × 10 4 cells per well The MCF-7 was seeded used for C, H, O, S, and N atoms, plus nifuroxazide in 96-well plate. The monolayers were washed with ster- and its complexes. In addition, during the optimization ile phosphate buffered saline (0.01 M, pH 7.2) after one process, the LANL2DZ base collection was used for Ce day of seeding and the cells were concurrently handled and U atoms for the matching complexes. The basis of with 100 L of various test material dilutions in a freshly LANL2DZ sets controlled electrons through effective core testing media and incubated at 37 C. A multichannel potentials (ECPs) close the nuclei and also contains cer- pipette was used to apply numerous two-fold dilutions of tain relativistic effects that are important for heavy met- the tested compound (100, 50, 25, 12.5, 6.25, 3.125, 1.56 als [16–18]. To visualize the optimized structures and and 0.78 g/mL). In a humidified incubator with 5% CO2 the related HOMO and LUMO orbitals, the Gaussview for one day, the microtiter plates were incubated at 37 C. program [19] had been used. Notable, both the Nif and The monitors were served by untreated cells. For each its complexes’ optimized structures were found to be concentration of the studied samples, three separate tests real minima, i.e. no hypothetical frequencies have been were carried out, each involving six replicates. Using the provided. crystal violet staining viability assay, the cytotoxic effects of the studied compounds were then calculated [23, 24]. 2.5. Antimicrobial Potency Absorbance in each well was then calculated at 570 nm Antimicrobial activity of Nif and their metal complexes using the microplate reader (SunRise, TECAN, Inc, USA). was investigated by a previously reported modified method The absorbance is proportional to the amount of cells in of Beecher and Wong [20] against different bacterial the culture plate that survive. The compound-mediated cell + lysis and the cytotoxic effect of doxorubicin (used as a and fungal species, such as S.IP: aureus 192.168.39.211, B. subtilis (G On:), Thu, 30 Sep 2021 22:45:07 E. coli, S. paratyphi (G−)andA.Copyright: fumigatus, G.American Can- Scientificpositive control)Publishers were then assessed using this colorimetric didum, S. Racemosum). The tested microorganism’sDelivered iso- bytechnique Ingenta [25]. Using Microsoft Excel, the cell viability lates were isolated from Egyptian soil and water then percentage was determined as follows: the percentage of = − × identified according to the standard mycological and bac- cell viability [1 (ODt/ODc)] 100%, where ODt is the Article teriological keys for identification of bacteria as stock cul- average optical density of wells treated with compound tures in the microbiology laboratory, Faculty of Science, and ODc is the mean optical density of untreated cells. The Zagazig University. The nutrient agar medium for antibac- compounds were compared utilizing the IC50 value which terial was (0.5% Peptone, 0.1% Beef extract, 0.2% Yeast was calculated from graphical plots of surviving cells ver- extract, 0.5% NaCl and 1.5% Agar–Agar) and czapeksDox sus compound concentrations.

medium for antifungal (3% Sucrose, 0.3% NaNO3,0.1% K2HPO4, 0.05% KCl, 0.001% FeSO4,2%Agar–Agar) 3. RESULTS AND DISCUSSION was prepared [21] and then cooled to 47 C and seeded Nif and its complexes were found to be air stable with with tested microorganisms. Sterile water agar layer was high and sharp m.p that suggest their purity and were dis- poured then solidified, the prepared growth medium for solved in DMF, DMSO solvents. Elemental studies verified bacteria (plate of 12 cm diameter, 15 ml medium plate). the stoichiometry and formulation of the Nif (Scheme 1) After solidification 5 mm diameter holes were punched and its chelates. C, H, N, Cl, M analyses determined by a sterile cork-borer. The investigated compounds were 1:2 (Metal:Nif) molar ratio for all complexes. The lig- introduced in Petri-dishes (only 0.1 ml) after dissolving in and and its complexes’ elementary studies show strong − DMSO at 1.0 × 10 3 M. These culture plates were then alignment with the proposed structures. Qualitative reac- incubated at 37 C for 20 h for bacteria and for seven tions revealed the presence of chloride, sulphate and nitrate days at 30 C for fungi and the activity was determined found as counter ion in Zr(IV), Ce(IV) and U(VI), respec- by measuring the diameter of the inhibition zone (in mm). tively. Molar conductivity values of Nif and their metal Bacterial growth inhibition was calculated with reference complexes in dimethylformamide with standard reference to the positive control, i.e., Gentamycin and Ketoconazole. 1×10−3 M solutions at room temperature were established to extend from 70.00 to 212.40 S cm2 mol−1. The results 2.6. Anticancer Activity Evaluation specified that the metal coordination complexes with their The compounds were tested against breast and colon car- counter ions can be an electrolyte. The results specified cinoma cell lines ((MCF-7) and (HCT-116)) contrast to that the complexes are electrolytes and the chloride, sul- non-cancer cell line of MCF-10A. All the cytotoxicity phate and nitrate ions have been detected as counter ions

1074 Mater. Express, Vol. 11, pp. 1071–1083, 2021 Synthesis, spectral, molecular modeling, biological and antitumor studies Materials Express Alosaimi et al. in zirconium, cerium and uranium chelates [26, 27]. Mag- netic calculations for complexes implied that all complexes were described as diamagnetism at room temperature. The complex structures implied in the elementary investigation are quite in alignment with their proposed formula.

3.1. FT-IR Studies In the range of 4000–400 cm−1, the IR spectra of the Nif free ligand and its metal complexes have been carried out and the most effective bands are described in Figure 1, in order to establish the coordinating site that could be involved in the chelation process. The analysis and evaluation of the Nif ligand IR spectrum with their complexes show that Nif interacted via the amide group oxygen (C O) and methine group nitrogen (C=N) which demonstrated simultaneously 1672 cm−1 and 1591 cm−1 in the spectrum of Nif. In the IR spectrum of chelates, the band belonging to (C O) amide and methine group (C N) transferred to lower wavenumbers (1664 cm−1, 1555 cm−1 for Zr(IV), Ce(IV) and 1664 cm−1, 1582 cm−1 for U(VI)) demonstrating the involvement of amide C O and methine C N moieties of metal ions [4, 28, 29]. Modern peaks in the region 467 cm−1–552 cm−1 could be attributed to (M–O) and (M–N) stretching vibra- Article tions [30]. The Ce(IV) complex was characterized by the Fig. 1. Infrared spectra for (A) Nif, (B) [ZrO(Nif) Cl]Cl · 3H O, (C) −1 2 2 presence of (M–O) at 521 cm representing hydration · IP: 192.168.39.211 On: Thu,[Ce(Nif) 30 Sep2(H 22021O)2](SO 22:45:074)2,(D)[UO2(Nif)2](NO3) 2H2 O. and/or coordination water molecules.Copyright: Also the stretching American Scientific Publishers −1 vibrations at 900 cm assigned to (M–OH2), supportedDelivered by Ingenta for the participation of water in coordination [31–33]. The The absorption intensity were marginally moved to proposed structure formulae on the basis of the IR results bathochromic and hypochromic shift upon chelation. The are presented in Scheme 2. appearance of new bands in the absorption spectra of all The most practicable framework for the complexes demonstrated the existence of their chelates. · The new bands at 489 (Zr(IV)), 486 (Ce(IV)) and 472 [UO2(Nif)2](NO3)2 2H2O complex can be found in Scheme 2. The four oxygen and nitrogen atoms of Nif (U(VI)) nm may be assigned to the ligand-to-metal charge ligands positioned in the equatorial regions around U(VI) transfer [39]. generate a plane of ﬁve rings. The two oxygen atoms of the uranyl group shared the axial places. The U(VI) 3.3. Nuclear Magnetic Resonance Spectra complex has one plane of symmetry corresponding to The 1HNMR spectra of the ligand and its diamagnetic Cs symmetry. The chelate is supposed to show 264 chelates provided proof of the bonding mode of Nif. The mono-degenerate vibrational fundamentals. These vibra- \ \\ tions are shared between A and A active IR motions. 1.0 Nif. The uranyl moiety has two stretching vibration peaks Zr(IV)-Nif. −1 −1 Ce(IV)-Nif. (asymmetric and symmetrical) at 904 cm and 818 cm . 0.8 U(VI)-Nif.

The results are very consistent with the data found for e c

n 0.6 other dioxo-uranium(VI) chelates [34, 35]. The calculated a b r

bond length and force constant values are 1.741 Å and o −1 s 0.4 459.409 Nm according to the known method [34, 35]. b A

0.2 3.2. UV-Vis Spectra

The UV-Visible spectral descriptions of Nif and its Zr(IV), 0.0 Ce(IV) and U(VI) chelates in DMSO-d from 200 to 800 6 200 300 400 500 600 700 800 nm are demonstrated in Figure 2. Absorbance of Nif at Wavelength (nm) 334 and 412 nm assigned to –∗ and n-∗ transitions, respectively. These transitions type usually happens in Fig. 2. Electronic absorption spectral data of Nif and its metal unsaturated hydrocarbons containing heteroatoms [36–38]. complexes.

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Table II. 1HNMR spectral data (, ppm) of Nif and its metal a consequence of the difference in the charge density of complexes. C N moiety through the coordination method [40].

Compounds 3.4. Thermogravimetric Techniques Assignments Nif Zr(IV)-(Nif) Ce(IV)-(Nif) U(IV)-(Nif) 2 2 2 The results of the degradation behavior of Nif and its H; (s, 2H, – 3.33 3.31 3.32 metal chelates are illustrated in Table III and displayed in H2O) Figure 3. Thermogravimetric (TG) curve of Nif occurs in H; (d, 2H, 7.23, 7.79 7.22–7.89 7.20, 7.70 7.22, 7.75 one step and is followed by a mass loss of 99.74%, which nitrofuran) + + + H; (d, 4H, 6.69–7.80 6.86–7.83 6.86–7.82 6.86–7.82 corresponds to the loss of 4C2H2 HCN 3CO 2NO · 1-benzene) loss. The thermal degradation of the [ZrO(Nif)2Cl]Cl H; (s, 1H, 8.38 8.57 8.50 8.47 3H2O complex occurs with two decay steps. The first CH N) stage of decomposition started at 418 K maximum tem- H; (s, 1H, 10.19 10.21 10.20 10.23 perature belongs to lack of 3H O (6.85%). The second Ar–OH) 2 H; (s, 1H, 12.01 12.04 12.00 12.05 stage reflected the loss of Nif moiety at maximum tem- –NH) perature 591 K and 818 K with mass loss of 75.76%. The thermal decomposition of [Ce(Nif)2(H2O)2](SO4)2 · and [UO2(Nif)2](NO3)2 2H2O complexes with the chemical formula (CeC24H22N6O20S2)and(UC24H22N8O20)take 1HNMR spectra of Nif ligand and its Zr(IV), Ce(IV) and place in one and two steps as indicated by DTG peaks U(VI) chelates are measured in Hexadeuterodimethyl sul- corresponding to the mass loss of coordinated and lat- foxide at 25 C utilizing Tetramethylsilane as a refer- tice water molecules and Nif molecule, respectively, giving ence. The chemical shifts of the various forms of pro- CeO2 and UO2 as a residue. The IR spectra of the final tons in the 1HNMR spectra of ligand and its chelates are products appear to be typical peaks of metal oxides as well seen in Table II. Spectrum of the Nif exhibited a singlet as the lack of chelated Nif ligand peaks. signals at 12.01 ppm and 10.19 ppm related to the NH

(H4) and OH (H9) groups, respectively,IP: 192.168.39.211 which are D On:2O- Thu,3.5. 30 ActivationSep 2021 22:45:07 Thermodynamic exchangeable [40, 41]. The singlet signalCopyright: at 8.38 American ppm is ScientificParameters Publishers Calculations assigned to the proton CH N (H3). NitrofuranDelivered protons byKinetic Ingenta parameters like E∗, H∗, S∗ and G∗ of the ther- emerged as doublet signals at 7.79 (H1) and 7.23 (H2) mogravimetric mechanism were mathematically assessed (Scheme 1), while aromatic signals were described as a using the coats-Redfern [42] and Horowitz-Metzger [43] Article four-line sequence at 7.80 (H5), 7.82 (H6), 6.69 (H7) and reported in Table IV. Higher activation energy (E∗) results 6.86 (H8) ppm. The signals of (NH) and (OH) of Zr(IV), illustrate the thermal stability of the complex [44]. The Ce(IV) and U(VI) chelates were detected at (12.04, 12.00, improvement in the G∗ value for the respective decom- 12.05) and (10.21, 10.20, 10.23), respectively, with no sub- position phases implies that the rate of elimination of the stantial difference with the parent Nif Ligand. The azome- following ligand will be lower than that of the preceding thine proton transfers downﬁeld, 8.57, 8.50 and 8.47 as one and that the TS∗ will increase from one point to

Table III. Maximum temperature Tmax ( C) and weight loss values of the decomposition stages for Nif, Zr(IV), Ce(IV) and U(VI) complexes.

Weight loss (%) Assignment

Compounds Decomposition T max ( C) Calc. Found Lost species + + + Nif. (C12H9N3O5) First step 311, 536, 649 99.97 99.74 4C2H2 HCN 3CO 2NO Total loss 99.97 99.74 – Residue · [ZrO(C12H9N3O5)2Cl]Cl 3H2 O First step 145 6.90 6.85 3H2O + + + + (ZrC24H24Cl2N6O14) Second step 318, 545 75.81 75.76 9C2H2 5CO Cl2 2NO 2N2O + Total loss 82.71 82.61 ZrO2 C Residue 17.28 17.20 + + + + [Ce(C12H9N3O5)2(H2O)2](SO4)2 First step 250, 537, 793 84.71 84.41 9C2H2 3N2O 6CO2 S2O 2H2O (CeC24H22N6O20S2) Total loss 84.71 84.41 CeO2 Residue 15.25 15.03 · [UO2(C12H9N3O5)2](NO3) 2H2O First step 80 3.67 3.52 2H2O + + (UC24H22N8O20) Second step 299, 472, 573 72.03 72.01 9C2H2 6CO2 4N2O Total loss 75.70 75.53 UO2 Residue 24.28 24.12

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· · Article Fig. 3. TGA and DTG diagrams for (A) Nif, (B) [ZrO(Nif)2Cl]Cl 3H2 O, (C) [Ce(Nif)2(H2O)2](SO4)2,(D)[UO2(Nif)2](NO3) 2H2 O.

IP: 192.168.39.211 On: Thu, 30 Sep 2021 22:45:07 another. This can be due to the structuralCopyright: rigidity American of the Scientificentropy withPublishers all complexes was observed to have null sign Delivered by Ingenta residual complex after the deletion of one or more lig- which also suggested its stability [44, 45]. Positive val- ands relative to the previous complex needing additional ues of H∗ mean that the method of decomposition is energy, TS∗, for its reordering prior to any change. The endothermic.

Table IV. Kinetic parameters operated for Nif and its complexes using Coats–Redfern (CR) and Horowitz–Metzger (HM).

Parameter

∗ ∗ ∗ ∗ Ts E A S H G Compounds (K) Method (KJ/mol) (s−1)(KJ/mol·K) (KJ/mol) (KJ/mol) Ra SDb

× 4 − Nif. (C12H9N3O5) 584 CR 43.18 7.60 10 0.152 43.41 94.12 0.988 0.158 HM 50.34 2.25 × 106 −0.124 50.57 91.94 0.985 0.194 809 CR 20.82 2.67 × 104 −0.164 17.81 87.70 0.985 0.206 HM 20.83 8.44 × 105 −0.255 17.82 141.11 0.984 0.219 × 4 − [ZrO(C12H9N3O5)2Cl] 418 CR 43.41 6.30 10 0.153 41.68 92.15 0.989 0.151 · × 5 − Cl 3H2 O HM 44.21 4.30 10 0.137 45.48 90.71 0.992 0.140 (ZrC24H24Cl2N6O14) 591 CR 130.09 3.00 × 107 −0.109 131.98 212.28 0.982 0.187 HM 146.32 7.76 × 108 −0.082 150.22 210.57 0.981 0.203 × 3 − [Ce(C12 H9N3O5)2 523 CR 38.12 6.50 10 0.172 35.38 92.21 0.999 0.030 × 4 − (H2O)2](SO4)2 HM 40.50 2.00 10 0.16 37.76 91.49 0.999 0.035 (CeC24H22N6O20S2) 810 CR 59.32 0.06 × 102 −0.237 52.48 247.86 0.997 0.082 HM 69.39 0.61 × 102 −0.219 63.55 243.91 0.998 0.079 × 3 − [UO2(C12H9N3O5)2] 353 CR 34.12 1.10 10 0.187 31.44 91.94 0.999 0.033 · × 4 − (NO3)2 2H2O HM 36.09 1.06 10 0.169 35.40 89.84 0.998 0.055 (UC24H22N8O20) 846 CR 196.72 8.53 × 109 −0.063 189.76 242.87 0.997 0.093 HM 229.38 5.70 × 1012 −0.009 232.41 240.20 0.998 0.091

Note: a = correlation coefﬁcients of the Arrhenius plots and b=standard deviation.

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3.6. Theoretical Study of Nif Ligand and Its Complexes 3.6.1. Geometrical Structure of Nif Ligand Nifuroxazide ligand geometric parameters while the atomic label scheme of the minimized geometry is shown in Figure 4 utilizing DFT computation view [44–47]. The two ligand molecules are quite planar, as expressed by all torsion angles that ranged between 0.00 and 180.00 in the case of the two ligands, all bond angles between atoms ranged between 105.58 and 131.58 , these results illustrate that almost all atoms have form of hybridization sp2. From the theoretical model, we ﬁnd that the Nifuroxazide molecule will act as a bidentate ligand via the methine group’s nitrogen atom (N13) and amide group’s oxygen atom (O16). In the Nifuroxazide molecule, the average bond distance of –C N bond ranges between 1.29Å and 1.33Å for C11-N13 and N13-N14, respectively and even the other bond distance of C15-O16 is 1.21Å. The distribution of charges on the donating nitrogen and oxygen atoms of the optimized Nif molecule geometry. There is a signiﬁcant built up of charge density of Nif molecule on nitrogen atom (N13), −0.186 and oxygen atom (O16), −0.477. All these values of charge densities enhancing the bidentate chelation of Nif ligand with metal ion through the one nitrogen atom of the methine group and oxygen atom of amide group. IP: 192.168.39.211 On: Thu, 30 Sep 2021 22:45:07 Copyright: American Scientific Publishers 3.6.2. Complexes Geometrical Structure Delivered by Ingenta A MO-treatment was applied to the Nifuroxazide molecule and its complexes Zr(IV), Ce(IV) and U(VI) in this study.

Article Fig. 5. Optimized geometrical structures of and Nif metal complexes The three metal ions Zr(IV), Ce(IV) and U(VI) chelated using B3LYP/Cep-31G. with the Nif ligand through two coordinated bonds, N13 and O16 [39]. Optimized complex structures of Zr(IV), Ce(IV) and U(VI) ions with Nif ligand (Fig. 5) revealed that all complexes had an octahedral with a 1:2 ratio of of the Nif ligand. In order to minimize the steric effect, the molecules of Nif were aligned in a perpendicular plane M:L, resulting a general formula of [M(Nif)2]. It was clear from the measurements that all the complexes were chem- to each other around the metal ion [39]. These complexes ically steady when compared their energy gaps with those are treated as octahedral structure, so the octahedral geometry of the Zr(IV) and Ce(IV) complexes tend to complete the six coordination sphere were achieved by one chloride anion and two water molecules, affording a molec- + +4 ular formula of [ZrO(Nif)2Cl] and [Ce(Nif)2(H2O)2] , respectively. By estimating the binding energy (BE), the stability of the optimized complexes was calculated, where the more negative BE correlates to the more stable complex [46]. Accordingly, both complexes are more stable than free ligand with BE values of −1002.93, −2587.90, −2632.64 and −2633.039 for Nif, Nif-Zr(IV), Nif-Ce(IV) and Nif-U(VI), respectively.

3.6.3. Global Reactivity Descriptors The various global chemical descriptors were measured according to on the Koopman’s theorem relations [39, 47– Fig. 4. The structure of minimized geometrical Nifuroxazide ligand 49] to obtain further knowledge on the stability of Nif using DFT calculations. ligand and its prepared complexes the data were tabulated

1078 Mater. Express, Vol. 11, pp. 1071–1083, 2021 Synthesis, spectral, molecular modeling, biological and antitumor studies Materials Express Alosaimi et al.

Table V. The calculated global chemical reactivity descriptors of the Nif and its complexes.

Compounds

Parameter Nif Zr(IV)-Nif Ce(IV)-Nif U(VI)-Nif

H −6.312 −8.956 −16.1362 −11.3428 L −3.064 −5.934 −15.4311 −9.1784 H –L 3.247 3.0213 0.70505 2.1644 IP 6.312 8.956 16.1362 11.3428 EA 3.064 5.934 15.4311 9.1784 4.688 7.445 15.7836 10.2606 1.532 1.510 8.4304 1.08220 −4.688 −7.445 −15.7836 −10.2606 7.173 18.348 14.7753 48.7188 S 0.326 0.3309 0.05930 0.000462 Nmax 4.12 5.93 1.91 10.48

in Table V. The energy gap and chemical hardness measurements indicate that the syntheized chelates were chem- ically active than its parent Nif ligand [46]. Highest occu- pied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy model predicts that electron delocalization observed in the Nif, Nif-Zr(IV), Nif-Ce(IV) and Nif-U(VI) with 3.247, 3.0213, 0.70505 Article and 2.1644 eV energy gap, respectively, as illustrated in Figure 6. Calculated energy gapIP: values 192.168.39.211 suggest that On: the Thu, 30 Sep 2021 22:45:07 Copyright: American Scientific Publishers synthesized complexes are more active than NifDelivered as they by Ingenta have a lower energy gap value relative to the free ligand. Fig. 6. Molecular orbital surfaces and energy levels of (A) · Nif, (B) [ZrO(Nif)2Cl]Cl 3H2O, (C) [Ce(Nif)2 (H2O)2](SO4)2,(D) [UO (Nif) ](NO ) ·2H O by using B3LYP/Cep-31G. 3.6.4. Antimicrobial Activity 2 2 3 2 The key purpose of any antimicrobial compound development is to suppress the microbe’s effect without any adverse effects on the health. The biological behavior complexes according to the equation given: of the metal complexes is regulated by numerous fac- tors [50–54]. The in vitro antimicrobial poteny of free Nif % Activity Index ligand and its complexes were tested for cultures of S. = Zone of inhibition by test compound diametre aureus, B. subtilis (G+), E. coli, S. paratyphi (G−), A. Zone of inhibition by standard diametre fumigatus, G. Candidum, S. racemosum relative to stan- ×100 (1) dard antibiotic, Gentamycin and ketoconazole are tabulated in Table VI. The data depicted in Figure 7 revealed The Zr(IV), Ce(IV) and U(VI) complexes had high that remarkable antimicrobial activities except for S. race- activity indexes than the free ligand [52]. The increased mosum the Nif and its U(VI) complex has no activities. antimicrobial effect of new prepared metal chelates was Zr(IV) complex was found to have the highest activ- explained by the concept of cell permeability of the tested ity against all the tested organisms relative to all com- microorganisms. In particular, the polarity of metal ions pounds. The sequence of inhibitory capacities growth is can be reduced through the partial sharing of the posi- : Zr(IV) > U(VI) > Ce(IV) > Gentamycin > Nif (for S. tive charge with the donor groups of the parent ligand and aureus), Zr(IV) Ce(IV) > Gentamycin > U(VI) > Nif (for as a consequence of overlap with the ligand orbitals. On B. Subtilis), Gentamycin > U(VI) > Ce(IV) > Zr(IV) > the other hand, the chelation process enhancing the delo- Nif (for E. coli), Gentamycin = U(VI) > Ce(IV) = calization of electrons above the chelate ring and hence Zr(IV) > Nif (for S. paratyphi), ketoconazole > Zr(IV) > can increase the lipophilic nature of the central ion. This U(VI) = Ce(IV) > Nif (for A. fumigatus), ketoconazole > increase in lipophilicity the penetration of the tested sub- Zr(IV) > U(VI) > Ce(IV) > Nif (for G. candidum)and stances inside the microorganisms cells [55]. ketoconazole > Ce(IV) > Zr(IV) (for S. racemosum). The Data are expressed in the form of mean±standard devi- activity indexes were determined for the Nif and its metal ation (S.D.) Statistical signiﬁcance P NSP not signiﬁcant,

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Table VI. Antibacterial, antifungal activities and the activity index (AI%) values of the synthesized compounds.

Microorganisms

Fungi Gram-positive Bacteria Gram-negative Bacteria A. fumigatus G. candidum S. racemosum S. aureus B. subtilis S. paratyphi E. coli

Inhibition Inhibition Inhibition Inhibition Inhibition Inhibition Inhibition Compounds zone AI zone AI zone AI zone AI zone AI zone AI zone AI

Nif 7 ± 0.50 41.18 4 ± 0.50 20 NA – 21 ± 1.01 87.5 19 ± 0.72 73.07 11 ± 0.26 64.70 8 ± 0.36 26.66 Zr(IV)-Nif 11.2+1 ± 0.10 65.88 8.9+1 ± 0.20 52.35 5.2+1 ± 0.41 32.5 31+2 ± 0.60 129.17 28+1 ± 0.88 107.69 16+1 ± 0.52 94.11 15+1 ± 0.00 50.00 Ce(IV)-Nif 8.2NS ± 0.25 48.23 7.9+1 ± 0.45 39.5 11.2+2 ± 0.40 70 25+1 ± 0.2 104.17 27+1 ± 0.55 103.84 15.9+1 ± 0.17 93.52 16.3+2 ± 0.30 54.33 U(VI)-Nif 11.3+1 ± 0.40 66.47 8.6+1 ± 0.7 43 NA – 29+1 ± 1.7 120.83 19.7NS ± 0.60 75.76 17+1 ± 0.1 100 24+3 ± 0.36 80.00 Standard Gentamycin – – – – – – 24 ± 1.4 100 26 ± 0.65 100 17 ± 0.5 100 30 ± 0.36 100 Ketoconazole 17 ± 0.50 100 20 ± 0.50 100 16 ± 0.62 100 – – – – – – – –

Note: NA: No activity; NS: Non-signiﬁcant.

P<0.05; P +1 P significant, P>0.05; P +2 P highly signif- and MCF-7 contrast to non-cancer cell line of MCF-10A. icant, P<0.01; P +3P very highly significant, P<0.001; The non-tumorigenic MCF-10A cell is utilized as a con- student’s-test (Paired). The P value was >0.05. All statis- trol in the selectivity analysis. The MCF-10A potency tical calculations were carried out using SPSS (1999). of the compounds analyzed is used to detect the Selec- tivity Index (SI). The data described as a fifty percent 3.6.5. Anticancer Studies compound concentration expected to suppress cancer cell In vitro study of the effectiveness of the free nifurox- growth (IC50) are plotted in Figure 8. All the compounds azide ligand and their metal compounds as possible anti- analyzed were shown to provide a certain inhibitory effect, cancer drug towards the tumorIP: cell 192.168.39.211 lines of HCT-116 On: Thu,the 30 Zr(IV) Sep 2021 chelate 22:45:07 in unique demonstrated greater efficacy Copyright: American Scientificfor antibreast Publishers and anticolonic tumor than other compounds. Delivered by Ingenta The minimum IC50 values sequence for MCF-7: Zr(IV) (7.01 gml−1) > Nif (9.2 gml−1) > U(VI) (11.50 g −1 > −1

Article ml ) Ce(IV) (20.20 gml ) and for HCT-116: Zr(IV) (6.07 gml−1) > Nif (7.99 gml−1) > U(VI) (16.99 g ml−1) > Ce(IV) (21.11 gml−1). The acute toxicity of Zr(IV) complex was not visible, so that it was advised to be used as a powerful anti-cancer drug, speciﬁcally in very low concentrations [39].

45 MCF-7 40 HCT-116 35 MCF-10A 30 25 20 values (µg/ml)

50 15 IC 10 5 0

Tested componuds Fig. 7. Biological activity statistical representation for Nif and its complexes. Fig. 8. Anticancer activity of Nif and their metal complexes.

1080 Mater. Express, Vol. 11, pp. 1071–1083, 2021 Synthesis, spectral, molecular modeling, biological and antitumor studies Materials Express Alosaimi et al.

4. CONCLUSIONS of Bisha, Saudi Arabia for funding this research work We introduced the synthesis and characterization of novel through Promising Initiative Project under Grant Number Zr(IV), Ce(IV) and U(VI) complexes containing Nif as (UB- Promising -4-1442). ligand. Based on the results of the physico-chemical and spectral techniques as well as the DFT measurements, the References and Notes data reveal that Nif acts as a bidentate at NO sites with 1. Edwards, D.I., 1986. Reduction of nitroimidazoles in vitro and DNA metal ions and that the metal complexes have octahe- damage. Biochemical Pharmacology, 35(1), pp.53–58. dral geometries. The presence of coordinated water was 2. Wardman, P., 1985. Some reactions and properties of nitro radical- confirmed by TGA and FT-IR studies. Using the Coats- anions important in biology and medicine. 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Received: 16 March 2021. Revised/Accepted: 11 May 2021. Article

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