Synthesis, characterization, in-vitro antimicrobial

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Mar 22, 2018 - Aderoju A. Osowole: Inorganic Unit, Department of Chemistry, ...... Advanced Inorganic Chemistry, 6th ed., John wiley, New York,. 1999.

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Research Article

Open Access

Festus Chioma*, Anthony C. Ekennia, Aderoju A. Osowole, Sunday N. Okafor, Collins U. Ibeji, Damian C. Onwudiwe, Oguejiofo T. Ujam*

Synthesis, characterization, in-vitro antimicrobial properties, molecular docking and DFT studies of 3-{(E)-[(4,6-dimethylpyrimidin-2-yl)imino]methyl} The First Decade (1964-1972) and Heteroleptic Mn(II), Co(II), naphthalen-2-ol Research Article and Zn(II) complexes Ni(II) Journal xyz 2017; 1 (2): 122–135

Max Musterman, Paul Placeholder

What Is So Different About provide evidence of six coordinated octahedral geometry for the complexes. The metal complexes’ low molar Neuroenhancement? Abstract: Heteroleptic divalent metal complexes [M(L) conductivity values in dimethylsulphoxide suggested Was ist so anders am Neuroenhancement? (bipy)(Y)]∙nH O (where M = Mn, Co, Ni, and Zn; L = Schiff that they were non-ionic in nature. The compounds https://doi.org/10.1515/chem-2018-0020 received November 23, 2017; accepted January 29, 2018.

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base; bipy = 2,2’-bipyridine; Y = OAc and n = 0, 1) have been displayed moderate to good antimicrobial and antifungal against S. aureus, P. aeruginosa, E. coli, B. cereus, synthesized from pyrimidine baseSelf-transformation ligand 3-{(E)-[(4,6- activities Pharmacological andSchiff Mental in Ethic P. mirabilis, K. oxytoca, A. niger, A. flevus and R. Stolonifer. dimethylpyrimidin-2-yl)imino]methyl} naphthalen-2-ol, Comparison The compounds also exhibited good antioxidant potentials 2,2’-bipyridine and metal(II) acetate salts. The Schiff base Pharmakologische und mentale Selbstveränderung im and its complexes were characterized by analytical (CHN with ferrous ion chelation and , 1-diphenyl-2-picrylethischen Vergleich elemental analyses, solubility, melting point, conductivity) hydrazyl (DPPH) radical scavenging assays. Molecular measurements, spectral (IR, UV-vis, 1H and 13C-NMR and docking studies showed a good interaction with drug https://doi.org/10.1515/xyz-2017-0010 MS) and magnetometry. The elemental analyses, Uv-vis targets used. The structural and electronic properties of received February 9, 2013; accepted March 25, 2013; published online July 12, 2014 spectra and room temperature magnetic moment data complexes were further confirmed by density functional theory calculations. Abstract: In the concept of the aesthetic formation of knowledge and its as soon as possible and success-oriented application, insights and profits without the *Corresponding Festus Chioma, Department of Chemistry, Keywords: Pyrimidinyl reference toauthors: the arguments developed around 1900. The main investigation also Schiff bases; 2-hydroxy-1Ignatius Ajuru University of Education, Rivers State, Nigeria, naphthaldehyde; antioxidant properties; molecular includes the period between the entry into force and the presentation in its current E-mail: [email protected]; Oguejiofo T. Ujam: Department of version. Their function as part of the literary portrayal anddocking; narrativeDFT. technique.

Pure and Industrial Chemistry, Faculty of Physical Sciences, University of Nigeria, Nsukka 410001, Enugu investigation, State, Nigeria, principal, period Keywords: Function, transmission, E-mail: [email protected] Anthony C. Ekennia: Department of Chemistry, Federal University DedicatedIkwo to Paul Placeholder Ndufu-Alike (FUNAI), P.M.B 1010, Abakaliki, Ebonyi State, Nigeria Aderoju A. Osowole: Inorganic Unit, Department of Chemistry, University of Ibadan, Oyo State, Nigeria The wide interest in pyrimidine-based compounds is Sunday N. Okafor: Department of Pharmaceutical and Medicinal mainly due to their applications in different areas such Chemistry, University of Nigeria, Nsukka 410001, Enugu State, Nigeria as pharmaceutical, agrochemical, and phytosanitary Collins U. Ibeji: Department of Pure and Industrial Chemistry, Faculty of industries [1,2]. Pyrimidine is known to be a vital Physical Sciences, University of Nigeria, Nsukka 410001, Enugubetween State, The main investigation also includes the period the entry into force and constituent of nucleic acids and employed as a synthetic Nigeria; Catalysis and Peptide Research Unit, School of Health Sciences, the presentation in its current version. Their function as part of the literary porPrecursor of Bioactive molecules. There are a wide spectrum University of KwaZulu-Natal, Durban 4041, South Africa trayal and narrative technique. Damian C. Onwudiwe: Material Science Innovation and Modelling of pharmacological active compounds of pyrimidine, and (MaSIM) Research Focus Area, Faculty of Agriculture, Science and its use in pharmaceuticals is becoming increasingly broad Technology, North-West University (Mafikeng Campus), Private Bag since the synthetic discovery of its substituted (amino, X2046, Africa; Department of Chemistry, SchoolOcean University, 2 Pei-Ning *MaxMmabatho, Musterman:South Institute of Marine Biology, National Taiwan hydroxyl, fluoro, etc.) derivatives. Pyrimidine derivatives of Road Mathematical and Physical Sciences, Agriculture, Keelung 20224, Taiwan (R.O.C), Faculty e-mail: of [email protected] have been reported to exhibit various pharmacological Science and Technology, North-West University Campus), Paul Placeholder: Institute of Marine Biology,(Mafikeng National Taiwan Ocean University, 2 Pei-Ning activities such as analgesic, anti-epileptic, antiviral, antiPrivate Bag X2046, Mmabatho 2735, South Africa Road Keelung 20224, Taiwan (R.O.C), e-mail: [email protected]

1 Introduction

1 Studies and Investigations

OpenAccess. Access. © and Placeholder, published Gruyter. This is is licensed under the Creative Commons Open ©���� 2018Mustermann Festus Chioma et al., published byby DeDeGruyter. Thiswork work licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives �.� License. Unauthenticated Attribution-NonCommercial-NoDerivatives 4.0 License. Download Date | 3/22/18 5:18 AM

Synthesis, characterization, in-vitro antimicrobial properties, molecular docking and DFT studies...

hypertensive minoxidil, antimycobacterial and potent phosphodiesterase inhibitors [3-6]. In addition, drugs with pyrimidinyl moiety are renowned chemotherapeutic agents and have been used in cancer and tumors treatment. For example, the small molecule multikinase inhibitors (sunitinib and sorafenib) are used for advanced renal-cell carcinoma treatment [7,8]. Also, 5-fluorouracil has been applied as an efficient tumor drug while a combination of 5-fluorouracil with bevacizumab has enhanced the treatment of metastatic colorectal cancer [9]. Furthermore, the pyrimidine derivative which is a potent and selective multi-targeted receptor tyrosine kinase inhibitor drug, pazopanib, (5-(4-[(2,3-dimethyl2H-indazoyl-6-yl)methylamino]-2-pyrimidinyl]amino-2ethylbenzenesulfon amide) has successfully passed the pilot phase in clinical trials and the development for use in renal cell cancer treatment [10]. Reportedly, Tyrosine kinases (2HCK) actively participate in the transduction of growth factor signals by catalyzing the phosphorylation of tyrosine residues in proteins. There are usually functional modifications of the proteins and mutations of this kinase can cause cancer [11]. Cryptogein (1LRI) is a small protein that has a sterol carrier activity as it acts as a sterol shuttle that helps the pathogen grow and complete its life cycle [12]. ATPase (2OBM) is a type III secretion system (T3SS) that is involved in the initial stages of selective secretion of specialized T3SS virulence effector proteins from the bacterial cytoplasm to the infected host cell, a process crucial to subsequent pathogenicity. In addition, zidovudine and pyrrolo-pyrimidine nucleoside derivatives are in use as anti-HIV and anti-hepatitis-c drugs [13]. The many therapeutic activities exhibited by pyrimidinyl containing drug/compounds could be attributed to their low toxicity and structural diversity [14]. Pyrimidine bioactive derivatives reportedly form stable Schiff bases which can be used as molecular metal ion chelators [15]. It has also been shown that the efficacy of pyrimidine bioactive molecules is enhanced in its coordination to metal ions [16-18]. Heteroleptic metal complexes of pyrimidinyl Schiff bases bearing hetero (N and O) atoms show high kinetic and thermodynamic stabilities, mixed chelation abilities in biological fluid systems and have the ability to prevent induced cellular oxidative stress damages [19-21]. The design and isolation of such complexes with enhanced pharmacological applications with low or non-toxic side effects have been a major challenge in drug discovery. These observations stimulated our efforts to investigate the ligating abilities of a new Schiff base derived from 2-hydroxy-1naphthaldehyde and 2-amino-4,6-dimithylpyrimidine towards the synthesis of mixed ligand complexes.

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This paper reports the synthesis and spectral characterization of divalent Mn, Co, Ni and Cu complexes with heterocyclic bidentate Schiff base derivative of 3-{(E)[(4,6-dimethylpyrimidin-2-yl)imino]methyl}naphthalen2-ol and 2,2’-bipyridine. The spectroscopic, bactericidal, fungicidal, antioxidant properties, and the interaction of the compounds with drug targets by molecular docking studies of the compounds were investigated. We will show how our compounds inhibit various biochemical functions of the proteins necessary for bacteria survival and oxidative process in the body. Computational theory methods (DFT) have been reported to give further understanding to the quantitative activity relationship (QSAR) and electronic properties of complexes [22,23] and their interaction with biological systems [24,25].

2 Experimental 2.1 Materials All analytical grade reagents/chemicals; 2-hydroxy1-naphthaldehyde, 2-amino-4,6-dimithylpyrimidine, 2,2’-bipyridine, Mn(CH3CO2)2·4H2O, Co(CH3CO2)2·4H2O, Ni(CH3CO2)2·4H2O and Zn(CH3CO2)2·2H2O and N(C2H5)3 were, purchased from Sigma Aldrich and used without further purification. The solvents (DMSO, dichloromethane, ethanol, methanol, acetic acid) were supplied as drum grades and distilled using standard methods [26] before use.

2.2 The apparatus and physical measurements The melting points of the ligand and complexes were determined using an open glass capillary tube on an Electro-thermal Temp-Mel melting point apparatus using open capillary tubes. Microanalysis for C, H and N was obtained on an Elementar instrument; Vario EL III CHNS analyzer. Infrared spectra of the compounds were recorded on a Perkin–Elmer Fourier-Transform Infrared Spectrum BX spectrophotometer using KBr disc in the range of 4000 to 350 cm−1. The NMR (1H and 13C) spectra of the ligand reference to tetramethylsilane (TMS) were recorded on Bruker Avance II 300 MHz NMR spectrophotometer at room temperature in 𝑑6-DMSO solvent. UV-vis spectra of the compounds were obtained at room temperature on a Lambda 25 UV/Visible double beam spectrophotometer in the range of 190–900 nm as a solid reflectance. The Unauthenticated Download Date | 3/22/18 5:18 AM

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Festus Chioma et al.

20 1 16

O OH

+

N H 2N

Acetic acid /Ethanol

N

∆/ R ef lu x/ 6 h

15 14 13

8

18 9

12

10 11

2

N

17

6

7

5

N N 3

4

19

OH 21

Scheme 1: Synthesis of Schiff base ligand, HL

molar conductance of the complexes was determined on the ELICO (CM-185) Conductivity Bridge in a 10−3M DMSO solution using a dip-type conductivity cell coated with a platinum electrode. The complexes were evaluated for magnetic susceptibility on a Johnson-Mathey magnetic susceptibility balance at room temperature. Diamagnetic corrections for the magnetic susceptibility were calculated using Pascal’s constants. Likewise, the metal ion contentpercentage ratios in the complexes were obtained volumetrically in the EDTA solution. The Electrospray Ionization Mass Spectrometry (ESI-MS) of the ligands were obtained by dissolving a small quantity of the material in 1–2 drops of dichloromethane, followed by dilution to about 2 mL using methanol. Mass Spectral data were recorded on a micrOTOF-Q II Mass Spectrometer in positive ion mode using pneumatically assisted electrospray ionization: capillary voltage, 2900 V; sample cone voltage, 15 V; extraction voltage, 1 V; source temperature, 80°C; desolvation temperature, 160°C; cone gas flow, 100 L h−1; desolvation gas flow, 100 L h−1; collision voltage, 2 V; MCP voltage, 2400 V. No smoothing of the data was performed and comparison of observed and calculated isotope patterns [27] was used in the ion assignment.

2.3 Synthesis 2.3.1 Synthesis of 3-{(E)-[(4,6-dimethylpyrimidin-2-yl) imino]methyl}naphthalen-2-ol, HL The pyrimidinyl Schiff base, 3-{(E)-[(4,6dimethylpyrimidin-2-yl)imino]methyl}naphthalen-2-ol (HL) was synthesized by a method previously reported in the literature for the synthesis of a closely related compound [16] according to (Scheme 1). 2-amino-4,6dimethylpyrimidine (2146 mg, 0.000017 mmol) dissolved in ethanol (10 mL) was carefully added to an ethanol (20 mL) solution of 2-hydroxy-1-naphthaldehyde (3000 mg, 0.000017 mmol). Acetic acid (2.5 mL) was added to catalyze the reaction and the stirring mixture was refluxed

for 6 h. After cooling in ice, a bright-yellow precipitate of the products was filtered under suction and recrystallized from ethanol and dried under a vacuum. Yield = 5060 mg, 59.30 %. mp: 194-196 oC; CHN (%)-Anal (Cald): C, 74.94 (73.89), H, 5.53 (5.47), N, 15.41, (15.23); IR(KBr) ν/cm-1: 3441b (OH), 1628s (C=N), 1593s, (C=C), 1537s (C-N), 1432s (C-C), 1290s (C-O), 981s (δC-H); UV/visible in cm-1 (Transition and molar absorptivity): 32362 (π→π* : є = 2.1 x 105 M-1 cm-1), 29019 (n→π* : є = 6.1 x 104 M-1 cm-1); 1H-NMR (300 MHz, DMSO-d6) δ ppm: 3.34 (s, 6H, CH3), 6.65-6.66 (d, 1H, H5); 7.83-7.84 (d, 1H, H17); 7.10-7.29 (d, 1H, H12);. 7.50-7.53 (d, 1H, H16); 7.64-7.66 (d, 1H, H15); 8.08 (s, 1H, H9); 7.31 (s, 1H, H10); 14.42 (s, 1H, OH); 9.55 (s, 1H, HC=N); 13C-NMR (75 MHz, DMSO-d6) δ ppm: 108.06 (C9); 141.34 (C10); 129.24-129.52 (C18,11); 116.93 (C17,12); 126.29 (C16,13); and 124.54 (C15,14); 153.4 (C8); 182.88 (C2); 168.74 (C4,6); 119.32 (C5) and 23.44 (C19,20). 2.3.2 Synthesis of Metal Complexes To a stirring solution of 3-{(E)-[(4,6-dimethylpyrimidin2-yl)imino] methyl}naphthalen-2-ol, HL(500 mg) in ethanol (20 mL) at 50 oC, Mn(II)(CH3COO)2∙4H2O (440 mg) dissolved ethanol (10 mL) was gradually added. 2,2’bipyridine (280 mg) was added in bits to the reaction mixture and buffered with 0.3 mL of [(C2H5)3N] to maintain a pH of 8-9 range. The resulting solution was refluxed for 6 h. After this, the precipitates of the product were filtered under suction, washed with dry ethanol and dried under vacuum in a desiccator over CaCl2. The Co(II), Ni(II) and Zn(II) complexes were synthesized from their acetate salts by the same procedure. The synthesized metal complexes were non-hygroscopic and stable at room temperature and reasonably soluble only in DMSO and DMF. [Mn(L)(bipy)(OAc)]: Yield: 590 mg, 75.20%; mp: 216-219oC; CHN (%): Anal (calcd): C, 63.90 (63.74), H, 4.62 (4.57), N, 12.85 (12.82); %metal (calcd) 10.23 (10.05); μeff(B.M.): 5.52; molecular weight(g/mol): 546.45; shade: yellowish brown; IR(KBr) ν/cm-1:1615s (C=N), 1571s (C=C), 1538s (C-N), 1362 (C-C), 1178s (C-O), 977m (δC-H), 540s (Mn-N), 497s (Mn-O); Electronic in cm-1 (transition and

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Synthesis, characterization, in-vitro antimicrobial properties, molecular docking and DFT studies...

molar absorptivity): 35087 (π→π*: є = 1.1 x 105 m-1 cm-1), 27100 (n→π* : є = 5.9 x 104 M-1 cm-1), 23809 (6A1g → 4T1g : є = 1.0 x 105 M-1 cm-1), 14970 (6A1g → 4T2g : є = 1.1 x 105 M-1 cm-1), 12840 (6A1g → 4Eg : є = 1.0 x 105 M-1 cm-1), molar conductance (ohm-1mol-1cm2): 4.72. [Co(L)(bipy)(OAc)]: Yield: 340 mg, 55.9%; mp: 310313oC; CHN (%): Anal (calcd): C, 63.40 (63.27), H, 4.63 (4.55), N, 12.88 (12.73); %metal (calcd) 10.37 (10.71); μeff(B.M.): 4.81; molecular weight (g/mol): 550.45; shade: pink; IR(KBr) ν/cm-1: 1616s (C=N), 1568s (C=C), 1528s (C-N), 1335s (C-C), 1183s (C-O), 830s (δC-H), 556s (Co-N), 499s (Co-O); Electronic in cm-1(transition and molar absorptivity): 31518 (π→π*: є = 1.1 x 105 M-1 cm-1), 29219 (n→π*: є = 5.7 x 104 M-1 cm-1), 22422 (4T1g→4A2g : є = 32 M-1 cm-1), 15015 (4T1g→ 4T1g(P) : є = 28 M-1 cm-1); molar conductance (ohm-1mol-1cm2): 8.96. [Ni(L)(bipy)(OAc)]: Yield: 450 mg, 46.70%; mp: 314316oC; CHN(%): Anal (calcd): C, 63.47 (63.33), H, 4.69 (4.54), N, 12.82 (12.74); %metal (calcd) 10.81 (10.67); μeff(B.M.): 3.16; molecular weight(g/mol): 550.0; shade: blueish brown; IR(KBr) ν/cm-1: 1616s (C=N), 1586s (C=C), 1527s (C-N), 1334s (C-C),1186s (C-O), 837s (δC-H), 539s (Ni-N), 457s (Ni-O); Electronic in cm-1(transition and molar absorptivity) 31830 (π→π* : є = 1.0 x 105 M-1 cm-1), 26018 (n→π*: є = 5.8 x 104 M-1 cm-1), 22220 (3A2g (F)→3T2g(F) : є = 43 M-1 cm-1), 18915 (3A2g(F)→ 3T1g(F) : є = 38 M-1 cm-1, 13280(3A2g(F)→3T1g(P) : є = 37 M-1 cm-1; molar conductance (ohm-1mol-1cm2): 5.63. [Zn(L)(bipy)(OAc)]∙H2O: Yield: 390 mg, 51.30%; mp: 289-292oC; CHN(%): Anal (Calcd): C, 60.64 (60.59), H, 4.83 (4.74), N, 12.22 (12.19); %metal (calcd) 11.44 (11.38); μeff(B.M.): 0.24; molecular weight(g/mol): 574.676; shade: bright yellow; IR(KBr) ν/cm-1: 3434b (OH), 1619s (C=N), 1589 (C=C), 1532s (C-N), 1334 m (C-C), 1188s (C-O), 835 m (δC-H), m 594 m (Cu-N), 452m (Ni-O); Electronic in cm-1(transition and molar absorptivity) : 31949 (π→π* : є = 1.0 x 105 M-1 cm-1), 26290 (n→π* : є = 5.6 x 104 M-1 cm-1), 23419 (M→L : є = 1 x 105 M-1 cm-1); molar conductance (ohm-1mol-1cm2): 9.71.

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Stolonifer (fungal species) using a well diffusion method of potato dextrose agar (PDA) as the medium. Ciprofloxacin and fluconazole were respectively employed as positive controls, and DMSO as a negative control for bacteria and fungi species. A 24 h old test 0.5 McFarland culture of each of the microbe was introduced to the germ-free agar medium. They were then poured into germ-free petri dishes, allowed to solidify and dried for about 15-20 min. With a sterilized metallic borer, 6 mm wells in each plate were bored in the agar media. The test compounds (12.5 µL of each prepared 250 µg/mL) prepared in DMSO were filled into the well using a micropipette. The bacterial and fungal plates were incubated for 24 h and 72 h at 35°C respectively. Activities were determined by evaluating the diameter of the zone displaying total inhibition (mm). Inhibition growths were compared with the positive controls. Each zone of inhibition was reported as an average of three independent experiments.

2.4.2 Antioxidant activities 2.4.2.1 Ferrous ion chelating assay The chelating ability of ferrous ion was determined by a procedure reported in literature [29]. 1 mL of FeSO4∙7H2O (400 μM in DMSO), 1 mL of 1,10-phenantroline (50 mg in 100 mL of DMSO) and 1 mL of the ligand test sample solution (1.0 mg/mL) was added to a solution containing 2 mL of DMSO, to form the reaction mixture. After about 15 mins of incubation at room temperature (301 K), absorbance of the mixture was measured spectrophotometrically at 546 nm. The blank contained the reaction mixture, except for the ligand test sample solution. � � � Ferrous chelatingability ability (%) = � � � × 100% Ferrous ion ion chelating � Ao: is the absorbance of the control at 30 min. Ao: is the absorbance of the control at 30 min. As: is the absorbance of the sample at 30 min. As: is the absorbance of the sample at 30 min.

2.4 Biological studies 2.4.1 Antimicrobial studies The Schiff base, 2,2’-bipyridine and the complexes were evaluated in vitro for antibacterial activity against some clinical isolates of Bacillus subtilis and Staphylococcus aureus(Gram positive species) and Klebsiella oxytoca, Escherichia coli, Proteus mirabilis and Pseudomonas aeruginosa (Gram negative species) using a well diffusion method [28] with Muller-Hinton agar nutrient (25 mL). Similarly, the antifungal activity of the compounds was investigated for Aspergillus niger, Aspergillus flevus and R.

2.4.2.2 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay scavenging assay The The 2,2-diphenyl-1-picrylhydrazyl radicalscavenging scavenging 2,2-diphenyl-1-picrylhydrazyl radical assay was used to assayantioxidant was used to evaluate the antioxidant activities of to the established activities of the synthesized compounds according the synthesized compounds according to the established test solution contained a mixture of 0.4 mL of various concentrations (50, 1 method. The test solution contained a mixture of 0.4 mL μg/mL) of the test compounds (ligands and their metal complexes) prepared in of various concentrations (50, 100, and 200 μg/mL) of 2.6 mL of a 0.025(ligands g/L 2,2-diphenyl-1-picrylhydrazyl in DMSO. The mixture the test compounds and their metal complexes) vigorously and with allowed in the dark at room temper prepared in DMSO 2.6 to mLincubate/equilibrate of a 0.025 g/L 2,2-diphenylminutes. Absorbance of eachThe mixture was obtained at 517 nm against a pre 1-picrylhydrazyl in DMSO. mixture was shaken vigorously allowed incubate/equilibrate in was the used to prepare t solution and of DMSO. Theto2,2-diphenyl-1-picrylhydrazyl darkAscorbic at roomacid temperature for 30 minutes. Absorbance served as the standard for all antioxidant of studies. All measur

carried out in triplicate, and the ability of the test compounds to chelate and scav

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The energy of the protein molecules and the coordination compounds wer

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Figure 1: Crystal structure of (A) hematopoietic cell kinase (2HCK)-quercetin complex, (B) ATPase (2OBM) from the type III secretion system (Force field MMFF94X). The binding of the ligand molecule with the pro and (C) Beta-cryptogein (1LRI)-cholesterol complex.

ure of 0.4 mL of various concentrations (50, 100, and 200

Figure 1: Crystalprepared structure of (A) (ligands and their metal complexes) in DMSO withhematopoietic

cell kinase (2HCK)-quercetin complex, (B) analyzed using MOE docking program to find the correct conformation (w ATPasein (2OBM) thewas type III secretion system and (C) Beta-cryptogein (1LRI)phenyl-1-picrylhydrazyl DMSO. Thefrom mixture shaken bonds,Density structureFunctional of molecule is not Studies rigid). Theory each mixture was obtained at 517 nm against a prepared 2.5.2 cholesterol cubate/equilibrate in the darkcomplex. at room temperature for 30 blank solution of DMSO. The 2,2-diphenyl-1-picrylhydrazyl

2.5.2 Density Functional Full optimization was Theory carriedStudies out for ligands and the standard for all antioxidant studies. All measurements complexes using density functional theory (DFT). Becke 3 diphenyl-1-picrylhydrazyl was used to prepare the standard. Fullcompounds optimization carried out for ligands and6-31+G(d,p) complexes using densit energy ofout the molecules and theof coordination were minimized using Yang par [30] was (B3LYP) in conjunction with were carried inprotein triplicate, and the ability the test Lee standard for all The antioxidant studies. All measurements were setBecke for all3atoms except metal ions. LANL2DZ basiswith 6-31+G(d compounds to chelate and scavenge ion and basis (DFT). Lee Yang parfor [30] (B3LYP) in conjunction e ability of the test compounds chelate and scavenge ferrous ferrous the Energyto minimization algorithm of Molecular Operating Environment (MOE, 2014) wasexcept used for for metal metalions. ions LANL2DZ (Mn, Co, Nibasis and set Zn).was B3LYP/ 2,2-diphenyl-1-picrylhydrazyl radical were determined set atoms used for metal ion hydrazyl radical were determined following the expression (Force field The binding of the ligand molecule with the protein was applied for 6-31+G(d,p)+LANL2DZ has molecule been successfully following theMMFF94X). expression below: Zn). B3LYP/ 6-31+G(d,p)+LANL2DZ has been successfully applied fo metal complexes and has been reported to be suitable [312,2-diphenyl-1-picrylhydrazyl scavenging effect analyzed MOE docking program to find the correct conformation (with the rotation[31-33]. of �� � using �� and Frequency has been reported to was be suitable Frequency × 100% scavenging effect % = 33]. calculation carried out to ascertain the calculation w mixture was obtained at 517 againstthe a standard. prepared blank was used to nm prepare Ascorbic acid served as

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2.5optimization Computational studies theM(II), M(II), Co(II), Co(II), Ni(II) Ni(II) and andZn(II), Zn(II),LLii,, LLjj are M(II) M(II)represent represent the are the coordinat Full was carried out for ligands and complexes using density functional theory the coordinated and n are the number of moles are the number ofligands, moles ofmthe ligands.

(DFT). Becke 3 Docking Lee Yang par [30] (B3LYP) in conjunction 6-31+G(d,p) basis set for all of thewith ligands. 2.5.1 Molecular

The changes in enthalpy Gibb’s free energy and in enthalpy Gibb’sCo, free energy atoms except for metal ions. LANL2DZ basis set was The usedchanges for metal ions (Mn, Ni and and entropy were also determ

and development2.5.1.1 is the Target ability Selection to identify and and Preparation select the entropy were also determined according to equation 1. All equation 1. All calculations were carried out using Gaussian 09 [34]. Zn). B3LYP/ been successfully applied for metal complexes have identified and selected the following drug targets calculations were carried out using Gaussian 09 [34]. The key step in6-31+G(d,p)+LANL2DZ drug design and(shown developmenthas is the ability

Ethical approval: The conducted research is not related to either human or animals use. have identified and selected the following drug targets They were loaded from protein data (http://www.rcsb.org). ascertain theFigure absence of imaginary (shown in 1); PDB code: 2HCK,frequencies. 2OBM and 1LRI to repare the proteins for docking. 9 study the antioxidant and antimicrobial activities of our compounds. They were loaded from protein data (http:// 𝑀 − 𝐿��𝑚���� (1) M(II) + 𝑚𝐿� +𝑛𝐿� +++ 3 Results and Discussion www.rcsb.org). Discovery studio was used to prepare the proteins for docking. M(II)The represent the M(II), Co(II), Ni(II) and Zn(II), L , Lj areElemental the coordinated ligands,conductance m and n energy of the protein molecules and the i 3.1 and molar 8 coordination compounds were minimized using the are the number of moles of the ligands. analyses Energy minimization algorithm of Molecular Operating Environment (MOE, 2014) (Force field MMFF94X). The The elemental (C, H, N) analyses results were in good The changes in enthalpy Gibb’s free energy and entropy were also determined according to binding of the ligand molecule with the protein molecule agreement with the proposed chemical composition of equation 1. All using calculations were carried Gaussian 09 [34]. Also, the elemental analysis indicated was analyzed MOE docking programout to using find the the compounds. correct conformation (with the rotation of bonds, structure the coordination of the ligands (HL and 2, 2’-bipy) of molecule is not The rigid). in either a 1:1:1 human molar or ratio. The complexes were generally Ethical approval: conducted research is not related to animals use.

select and the antimicrobial appropriate drug target(s). We K, 2OBM and 1LRItotoidentify study theand antioxidant

Ethical calculation approval: The was conducted research and has been reported to be suitable [31-33]. Frequency carried out istonot related to either human or

9

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Synthesis, characterization, in-vitro antimicrobial properties, molecular docking and DFT studies...

anhydrous, except for the Zn(II) complex which had a single H2O molecule outside its coordination sphere. The molar conductance measurements obtained in DMSO for the divalent metal complexes were within 6.24–15.2 ohm−1cm2mol−1. The values indicated a non-ionic nature for the complexes, as values above 23 ohm−1cm2mol−1 and 90 ohm−1cm2mol−1 w were regularly estimated for 1:1 and 2:1 electrolytes respectively [35,36].

3.2 FTIR spectra studies Significant infrared bands were tentatively assigned compared to literature reports of similar systems[37-39]. The IR spectrum of the ligand displayed a broad absorption band at 3441 cm-1 which was assigned to intramolecular H-bonding vibration (ʋ O-H...N) of an enol tautomer which is common in Schiff bases bearing hydroxyl groups [40]. The band (ʋO-H...N) was not observed in the spectra of the metal(II) complexes indicating deprotonation of the hydroxyl group and a possible coordination of the ligand through the deprotonated naphthol oxygen atom to the metal ions. The broad band at 3434 cm-1 in the spectrum of the Zn(II) complex was attributed to the OH group of water molecules. The sharp to medium bands that appeared between 3013 and 3001 cm−1 in the spectra of the metal(II) complexes were assigned to stretching vibrations of the (Ar–H) group in the aromatic rings while the bands due to the aliphatic C-H groups of the methyl substituents were observed in the range of 2929-2913 cm-1. The spectra of the metal(II) complexes showed that the absorption band at 1628 cm-1 in the spectrum of the ligand that was assigned to the stretching vibration of the imine moiety shifted to a lower/higher frequency within the range of 1614-1667 cm-1, indicating an involvement of the imine nitrogen atom in coordination with the metal ions [41]. Furthermore, the characteristic stretching vibration bands of C=N and C=C groups were observed as lone bands in the spectra of the metal(II) complexes but shifted to lower/higher frequencies by ±10-30 cm-1 with almost equal intensity as those in the spectrum of the Schiff base around 1628 and 1639 cm-1; and 1593 and 1580 cm-1 respectively. This is supportive of the involvement of an imine N donor atom of C=N in complexation to the metal ions while the latter was indicative of an aromatic ring conjugation which is an effect of coordination [42, 43]. The splitting of the bands of the imine ν (C=N) group in the spectra of the metal(II) complexes indicated Fermi resonance [44]. The band at 1290 cm-1 in the spectrum of the Schiff base ligand that was attributed to v (C-O) were significantly shifted to higher or lower wavenumbers in the spectra of the metal complexes

 189

as a consequence of metal coordination. The appearance of new bands around 499-452 cm-1 and 594-533 cm-1 which were assigned to vibration bands of ν (M-O) and ν (M-N) bonds in the spectra of the metal complexes [45,46] were indicative of the involvement of the enol O and imine N atoms in coordination with the metal ions.

3.3 Nuclear Magnetic Resonance (1H- and 13 C-) spectral analysis The 1H-NMR spectrum of 3-{(E)-[(4,6-dimethylpyrimidin2-yl)imino]methyl}naph thalene-2-ol, HL (supplementary material SM1) which showed sharp singlet at 3.34 ppm was assigned to the methyl protons on the pyrimidine ring, while the proton on C5 resonated at 6.66 ppm. The napthalene ring protons (H17, H12, H16 and H15) were observed as doublets at 7.83-7.84, 7.10-7.29, 7.50-7.53 and 7.64-7.66 ppm and singlets (H9 and H10) at 8.03 ppm and 7.31 ppm respectively. Furthermore, the appearance of resonance signals at 14.42 ppm due to a phenolic proton and at 9.55 ppm due to imine moiety proton in the ligand spectrum corroborates the presence of OH and formation of the ligand. The appearance of a peak at 9.55 ppm was due to a proton of the imine moiety in the ligand and was indicative of the formation of a Schiff base ligand. Carbon-13 NMR data reveals the carbon skeleton of organic compounds which support the assignment of the hydrogen atoms [47]. The resonance signals typical of the napthalene C11-C20 atoms were observed at 108.06, 141.34, 129.5, 126.29, 124.54 and 119.32 ppm respectively. Also, the signal at 153.4 was consistent with the imine carbon atom (C8), while observed resonance signals at 182.88 ppm, 168.74 ppm and 116.8 ppm were respectively attributed to C2, C4,6 and C5 atoms of the pyrimidine moiety, and C19,20 resonated as a singlet at 23.44 ppm.

3.4 Electrospray Ionization Mass Spectrum (ESI-MS) Data The ESI-mass spectrum (see SM2) of 3-{(E)-[(4,6dimethylpyrimidin-2-yl)imino]methyl} naphthalen2-ol ligand was obtained to ascertain stoichiometric compositions and the fragmentation pattern of the Schiff base ligand. The ligand mass spectrum showed two main pathways of fragmentation with a base peak m/z, 278.12 consistent with the observed formula weight (278.85) of the synthesized ligand. This corroborates the condensation of 2-hydroxy-1-napthaldehyde and 2-amino4,6-dimethylpyrimdine to form the HL ligand. The peaks Unauthenticated Download Date | 3/22/18 5:18 AM

m/z 280.11 which could be attributed to extra mass units, a consequence of carbon-13 presence and another medium peak at 276.12 due to the loss of protons. Figure 2 and Scheme

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at m/z 250.17, 193.66 and 142.92 were due to a loss of the COH, NC2H2O and C2N2H moieties while the peak at m/z 124.81 was probably due to the loss of OH respectively. Furthermore, the spectrum displayed a L+1 peak at m/z 279.24. Also a low intensity peak was observed at m/z 280.11 which could be attributed to extra mass units, a consequence of carbon-13 presence and another medium peak at 276.12 due to the loss of protons. Figure 2 and Scheme 1 shows the mass spectrum and the fragmentation pattern of 3-{[(4,6-dimethylpyrimidin-2-yl)imino] methyl} napthalen -2-ol respectively.

1 shows the mass spectrum and the fragmentation pattern of 3-{[(4,6-dimethylpyrimidin-2yl)imino] methyl}napthalen -2-ol respectively.

11

9

13 14

17 18

12

7

20

5 N

16

4

3

OH

CH3

6

CH3

15

17

18

12 13

N

6

2

N

1

8

N

9

14

7

10

5 4

CH3 19

3

OH

11

21

278.1283

127.0719 204.8169 154.2831 231.9016

Figure 2: Enlarged Mass Spectrum of 3-{(E)-[(4,6-dimethylpyrimidin-2-yl)imino]methyl}

Figure 2: Enlarged Mass Spectrum of 3-{(E)-[(4,6-dimethylpyrimidinnaphthalen-2-ol (See SM2). 2-yl)imino]methyl} naphthalen-2-ol (See SM2).

3.5 Electronic spectra and magnetic moment measurements The UV-Vis spectra of the compounds displayed intraligand (𝜋∗←n, 𝜋∗←𝜋) and intra/inter metal complex (d-d, L→MCT) transitions. The assignment of geometry to the metal complexes was (Figure 3) on the basis of electronic absorptions and room temperature magnetic moment measurements [15,48]. Two absorption bands were observed in the ultraviolet spectrum of the Schiff base ligand around 32362 and 29019 cm-1 which were consistent with 𝜋∗←n and 𝜋∗←𝜋transitions. These bands were also observed at lower wavenumbers in the spectra of the metal(II) complexes due to complexation of the ligands (HL and 2,2’-bipyridine) to the metal ions. Mn(II) complexes are usually characterized by high spins and their electronic spectra are characterized by weak spins and no parity transitions. The electronic transitions often arise from the presence of a 6S ground term with an upper quartet (4G) state. High spin manganese(II) complexes exhibit three weak bands due to 6A1g→4T2g(G), 6 A1g→4Eg(G), and 6A1g→4T1g transitions [49] in an octahedral field. The Mn(II) complex in our study exhibited three weak bands at 12840 cm-1, 14970 cm-1 and 23809 cm-1 and were assigned to 6A1g→4Eg(G), 6A1g→4T2g(G) and 6A1g→4T1g transitions respectively. An octahedral geometry was assigned to the Mn(II) complex. The assignment of a high spin octahedral geometry to the [Mn(L)(bipy)(OAc)] complex was consistent with an observed magnetic moment value of 5.52 B.M [50,51] that approximated the spin only magnetic moment of 5.90 B.M due to the absence of orbital contribution when 6A ground term was involved [52]. The UV spectrum of the Mn(II) complex showed two absorptions at 27100 cm-1 and 35087-31545 cm-1 and was assigned to 𝜋∗ ← n and 𝜋∗← 𝜋 transitions respectively. High spin Co(II) complexes with 4T2(t25e2) and2E(t26e1) configurations usually experience spin crossover equilibrium [53]. In the visible spectrum of the Co(II)

N

2

N

8

10

CH3

1

H 15 16

CH 3

N

CH 3

+

N N

CH 3

+

N

-OH N

17.006

N

CH 3

OH

-C2H 6 31.008

-C 2H6OH 47.076 +

N

+

N

N

N

N

N

-C 4N2H 73.088

-C3H 37.038 N

+

+

N

N -C 2N3H

-HCN 27.038

67.088 +

Scheme 2: Fragmentation pattern of 3-{(E)-[(4,6-dimethylpyrimidin12 2-yl)imino]methyl}naph thalen-2-ol ligand.

complex, two absorption bands at 17182 cm-1 and 12903 cm-1 were observed in the visible spectrum of the Co(II) complex studied, while the absorption band around 5000–7000 cm-1 was not seen as it tailed into the infrared section. The observed absorption bands were typical of 4 T1g→4A2g (υ1) and 4T1g→4T1g(P) (υ3) transitions consistent of a d7(high spin) octahedral system bearing a 4F ground term [52-54]. The non-appearance of the band due to the υ2 transition in the visible region of the spectrum was due to the band feeding into the infrared region [52]. Magnetic moment values of 4.20-4.60 B.M were expected for regular tetrahedral d7 cobalt(II) complexes [55]. High spin octahedral Co(II) complexes displayed magnetic moment values that were close to that of Co2+ high spin tetrahedral complexes, but were distinguished by the magnitude of µeff deviations from the spin only value of 4.7-5.2 B.M [56]. The assignment of high spin octahedral geometry to the synthesized Co(II) complex was validated by the calculated effective magnetic moment value of 4.81 B.M since µeff of divalent cobalt complexes were likely to Unauthenticated Download Date | 3/22/18 5:18 AM

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 191

Should be: be higher than the spin-only value for the six coordinate octahedral complexes owing to orbital contributions [53]. The ultraviolet spectrum of the Co(II) complex showed two bands at 31518 and 29219 cm-1. The former was assigned to the 𝜋∗←𝜋 transition, while the latter was consistent with 𝜋∗←n transition. High spin Ni(II) complexes are generally expected to exhibit three d-d transitions in the visible region. The Ni(II) complex showed three visible spectral bands at 13280, 18915 and 22220 cm-1 which were assigned to 3A2g(F)→3T2g(F), 3 A2g(F)→3T1g(F) and 3A2g (F)→3T1g(P) transitions respectively [57,58]. This assignment was consistent with octahedral Ni(II) complexes. The magnetic susceptibility measurements of Ni(II) complexes gave values less than zero for square [M = Mn. Co and Ni, n = o; Zn, n = 1] planar geometry due to their diamagnetic nature. The Ni(II) complex of tetrahedral geometry paramagnetic in Figure 3: Proposed structure of the metal(II) complexes. Pagevalues 8/linewithin 15 nature possessed magnetic moments (µ eff ) 3.20-4.20 B.M [59]. A magnetic momentIs: value of 3.16 B.M 3.6.2 Electronic andmetal thermodynamic analysis Figure 3: Proposed structure of the (II) complexes was observed for the Ni(II) complex in our study. The value Should be: Figure 3: Proposed structure of the metal(II) complexes conformed to a high spin octahedral geometry as octahedral Molecular polarizability and electron densities are related Ni(II) complexes were expected to have magnetic moments to the frontier molecular orbitals [62,63] (Figure 5). The within 2.90–3.30 BM. Two absorption bands were observed tendency for a system to donate electrons is linked to in the ultraviolet spectrum of the synthesized Ni(II) complex the EHOMO and overall the higher the EHOMO energy (less and were assigned to 𝜋∗← n (26018 cm-1) and 𝜋∗←𝜋 (31830 negative), the greater the ability to donate electrons [25,64]. As shown in Table 1, all the metal(II) complexes possess cm-1) transitions. The electronic spectrum of the Zn(II) complex did low ∆E (ELUMO - EHOMO) gap indicating high reactivity. The not show any d-d transition band in its visible spectrum Mn(II) complex has a higher tendency to donate electron which was expected; but instead, a M→L charge transfer to an electron accepting species compared to other studied transition at 23419 cm-1 [56]. The intra-ligand bands systems. The Co(II) complex has the lowest tendency observed in the UV spectrum at 26290 cm-1 and 31949 to accept an electron; this is also evident in the ∆E gap cm-1 region were due to 𝜋∗← n and 𝜋∗←𝜋 transitions. indicating a lower tendency for electrons to move to the Zn(II) complexes with 3d10(t2g6eg4) configuration displayed excited state. Thermodynamic parameters of complexes are magnetic moments expected for zero unpaired electrons. The synthesized Zn(II) complex exhibited a magnetic presented in Table 2. Thermodynamic stability of susceptibility value of 0.24 B.M. which was supportive complexes is determined by the magnitude (more of its diamagnetism nature [60]. The Zn(II) complex was negative) ∆G [65]. ∆G is also a measure of the spontaneity of a complex formation [25,65]. The high negative ∆G value assigned an octahedral geometry of all metal complexes shows spontaneity of complex formation. Comparing metal complexes, the magnitude of ∆G for the Mn(II) complex is larger compared to the 3.6 DFT Computational analysis Ni(II) complex, Co(II) complex and Zn(II) complex. This shows that the Mn(II) complex is thermodynamically 3.6.1 Optimized geometries more stable. Negative ∆H for all metal complexes suggests The optimized geometries of studied complexes are shown the formation of energetically favorable noncovalent in Figure 4 with core bond length in Ångström. The bond interactions between atoms [65]. Entropy is denoted as the distance of Mn(II), Ni(II) and Co(II) complexes are quite degree of disorderliness of a system [66]. The increase in similar with about 0.01-0.05 Å except for that of Zn(II)-N negative entropies are in the order of Co(II) ˂ Zn(II) ˂ Ni(II) ˂ which is about 1-2 Å different from others. Metal-ligand Mn(II). This reflects the degree of freedom of ligand-metal bond distances obtained agreement with similar bond complex formation. distances reported in literature [25,61].

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Table 2: Thermodynamic parameters of metal complexes +LANL2DZ. Complex

∆G (kJ/mol)

∆H (kJ/m

[Mn(L)(bipy)(OAc)]

-822.23

1891.17

[Co(L)(bipy)(OAc)]

-734.22

-1140.82

[Ni(L)(bipy)(OAc)]

-411.52

-1822.52

[Zn(L)(bipy)(OAc)].H2O

-602.44

-1542.11

Allobtained energies were Figure 4: Optimized structures of metal-ligand complexes with bond distances at B3LYP/

corrected for zero-point energy contri

Figure 4: Optimized structures of metal-ligand complexes with bond distances obtained at B3LYP/ 6-31+G(d,p)+LANL2DZ. 6-31+G(d,p)+LANL2DZ.

3.8.2 Electronic and thermodynamic analysis

Table 1: Calculated frontier molecular orbitals energies (EHOMO, EUMO, 3.6.3 bond orbital (NBO) analysis 3.8.3Natural Natural bond orbital (NBO) ∆E) and dipole moments ofand metal complexes obtained using B3LYP/ Molecular polarizability electron densities are related to the frontier molecular orbitals 6-31+G(d,p)+LANL2DZ.

analysis

and perturbation theory analysis of the [62,63] (Figure 5). The tendency for a system to donate electrons is linked the EHOMO The order Thetosecond second order perturbation theory analysis overall the higher the EHOMO the greater the ability to matrix donate electrons Fock in the NBO basis was calculated to determine Complex E energy E (less negative), ∆E Dipole moment HOMO

LUMO

of the Fo

calculated determine the donor-acceptor (eV)1, all (eV) (Debye) possess low the between ligand interactions and [25,64]. As shown in Table the metal(eV) (II) complexes ∆E donor-acceptor (ELUMO - to EHOMO ) interactions

bet

[Mn(L)(bipy)(OAc)] -5.45 -5.32 0.17 11.21 metals. This was carried out tothe understand electron gap indicating high reactivity. The Mn (II) complex has a higher tendency to donate carried outelectron to understand electronthe delocalization betwe [Co(L)(bipy)(OAc)] -7.84 -6.80 1.04 10.34 delocalization between ligand and metal [67]. This is to an electron accepting species compared to other studied systems. The Co (II) complex has [Ni(L)(bipy)(OAc)] -6.23 -5.68 0.55 11.01 calculatedasasthe thehighest higheststabilization stabilization energy, E2 from secon calculated energy, E2 from the lowest tendency to evident in the ∆E gap indicating a lower O accept -7.31an electron; -6.73 this 0.56is also 10.99 [Zn(L)(bipy)(OAc)]∙H 2

tendency for electrons to move to the excited state. Table 2: Thermodynamic parameters of metal complexes obtained at B3LYP/ 6-31+G(d,p) +LANL2DZ. 16 Complex [Mn(L)(bipy)(OAc)]

∆G (kJ/mol) -822.23

∆H (kJ/mol) 1891.17

∆S (J/mol/K) -1790.74

[Co(L)(bipy)(OAc)]

-734.22

-1140.82

-1008.33

[Ni(L)(bipy)(OAc)]

-411.52

-1822.52

-1762.11

[Zn(L)(bipy)(OAc)].H2O

-602.44

-1542.11

-1480.62

All energies were corrected for zero-point energy contributions

second perturbation theory [68]. This is defined by the defined by the equation: equation:

𝐸 � = ∆𝐸𝑖𝑗 = 𝑞𝑗

𝐹(𝑖,𝑗)� 𝜀𝑗 �𝜀𝑖



(2)

Where qj is the donor orbital occupancy, ei and ej are donorand orbital 𝜀𝑖 offand 𝜀𝑗 are dia Where matrix 𝑞𝑗 is the diagonal elements F(i, j) occupancy, is the NBO Fock diagonal matrix element. is the NBO Fock off-diagonal matrix element. According to Reed et al. [69] NBO terms the wave functions based on the Lewis occupied and non-Lewis According localized to Reedorbitals et al. [69] NBO the ofwave functi unoccupied [69] and theterms strength electron delocalization associated with E2 derived from and non-Lewis unoccupied localized orbitals [69] and the i and j Fock matrix. A strong intramolecular charge transfer is associated a highfrom E2 value [63,70]. Results associated with E2with derived i and j Fock matrix. A stro

is associated with a high E2 value [63,70]. Results presente

Unauthenticated and Ni (II) had a stronger intramolecular charge transfer wi Download Date | 3/22/18 5:18 AM

for Mn (II) as the highest due to electron delocalization

[Ni(L)(bipy)(OAc)]

-6.23

-5.68

0.55

11.01

[Zn(L)(bipy)(OAc)]∙H2O

-7.31

-6.73

0.56

10.99

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 193

17

Figure 5: Frontier molecular orbital (HOM-LUMO) diagram showing the distribution of

Figure 5: Frontier orbital (HOM-LUMO) diagram showing the distribution of electron density obtained by B3LYP/ electron densitymolecular obtained by B3LYP/ 6-31+G(d,p)+LANL2DZ. 6-31+G(d,p)+LANL2DZ.

Thermodynamic parameters of complexes are presented in Table 2. Thermodynamic stability of complexes is determined by the magnitude (more negative) ∆G [65]. ∆G is also a measure of the spontaneity of a complex formation [25,65]. The high negative ∆G value of all metal complexes shows spontaneity of complex formation. Comparing metal complexes, the magnitude of ∆G for the Mn (II) complex is larger compared to the Ni (II) complex, Co (II)

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perturbation stabilization energies presented in Table 3 suggests that Mn(II)Table and Ni(II) a Table 3: Second-order 3: had Second-order perturbation energies corresponding to the corresponding to the majorstabilization intermolecular charge transfer 2 stronger intramolecular charge transfer with an E value interaction (Donor-Acceptor) of ligand-metal complexes obtained intermolecular transfer interaction (Donor-Acceptor) of ligand-metal com of 164.44 kcal/mol for Mn(II) as the highest due to electroncharge B3LYP/ 6-31+G(d,p)+LANL2DZ. delocalization around the ligand (HL). obtained Figure 6 B3LYP/ shows 6-31+G(d,p)+LANL2DZ. atoms involved in charge transfer. This also agrees with Donor Acceptor E2 (kcal/mol) Donor Acceptor E2 (kcal/mol) the result obtained for frontier molecular orbitals (∆E [Mn(L)(bipy)(OAc)] [Mn(L)(bipy)(OAc)] gap). LP* (Mn) 74 LP(O * )

3.7 Antimicrobial Studies

LP(O37) LP(O38) LP(N30) LP(O37)

37 LP (Mn) LP* (Mn) LP(O * 38) LP (Mn) * 30) LP* (Mn) LP(N LP (Mn) * ) σ*(O13-Mn) 37 -Mn) σLP(O (O13 [Co(L)(bipy)(OAc)] [Co(L)(bipy)(OAc)] ) LP* (Co) LP(O 37 LP* (Co) * ) LP* (Co) LP(O 38 LP (Co) * ) LP* (Co) LP(N(Co) 30 LP * ) σ*(O13-Co) 37 -Co) σLP(O (O13 [Ni(L)(bipy)(OAc)] [Ni(L)(bipy)(OAc)] * ) LP* (Ni) LP(O LP (Ni) 37 * ) LP* (Ni) LP(O(Ni) LP 38 * ) LP* (Ni) LP(N LP (Ni) 30 * ) σ*(O13-Ni) σLP(O (O13 37 -Ni) [Zn(L)(bipy)(OAc)].H2O [Zn(L)(bipy)(OAc)].H2O * ) LP* (Zn) LP(O(Zn) LP 37 * ) LP* (Zn) LP(O(Zn) LP 38 * LP ) LP* (Zn) LP(N(Zn) 30 * σLP(O (O13 )-Zn) σ*(O13-Zn) 37

74 48.22 48.22 164.44 164.44 30.32 30.32

The mean inhibitory activities of the ligands and their 43.64 LP(O ) 4 43.64 complexes against the tested microbes are shown in37 Table 31.11 and Table 5. Broad-spectrum antibacterial activities LP(Oagainst 31.11 38) 32.01 pathogenic microbes have been reported forLP(N enol30Schiff ) 32.01 0.81 bases [71,72]. Coordination between biologically LP(O37active ) 0.81 Schiff bases and metal ions are important components in the design of new metal-based therapeutic agents The 63 LP(O[71]. 63 37) synthesized compounds exhibited significant activities 36.00 LP(O38) 36.00 against the screened microbes with variable grades of 155.06 LP(N30) 155.06 inhibitory properties. All the microbes were susceptible 27.96 LP(O37) 27.96 to the Schiff base ligand (3-{(E)-[(4,6-dimethylpyrimidin2-yl)imino] methyl}naphthalen-2-ol) and 2,2’-bipyridine) 38.77 38.77 37) mm with inhibitory zones of 5.5–17.0 mm and LP(O 8.5-26.0 28.61 28.61 38) the respectively. The sensitivities of the microbesLP(O towards LP(N ) 34.66 34.66 Schiff base could be attributed to the presences of30–C=N) 11.88 11.88 moiety, chacoginde and nitrogen donor atomsLP(O and 37 phenol group which have been reported to improve antibacterial/ antifungal activities [73]. The metal(II) complexes were generally more active than the ligands and in some cases had comparable activity to those of the positive control drugs. The Co(II) complex had inhibitory zones of 16.0-21.5 mm against all the tested microbes’ with the exception of P. mirabilis. Additionally, Mn(II) and Ni(II) complexes showed inhibitory effects greater than that of the ligands against only P. aeruginosa and P. aeruginosa respectively. The increased sensitivity of the complexes might be attributed to hyper conjugation of the coordinated aromatic system and enhanced liposolubiliity [74] which leads to a decrease in the polarity of metal ions and raises delocalization of π-electrons over the complex ring [20]. Permeation of the metal(II) complexes through the lipid layers of the microbial membrane was favored by the latter, thus improving antimicrobial activity [20,75]. Furthermore, chelation Figure 6: Representation of intermolecular charge transfer for the Figure 6: Representation of intermolecular charge transfer for the complexes obtained also deactivated various cellular enzymes, essential for in complexes obtained from the Fock-matrix in NBO analysis.  the Fock-matrix NBO analysis. The curved arrows (a, b, c and The d) represent the dir curved arrows (a, b, c and d) represent the direction* of charge metabolic pathways in the microorganisms [76]. The Co(II) of charge transfer from lone pair to antibonding (LP→* LP and σ*).2+M = Co2+, Zn2+ from lone pair to antibonding (LP→ LP and σ*). M = Co , 2+ complex displayed the best antibacterial of all transfer . Mnactivity Zn2+, Ni2+, Mn2+. other synthesized compounds and compared favorably to 20 the activity of ciprofloxacin against some microbes. The

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 195

Table 4: Antibacterial data of ligand (HL) and the metal(II) complexes. Escherichia coli 17.0±2.8

Klebsiella oxytoca 15.0±0.0

Pseudomonas aeruginosa 12.0±2.8

Staphylococcus aureus 16.0±1.4

Proteus mirabilis

HL

Bacillus cereus 5.5±2.1

bipy

15.5 ± 0.7

12.0 ± 2.8

26.0 ± 2.8

8.5 ± 0.7

17.0 ± 4.2

19.5 ± 2.1

[Mn(L)(bipy)(OAc)]

15.0±1.4

10.0±1.4

15.5±2.1

21.0±2.8

9.5±0.7

13.5±2.1

[Co(L)(bipy)(OAc)]

16.0±0.0

20.0±1.4

21.5±3.5

16.0±2.8

18.0±2.8

11.0±2.8

[Ni(L)(bipy)(OAc)]

12.5±2.1

14.0±2.8

17.5±3.5

18.5±1.7

9.5±2.1

16.0±2.8

[Zn(L)(bipy)(OAc)]∙H2O

Compounds

14.0±2.8

16.0±0.7

14.0±2.8

8.5±0.7

12.0±1.4

5.5±0.7

13.5±0.7

+

33.0 ± 3.5

32.0 ± 1.4

36.0 ± 2.8

26.5 ± 0.7

29.0 ± 2.1

23.0 ± 1.4

-DMSO

0.0±0.0

0.0±0.0

0.0±0.0

0.0±0.0

0.0±0.0

0.0±0.0

Ciprofloxacin

Table 5: Antifungal result for ligand (HL) and the metal(II) complexes. Fungal/Compounds

Aspergillus niger

Aspergillus flevus

Rhizopus stolonifer

HL

19±1.4

21±0.7

-

Bipy

16±1.6

19±1.4

13±0.7

[Mn(L)(bipy)(OAc)]

39±0.0

49±2.8

39±0.7

[Co(L)(bipy)(OAc)]

-

21±0.7

27±0.0

[Ni(L)(bipy)(OAc)]

15±0.0

-

29±1.0

[Zn(L)(bipy)(OAc)]∙H2O +

Fluconazole

-DMSO

17±2.1

21±0.0

-

36±0.3

29±0.7

38±0.3

-

-

-

compound could be an antibiotic drug research interest in the near future [77,78]. The Schiff base and its metal(II) complexes exhibited moderate to good antifungal activity against the tested fungal organisms. The results are presented in Table 5. However, R. Stolonifer was resistant to the ligand and the Zn(II) complex, while the Ni(II) and Co(II) complexes were inactive against Aspergillus flevus and Aspergillus niger.

3.8 Antioxidant Studies 3.8.1 Ferrous ion chelating ability The synthesized compounds were studied for their antioxidant potential using ferrous ion chelating ability and 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging antioxidant assays. While the antioxidant potential of the metal complexes was assessed using only the DPPH radical scavenging assay, the Schiff base ligand was evaluated using the two assays. The antioxidant activity of the Schiff base ligand was determined by the ferrous ion-chelating assay (FICA) and was expressed as an equivalent of the standard antioxidant agent, ascorbic

acid. The results presented in Figure 7 show that the ligand possessed good chelating ability towards the ferrous ion. The FICA values of 55.23% and 69.74% at concentrations of 50 and 200 mg/mL were higher than that of ascorbic acid at equivalent concentrations.

3.8.2 DPPH radical scavenging ability The use of DPPH radical scavenging studies for antioxidant evaluation of the compounds is considered a reliable and reproducible method in antioxidant activity studies. The ligands and their complexes were screened for free radical scavenging effects with the DPPH radical at various concentrations (200, 100 and 50 g/mL) in 1mL DMSO. The results of the DPPH radical scavenging activity for the compounds on the basis of percent inhibition are presented in Figure 10. A critical examination of the values indicates that the compounds generally exhibited good DPPH radical scavenging activities. The ligands displayed DPPH radical scavenging ability values, but were lower than that of the standard drug (ascorbic acid). However, the antioxidant potentials of the ligands improved considerably after chelation with divalent metal ions. Generally, the metal Unauthenticated Download Date | 3/22/18 5:18 AM

assay (FICA) and was expressed as an equivalent of the standard antioxidant agent, ascorbic acid. The results presented in Figure 7 show that the ligand possessed good chelating ability Compounds

Antioxidant

towards the ferrous ion. The FICA values of 55.23% and 69.74% at concentrations of 50 and

2HCK

2OBM

-5.36

-5.07

196 

Festus Chioma et al.

200 mg/mL were higher than that of ascorbic acid at equivalent concentrations.

HL 80 70

50 40 30 20 10 0

Ic50

Ic100

Ic200

HL

55,23

53,26

69,74

Ascorbic Acid

53,96

57,33

66,2

HL

Ascorbic Acid

Figure 7: Ferrous chelating data of the ligand.

1LRI -6.37

Table 6: Free binding energy(kcal/mol) of complexes [Mn(L)(bipy)(OAc)] -4.57 -4.86and ligand.

-4.93

[Co(L)(bipy)(OAc)]

-5.43

-4.74

-4.64

Antioxidant Antimicrobial [Ni(L)(bipy)(OAc)] -4.86 HCK OBM-4.37 LRI HL -5.36 -5.07 -4.61 -6.37 [Zn(L)(bipy)(OAc)]∙H -5.68 2O [Mn(L)(bipy)(OAc)] -4.57 -4.86 -4.93 Co-crystallized ligand -5.34 [Co(L)(bipy)(OAc)] -4.74 -4.64 -5.0 -5.43 [Ni(L)(bipy)(OAc)] -4.86 -4.37 ND -5.28 Ascorbic acid -4.72 -5.68 -4.61 -5.30 [Zn(L)(bipy)(OAc)]∙H2O Ciprofloxacin ND -4.54 Co-crystallized ligand -5.34 -5.0 NA Fluconazole ND Ascorbic acid -4.72 ND ND ND Ciprofloxacin ND -4.54 ND ND: not determined, NA: not available Fluconazole ND ND -5.03 Compounds

60

Antimicrobial

Figure 7: Ferrous chelating data of the ligand.

-5.28 -5.30 NA ND ND -5.03

ND: not determined, NA: not available

3.7.2 DPPH radical scavenging ability 120of DPPH radical scavenging studies for antioxidant evaluation of the compounds is The use

considered a reliable and reproducible method in antioxidant activity studies. The ligands and 100 their complexes were screened for free radical scavenging effects with the DPPH radical at 80

various concentrations (200, 100 and 50 g/mL) in 1mL DMSO. The results of the DPPH radical 60 scavenging activity for the compounds on the basis of percent inhibition are presented in Figure 40 10. A critical examination of the values indicates that the compounds generally exhibited good DPPH radical scavenging activities. The ligands displayed DPPH radical 20

scavenging ability values, but were lower than that of the standard drug (ascorbic acid). 0

[Mn(L)(Bipy)( [Co(L)(Bipy)( [Ni(L)(Bipy)( [Zn(L)(Bipy)( However, the antioxidant potentials of the ligands improved considerably afterAscorbic chelation HL Bipy Acid with OAc)]

OAc)]

OAc)]

OAc)].H2O

95,13

98,53

87,66

95,26

99,4

88,66

divalent ions. Generally, the complexes 95,03 displayed 96,96 better DPPH Ic50 metal 86,56 74,76 97,43metal 95,76 86,26 radical Ic100 activities 87,33 compared 76,23 to the98,5 scavenging precursor 95,8 ligands. Ic200

88,1

77,4

98,8

90,4

The antioxidant results of the compounds be used Ic50 can Ic100 Ic200 for further studies in design of drugs for the treatment of pathological diseases arising from oxidative stress. Figure 8: Histogram presentation of DPPH radical scavenging results. Figure 8: Histogram presentation of23DPPH radical scavenging results.

3.8 Molecular docking studies Thecomplexes molecular docking studies werebetter undertaken to closely examine the interaction between displayed DPPH radical scavenging

activities compared to the precursor ligands. The antioxidant results of the compounds can be used indicate that our compounds can inhibit the biochemical processes of these proteins. for further studies in design of drugs for the treatment of Figure 9: 2HCK-[Zn(L)(bipy)(OAc)]∙H2O complex. [Zn(L)(bipy)(OAc)]∙H2O gave the highest antioxidant activity (-5.68 kcal/mol). This corroborated Figure 9: 2HCK-[Zn(L)(bipy)(OAc)]∙H2O complex. pathological diseases arising from mode oxidative well with the antioxidant result in Figure 8. The binding of the Znstress. (II) complex with the drug the synthesized compounds and some drug target proteins. The results in Table 6 show that the compounds interacted favorably with the active binding sites of the proteins. Strong binding affinities

target is shown in Figure 9. Figure 10 shows the binding mode of [Mn(L)(bipy)(OAc)] in the binding cavity of 2OBM. The ligand, HL with the highest inhibitory activity against the fungi protein (1LRI), activity

against the fungi protein (1LRI), interacted with the following active amino acid residues: TYR 47, TYR 87, through hydrogen and hydrophobic bonding (Figure 11). The binding affinity is higher than that of the LEU 15 and LEU 82 through hydrogen and hydrophobic standard drug that was used. The molecular docking studies were undertaken to bonding (Figure 11). The binding affinity is higher than closely examine the interaction between the synthesized that of the standard drug that was used. compounds and some drug target proteins. The results in Table 6 show that the compounds interacted favorably with the active binding sites of the proteins. Strong 4 Conclusion 25 binding affinities indicate that our compounds can inhibit the biochemical processes of these proteins. [Zn(L)(bipy) The proposed structures of the synthesized Schiff base (OAc)]∙H2O gave the highest24antioxidant activity (-5.68 ligand, HL and its Mn(II), Co(II), Ni(II) and Zn(II) complexes kcal/mol). This corroborated well with the antioxidant were on the basis of analytical and spectroscopic data. result in Figure 8. The binding mode of the Zn(II) complex Experimental results indicate the adoption of octahedral with the drug target is shown in Figure 9. Figure 10 shows geometry for the metal(II) complexes and the participation the binding mode of [Mn(L)(bipy)(OAc)] in the binding of the Schiff base in chelation in a bidentate fashion. The cavity of 2OBM. The ligand, HL with the highest inhibitory geometry of the compounds was investigated using DFT

3.9 Molecular docking studies

interacted with the following active amino acid residues: TYR 47, TYR 87, LEU 15 and LEU 82

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Synthesis, characterization, in-vitro antimicrobial properties, molecular docking and DFT studies...

 197

Conflict of Interests: Exclusively, the authors declare that there is no conflict of interest with respect to the publication of this research article.

References [1]

[2]

[3]

[4] Figure 10: 2OBM-[Mn(L)(bipy)(OAc)] complex. [Mn(L)(bipy)(OAc)] complex. Figure complex. Figure10: 10: 2OBM2OBM-[Mn(L)(bipy)(OAc)]

[5]

[6]

[7] [8]

[9]

[10]

Figure 11: 2D Ligand Interactions between 1LRI and HL.

Figure 11: 2D Ligand Interactions between 1LRI and HL.

calculations and their thermodynamic and electronic 26 parameters. Physicochemical results showed that the compounds were non-hygroscopic, solid and stable at room11:temperature. Generally,between the metal(II) Figure 2D Ligand Interactions 1LRI andcomplexes HL. displayed a better antimicrobial activity compared to the ligands. The compounds also demonstrated good ferrous26 ion chelating and DPPH radical scavenging abilities which were comparable to those obtained for ascorbic acid at the same concentrations. The molecular docking studies confirmed the compounds were inhibitors of 2HCK, 2OBM and 1LRI protein drug targets.

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