Spectroscopic and molecular structure characterization of Cu(II), Co(II), Ni(II) and Fe (III) amoxicillin antibiotic drug complexes in alcoholic media

ACCEPTED MANUSCRIPT

Spectroscopic and molecular structure characterization of Cu(II), Co(II), Ni(II)

and Fe (III) amoxicillin antibiotic drug complexes in alcoholic media

1

2, 3*

1, 2

M.A. Hussien , Samy M. El-Megharbel

and Moamen S. Refat

1

2

Department of Chemistry, Faculty of Science, Port Said University, Port Said, Egypt

Department of Chemistry, Faculty of Science, Taif University, Al-Hawiah, Taif, P.O.

Box 888 Zip Code 21974, Saudi Arabia

3

Department of Chemistry, Faculty of Science, Zagazig University, Zagazig 44519,

*

Corresponding author: Dr. Samy M. El-Megharbel

E-mail address: samyelmegharbel@yahoo.com

Abstract

Herein, this paper aimed to preparation, molecular structure characterizations,

spectroscopic and thermal studies of Cu(II), Co(II), Ni(II) and Fe(III) chelates of

amoxicillin (AMX) antibiotic drug. The stoichiometry of 1:2 (Metal : AMX)

complexes were explained by microanalytical analyses and spectroscopic tools (e.g.,

FTIR, ESR and UVvis.). The values of molar conductance for the AMX complexes

dissolved in dimethylsulfoxide led to electrolytic behavior. These outcome data prove

that AMX acts with mentioned metal chlorides as a tridentate chelate through –NH₂,

–

NH, and oxygen of carbonyl β-lactam groups. The general formula of AMX

2

+

complexes can be summarized as [M(AMX-Na) ].xCl.yH O (where M= Cu (x= 2,

2

+

2+

3+

y= 4), Co (x= 2, y= 2), Ni (x= 2, y= 1) and Fe (x= 3, y= 0). The activation

thermodynamic parameters E*, ΔS*, ΔH* and ΔG* were estimated using two official

methods as Coats–Redfern and Horowitz–Metzger dependent on thermogravimetric

curves. The molecular structure of AMX drug was optimized by HF method with 3-

2

1G basis. The molecular docking analysis was carried out using the receptor of

prostate cancer mutant 2Q7Khormone.

Key words: Amoxicillin, spectroscopic, complexation, thermal, 2Q7Khormone.

1

- Introduction

The trend of metaldrug complexes as bioinorganic branch has been received a great

attention compared with free drugs [1-6]. The metaldrug binding led to drastic changes in

the pharmaceutical properties of drugs [3, 5]. The type of metal ions was an essential

backbone in the metallo (antibiotic skeletons, that made to modify the medical

efficiency [7-10]. Antibiotics metal complexes were found more therapeutic effective

rather than their mentioned antibiotics [8-10]. The literature survey revealed greater

attention for the important roles of metal chelates as antitumor activities [11, 12]. The

transfer of metal ion from the ligand to the viruses associated with cancer is a

mechanism for releasing the anticancer drug in the locality of the tumor [12].

The biosynthesis of biocompatible gold nanoparticles (GNPs) from an aqueous

extract of the aerial parts of a pteridophyte, “Adiantum philippense” by microwave

irradiation and its surface functionalization with broad spectrum beta lactam

antibiotic, amoxicillin (Amox) has been discussed [13], The functionalization of

amoxicillin on GNPs (GNP-Amox) was carried out via electrostatic interaction of

protonated amino group and thioether moiety mediated attractive forces.

Different chemometric models were applied for the quantitative analysis of

amoxicillin (AMX), and flucloxacillin (FLX) in their binary mixtures [14], namely,

partial least squares (PLS), spectral residual augmented classical least squares

(SRACLS), concentration residual augmented classical least squares (CRACLS) and

1

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artificial neural networks (ANNs). All methods were applied with and without

variable selection procedure (genetic algorithm GA). The methods were used for the

quantitative analysis of the drugs in laboratory prepared mixtures and real market

sample via handling the UV spectral data. Robust and simpler models were obtained

by applying GA. The proposed methods were found to be rapid, simple and required

no preliminary separation steps.

Amoxicillin is (Fig. 1) an analog of ampicillin, derived from the basic penicillin

nucleus [13-15]. Amoxicillin is a member of penicillin‟s group which is a very important

class of βlactamic antibiotics used in therapy because of its specific toxicity towards

bacteria. From a coordination chemistry perspective, it has been demonstrated that all the

βlactamic antibiotics possess a number of potential donor sites and they are known to

interact effectively with several metal ions and organometallic moieties [16, 17]. Atoms

involved in coordination and the structure of these complexes depend on several factors,

including reaction medium, pH, conformational equilibrium occurring in solution state and

the nature of the side chain bonded of the βlactamic ring. The βlactam antibiotics possess a

number of potential donor sites, which interact effectively with Lewis acidic metals [18, 19].

The stereochemistry and geometries of such complexes are highly dependent on several

factors, including the reaction medium, pH and the nature of the side chain bonded to the

phenyl of the βlactam ring. The pharmacology, clinical efficiency, resistance with enzymes

to βlactam antibiotics and coordination chemistry with amoxicillin has been reported [20-

22].

H N

O

2

O

HN

N

OH

H

S

HO

Fig. 1: The amoxicillin antibiotic drug (AMX)

Amoxicillin trihydrate and ampicillin trihydrate have been coordinated to copper salts

in a 1:1 molar ratio in the presence of biuret reagent to form mixed ligand copper complexes

[23], which were further used for the treatment of the infections caused by most of the Gram

positive and Gram negative bacteria [24]. Their protein synthesis-inhibiting properties [25]

due to their acidic nature were also reported [26]. The basic nucleus of the antibiotics is

6amino penicillanic acid, which consists of a thiolidine ring linked to a βlactam ring with a

side chain [27, 28]. Many studies concerning the biochemical and pharmaceutical effects of

antibiotics when complexed with metal ions have been a subject of great interest for many

scientists. Amoxicillin antibiotic, known as 6[D(p-hydroxyphenyl) acetamido]

pencilanic acid, has effect against urinary tract infection and used in the treatment of

respiratory infections and meningitis [29]. The metal complexation behavior of amoxicillin

was studied extensively. Lyle and Yassin [30] studied the differential pulse polarographic

behaviour of nickel (II) complex with amoxicillin at the dropping mercury electrode. Novel di

and tri organotin (IV) derivatives of amoxicillin of the type R SnCl(Amox).2H O,

2

R Sn(Amox) .2H O and R SnCl(AmoxH)Na.2H O (R = Me, Bu and Ph) had been

2

3

2

reported [31], these studies suggested that amoxicillin in the diorgano derivatives behaved

2

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as monoanionic (Amox = deprotonated amoxicillin) bidentate ligand, coordinating the tin

(IV) ion through the ester type carboxylate and lactamic carbonyl. However in the

triorgano derivative, R SnCl(AmoxH)Na.2H O, the tin is coordinated only through the

3

2

lactamic carbonyl that acts as monodentate ligand. In both R SnCl(Amox)2H O and

2

R SnCl(AmoxH)Na.2H O trigonal bipyramidal configuration were proposed while in

3

2

R Sn(Amox) .2H O the coordination geometry at Sn(IV) was skewtrapezoidal

2

bipyramid, with two chelating amoxicillin acted as bidentate ligand in the trapezoidal plane

and the organic molecules in axial positions. Novel triorganotin(IV) complexes of two

βlactamic antibiotics, 6-[d-(−)βaminophydroxyphenylacetamido] penicillin and 6-[d-

(−)-α-aminobenzyl]penicillin, have been synthesized and investigated both in solid and

solution states. These complexes corresponded to the general formula R Sn(IV)antib·H O

3

2

(R=Me, n-Bu, Ph; antib=amox=amoxicillinate or amp=ampicillinate) [32]. Amoxicillin acted

as monoanionic bidentate ligand coordinating the metal ion through carboxylate as well as

through the lactamic carbonyl group in its complexes with some transition metal ions; Ag(I),

Cu(II), Co(II), Zn(II) and Ni(II) [33]. To know whether the amoxicillin act as ionic or in

neutral manner on coordination, The synthesis and characterization of heterobinuclear

complexes of the general formula [MCl (AmoxH)MCl ] (where M = titanium (III),

3

2

chromium (III) and iron (III); M = zinc (II) and cadmium (II); AmoxH = amoxicillin) were

described [34] and amoxicillin exhibited penta-dentate manner. The three sites along with the

three chloride ions were used to form the most probable octahedral geometry around the

trivalent metal ions Ti(III), Cr(III) and Fe(III), while the other two sites with the two other

chloride ions were utilized to form the most probable tetrahedral arrangement around the

divalent metal ions Zn(II) and Cd(II). Complexes of amoxicillin with Bi(V) were obtained in

acidic media [35]. The new complexes of amoxicillin with some transition metal ions such as

Ag(I), Cu(II), Co(II), Zn(lI) and Ni(II) showed an enhanced antibacterial activity against

several Escherichia coli, Staphylococcus aurous, Pseudonomous aerugionosa compared to

the simple antibiotic [33]. Metal such as Co (II), Ni (II), Cu (II) and Bi (V) were coordinated

to a novel ligand which was made by coupling gentamicin and amoxicillin. These were

studied by various spectroscopic techniques which indicated a square planar arrangement of

ligand around the Co(II) ions [36]. Also, complexes of Co(II), Zn(II), Ni(II) and Mn(II) with

cinnemaldehyde , pchlorobenzaldehyde and amoxicillin trihydrate were synthesis and

characterized [37]. The interaction of amoxicillin with Zn (II) ion has been found to form one

complex of 1:1 metal to ligand composition. The results showed that the complex formation

was affected by the nature of solvents, time, pH and temperature [38]. The interaction of

Al(III) with amoxicillin (L) was studied by the pH-metric titration in aqueous solutions at 20

°

C and ionic strength 0.1 (KNO ). In weakly acidic medium, complexes with the composition

3

Al(OH)L and Al(OH) L were formed [39].

2

In continuation of our work in the branch of metaldrug interactions [40-45],

this study aimed to synthesis, theoretical calculations, spectroscopic characterizations,

thermal stabilities and their molecular docking calculation of amoxicillin antibiotic

drug complexes of Cu(II), Co(II), Ni(II) and Fe(III) ions in alcoholic media. The

experimental studies have been matched with suggested structures.

2

- Experimental

2

-1- Materials

Amoxicillin trihydrate antibiotic drug was received from the Aldrich chemical

company. All of chemicals used in this study were of analytically reagent grade,

commercially available from BDH and used without previous purification like CuCl₂,

CoCl , NiCl and FeCl salts.

2

3

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2

-2- Preparations

The copper(II), cobalt(II), nickel(II) and iron(III) amoxicillin complexes were

synthesized similarly according to the following procedure: 2 mmol of amoxicillin

trihydrate ligand was dissolved in 20 mL methanol then mixed with 20 mL of

methanolic solution of 1 mmol of each metal salts CuCl , CoCl , NiCl and FeCl . A

2

3

mixture of 1:2 ratio (metal ions: AMX) at pH 7–8 (adjusted by adding 1 M a

methanolic sodium hydroxide solution) was heated under reflux and continuous

o

stirring at 50–60 C for about 4 hrs. The mixtures were remaining overnight at room

temperature until precipitation settled down. The colored precipitates were filtered off

and washed three times using methanol solvent. The solid products were dried under

vacuum over anhydrous CaCl . The yield percent of the products collected were about

2

7

2–89%.

2

-3-Instruments

The microanalytical analyses of %C, %H and %N percentages were

calculated using a Perkin Elmer CHN 2400 (USA). The molar conductivities of AMX

-3

3

complexes with 10 mol/cm concentration in DMSO solvent were measured by

Jenway 4010 conductivity meter. The UV-vis absorption spectra were recorded in

DMSO solvent within 800-200 nm range using a UV2 Unicam UV/Vis

Spectrophotometer fitted with a quartz cell of 1.0 cm path length. The infrared spectra

-1

with KBr discs were recorded on Bruker FT-IR Spectrophotometer (4000–400 cm ).

Magnetic moments were calculated using the Magnetic Susceptibility Balance,

o

Sherwood Scientific, Cambridge Science Park, Cambridge, England, at Temp 25 C.

The thermal studies TG/DTG–50H were carried out on a Shimadzu thermo

o

gravimetric analyzer under nitrogen till 800 C. ESR measurements of powdered

samples were recorded at room temperature using an X-band spectrometer utilizing a

1

00 kHz Magnetic Field Modulation with diphenyl picrylhydrazyle (DPPH) as a

reference sample.

3

- Results and Discussion

3

-1- Analytical and physical data

The formulas and physicochemical behavior of the AMX antibiotic drug with

CuCl , CoCl , NiCl and FeCl salts are listed in Table 1. The AMX solid compounds

2

3

are stable at room temperature with higher melting points. The binding of AMX drug

towards mentioned metal ions was assigned based on FTIR, UVvis., ESR,

magnetic analyses as well as thermal analyses and molar conductance. The ratio of

%carbon, %hydrogen, %nitrogen, %chloride and %metal ions in experimental work

are in agreement with the theoretical data. These data led to 1:2 (metal:AMX)

stoichiometry for all complexes. The electrolytic behavior [46] of the AMX

complexes are due the presence of chloride ions in ionic form outside the chelation

sphere. The effective magnetic moment of paramagnetic complexes of AMX was

calculated at room temperature. The results are matched with the speculated formulas;

2

+

2+

[

M(AMX-Na) ].xCl.yH O (where M= Cu (x= 2, y= 4) complex 1, Co (x= 2, y= 2)

2 2

2

+

3+

complex 2, Ni (x= 2, y= 1) complex 3, and Fe (x= 3, y= 0) complex 4 (Fig. 2).

4

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OH

O

NH

H

N

O

ONa

NH₂

S

O

N

H

O

Cu

S

H N

NH

NaO

2

O

.

2Cl.4H O

2

HO

OH

O

H

N

O

ONa

NH

NH₂

S

O

N

H

O

Co

S

H N

NH

NaO

2

O

.

2Cl.2H O

2

HO

OH

O

H

N

O

ONa

NH

NH₂

S

O

N

H

O

Ni

S

H N

NH

O

NaO

2

O

.

2Cl.H O

2

HO

5

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OH

O

H

N

O

NH

NH₂

ONa

S

O

N

H

O

Fe

S

NaO

H N

2

NH

O

.

3Cl

HO

Fig. 2: Speculated formulas of complexes 14

Table1: Microanalytical and physical data of AMX drug and their metal complexes

Elemental analysis, % Found % (Calcd.)

Λm

o

Compounds

Color

M.P/ C

(

S)

12

C

H

N

Cl

M

AMX

White

Green

>200

250

52.59

39.17

5.24

4.52

11.50

8.56

-

>

7.23

6.48

Complex 1

116

(

39.14) (4.33) (8.45)

40.86 4.29 8.93

40.80) (4.24) (8.90)

41.67 4.15 9.11

41.54) (4.09) (9.06)

41.02 3.87 8.97

(40.97) (3.82) (8.90)

(7.18)

7.54

(7.41)

7.69

(7.62)

11.35

(11.24)

(6.41)

6.27

(6.22)

6.36

(6.30)

5.96

(5.94)

>

250

Complex 2

Complex 3

Complex 4

Red

104

98

Green

Dark

brown

>250

186

3

-2-FT-IR spectra

This instrument of analyses is an important tool to identify the chelation mode

and the place of coordination. FTIR spectra of free AMX drug and their complexes

5 are shown in Fig. 3 and the band assignments are refereed in Table 2.

i. In case of AMX free drug, there are two characteristic bands at 3461 and 3187

1

-1

cm , that can be assigned to ν

and ν₍_N_–_H₎, respectively [47]. These bands are

(O–H)

absent or shifted to lower wave numbers in AMX complexes 14 due to the

participated in binding towards metal ions.

ii. In the free AMX drug the stretching vibration bands of phenolic –OH and –CH

-1

benzene ring are overlapped in complexation within the range of 30003500 cm .

These results denied the bonding through the –OH phenolic group.

-1

iii. The stretching vibration band ν₍_C₌_C₎of benzene ring is presented at 1516 cm in

-1

case of free AMX drug, this band is exhibiting at the same frequency ~ 1513 cm

in case of AMX complexes 14.

6

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-1

iv. The carbonyl group of β-lactam ring presence at 1776 cm in case of free AMX

drug, this band ν₍_C₌_O₎(β-lactam) is absent or shifted to lower wave numbers in case

of the IR spectra of the AMX complexes 14 due to the involvement in the

coordination toward the metal ion [48].

-1

v. The amido group is existed at 1687 cm in the free AMX drug, this band was

-1

shifted to lower wave numbers at 1641, 1611, 1648 and 1635 cm for the AMX

complexes 14. These data prove that the –NH-CO amido group sharing in the

coordination fashion.

vi. The –COOH carboxylic group band in case of AMX free drug is presently at 1713

-1

cm , this band was absent in the spectra of the AMX complexes 14. This data can

be assigned to the deprotonation of carboxylic group by sodium metal in the

-

neutralization state. The difference wave numbers between Δν = ν COO - ν COO

as

s

)

asymmetric and symmetric stretching vibrations of carboxylic group is larger

-1

than >200 cm , this data supported the formation of ionic bonds [49] between

carboxylic and sodium metal ions.

-1

vii. The presence of bands at 500–600 cm are assigned to the ν

stretching,

(M–O)

vibration bands between metal ions and oxygen's of the carbonyl group.

-1

viii. The bands within the range of 500–400 cm are assigned to ν(

stretching,

M-N)

vibration bands between metal ions and amino group. The infrared spectroscopic

results supported that AMX drug acts as a 1:2 tridentate ligand molecule with

respect metal ions via amino, amido and β-lactamic groups.

-1

ix. In AMX complexes, the distinguish band at ~ 3400 cm with a broad intensity is

assigned to the presence of the water molecules inside or outside coordination

sphere.

100

A

95

90

85

80

75

70

65

60

55

4000

3500

3000

2500

2000

1500

1000

500

-1

cm

7

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100

B

95

90

85

80

75

70

65

60

55

4000

3500

3000

2500

2000

1500

1000

500

-1

cm

1

20

00

C

1

80

60

40

20

4000

3500

3000

2500

2000

1500

1000

500

-1

cm

8

ACCEPTED MANUSCRIPT

D

1

05

00

1

95

90

85

80

75

70

4000

3500

3000

2500

2000

1500

1000

500

-1

cm

100

90

80

70

60

50

4000

3500

3000

2500

2000

1500

1000

500

-1

cm

Fig. 3AE: FTIR spectra of AMX free drug and complexes 14

Table 2: Main FTIR spectral bands and their assignments of a free AMX drug and

their complexes 14.

AMX

461

Cu(II)

3421

Co(II)

3403

Ni(II)

3415

Fe(III)

3403

Assignments

ν(OH); COOH+H O

3

2

9

ACCEPTED MANUSCRIPT

3

1

-

187

776

687

-

ν(NH)

1709 sh

1641

573

1739 sh

1635

654

ν(C=O); β-lactam

ν(C=O); amido group

ν(M-O)

1611

575

500

1648

618

545

-

499

569

ν(M-N)

3

-3-Electronic spectra, effective magnetic moments and ESR spectra

The UVvis absorption spectra of AMX and their complexes 14 within the

range of 200-1000 nm were scanned and assigned. The electronic spectrum of AMX

free drug has two characteristic absorption regions at 260-285 nm and 330-370 nm

due to the intraligand excitation indicating the effect of the functional groups [50].

Base on chelation, there are some electronic changes due to the interaction of AMX

drug with metal ions. The UV-vis. Absorption spectra of AMX complexes 14 have

π→π* transitions at 280300 nm due to aromaticity of double bond characters [51],

and n→π* transitions were exhibit at wavelengths 325400 nm, that can be assigned

to β-lactam, carboxylate, amino, amido, and dimethyl thiazolidine groups [52].

Cu(II) complex 1

The reflectance spectra of Cu(II) complex 1 has two distinguish bands



1

2

exhibited at 15873 and 20618 cm that can be assigned to E → T and B → A

g

2g

1g

transitions, respectively. The octahedral geometry around Cu(II) ions is additionally

proved by estimation of the effective magnetic moment (μ ). The experimental μ of

eff

Cu(II) complex 1 has 1.88 BM, that matched with octahedral structure [53]. The

magnetic moment values are excluded any metal–metal interaction with neighbor

moieties. The electron spin resonance spectrum of Cu(II)AMX complex 1 scanned

as a polycrystalline samples Figs. 4. The experimental data show that g =1.8601 and

║

g = 1.7619. The values of both g and g are less than 2. This suggestion due to

┴

║

┴

octahedral geometry of the copper(II) complex 1. The G = (g − 2)/( g − 2), which

║

┴

measure the exchange interaction between the copper centers in a polycrystalline solid

has been calculated. According to Hathaway [54, 55], if G > 4, the exchange

interaction is negligible,but G < 4 indicates considerable exchange interaction in the

solid complexes. In case of copper(II) complex 1, the „G‟ value less than 4 indicating

the exchange interaction in solid complex. For transition metal compounds,large

variations arise in the values of g-factor because of loss of orbital degeneracy and

spin-orbit coupling. The value of g-factor in transition metal complex gives very

important information about the structure of the complex. The molecular orbital

2

coefficients α and β for identify to (covalence of inplane σbonding between 3d

and ligand orbitals) and (covalence inplane bonding), respectively, were estimated

by using the following relationships [56];

g_┴- 2.0023) + 0.04

−

1

Where, λ =−828 cm for the free copper(II) ion and E is the electronic transition

2

energy. The lower value of β compared to α indicates that the inplane bonding is

more covalent than the inplane σbonding, the data in a good agreement with

1

0

ACCEPTED MANUSCRIPT

2

literature [54, 55]. The α value for copper(II) complex indicates a considerable

covalency in the bonding between the Cu(II) ion and the AMX ligand.

0

.4

.2

.0

3

000

4000

5000

6000

-0.2

-0.4

-0.6

Fig. 4: ESR spectrum of Cu(II)AMX complex 1.

Co(II) complex 2

The electronic spectrum of cobalt(II) complex 2 has three absorption bands at

-

1

4

1

2345, 15504 and 18182 cm , which can be attributed to T (F)→ T (F) (ν1),

1g 2g

4

T (F)→ A (F) (ν2) and T (F)→ T (P) (ν3), respectively, based on the octahedral

1

g

2g

1g

geometrical structure [57]. The octahedral geometry of cobalt(II) complex is further

supported by the value of the ν2/ν1 ratio, which is 1.26 [58]. The ligand field

-1

parameters such as the Racah inerelectronic repulsion parameter (B' = 798 cm ),

ligand field splitting energy (10D = 11083), covalency factor (β = 0.810) and ligand

q

-1

field stabilization energy (LFSE = 13.30 kcal. mol ) have been calculated [58]. For

the Co(II) complex, the Racah Racah innerelectronic repulsion parameter (B') is

calculated based on the following relationship [58];

2

0.5

B' = 1/510 {7(ν32 ν2) + 3[81 ν3  16 ν2(ν2 ν3)] }

The ligand field splitting energy (10D ) is estimated from the following relationship;

q

1

0D = 1/3 (ν2 ν3) + 15B'

q

The covalency factor (β) is resulted from the following relationship;

β = B'/B (B is the free cobalt ion)

The ligand field stabilization energy (LFSE) is calculated from the following

relationship;

LFSE = 10D_q

1

ACCEPTED MANUSCRIPT

-1

The B' value is lower than free ion (985 cm ), that is due to orbital overlap and

delocalization of dorbital. The covalency factor (β) is less than unity, this can be

assigned upon the metalligand bonds have a considerable of covalent character.

The magnetic moment of the Co(II) complex is 4.86 B.M, which is

characteristic for an octahedral environment.

Ni(II) complex 3

The electronic absorption spectrum of Ni(II) complex 3 exhibit three bands at

-

1

3

2

(

5641, 17544 and 11976 cm which attributed to A (F)→ T (P), (ν3), A → T

2g 1g 2g 1g

3

F), (ν2) and A → T (F), (ν1), respectively, due to octahedral geometry [59].

Beside of these three bands, there is a charge transfer band is existed at 29412 cm .

The Racah inter-electronic repulsion parameter (B'= 593 cm ), ligand field splitting

energy (10Dq= (ν1) 11976 cm ), covalency factor (β = 0.5711) and ligand field

stabilization energy (LFSE = 14.371 kcal. mol ) has been calculated. Both 10Dq and

B parameters were calculated upon following equations [60-62];

2g 2g

-

1

-1

2

B' = (2 ν1 + ν2 - 3 ν1 ν2) / (15 ν2 - 27 ν1)

-1

β= B'/B (where, B is the free nickel ion = 1038 cm )

LFSE = 12Dq

o

The percentage lowering of energy in free gaseous ion (β = 42.89%) is calculated

from the following relationship;

o

β = 100 – (β x 100)

-1

The fraction of ν2/ν1 (1.4649 cm ) is found at the limit of octahedral

geometry [60, 61]. The low values of ν2/ν1 are due to the strong interaction between

3

T (P) and T (F) states.

1

g

1g

The effective magnetic moment μ_e_f_fdata of Ni(II) complex 3 is 3.45 BM

within the high spin octahedral (3.00-3.50 BM). The high spin data are due to arise

3

from the spin orbit coupling which causes an orbital contribution to the quenched A₂_g

ground state of Ni(II) ion in an octahedral structure [60].

Fe(III) complex 4

The observed magnetic moment of iron(III) complex 4 is 5.82 B.M. Within the

2

3

accepted range and hence an octahedral geometry, involving d sp hybridization [60].

-1

The solid reflectance spectrum of iron(III)AMX complex 4 has a band at 21276 cm

6

that can be assigned to A →T (G) transition.

1

g

2g

3

-4- TGDTG analyses and calculation of thermodynamic parameters

The TGADrTGA thermal analyses curves of AMX complexes 14 are

refereed in Figs. 5AD and the interpretation of mass loss (%) with various

temperature ranges are assigned in Table 3. The thermal decomposition mechanisms

2

+

2+

of [M(AMX-Na) ].xCl.yH O (where M= Cu (x= 2, y= 4), Co (x= 2, y= 2), Ni

(

2

3

+

x= 2, y= 1) and Fe (x= 3, y= 0) complexes can be deduced as follows:

o

5

0140 C

i- [Cu(AMXNa) )].Cl .4H O 

2

1

2

ACCEPTED MANUSCRIPT

[

Cu(AMXNa) )].Cl + 4H O

2

o

1

40800 C

[

Cu(AMXNa) )].Cl  Cl + AMXNa (dec.) + CuO↓ + 8C

2

o

5

0120 C

ii- [Co(AMXNa) )].Cl .2H O 

2

[

Co(AMXNa) )].Cl + 2H O

2

o

1

20800 C

[

Co(AMXNa) )].Cl  Cl + AMXNa (dec.) + CoO↓ + 22C

2

o

5

0150 C

iii- [Ni(AMXNa) )].Cl . H O 

2

[

Ni(AMXNa) )].Cl + 2H O

2

o

1

50800 C

[

Ni(AMXNa) )].Cl  Cl + AMXNa (dec.) + NiO↓ + 23C

2

o

1

50800 C

iv- [Fe(AMXNa) )].Cl 

2

3

1

½Cl + AMXNa (dec.) + FeO↓ + 3C

2

Generally, the thermal decomposition of copper(II), cobalt(II), nickel(II) and iron(III)

complexes 14 of AMX is operated under nitrogen atmosphere. These complexes do

not have coordinated water molecules, but contain 04 uncoordinated water

molecules. The crystallized water molecules were liberated in one step (first step

o

5

0150 C). The dehydrated complexes exhibited transition phases and

decomposition of AMX located in the second and subsequent steps. The final residual

products were identified as the respected metal oxides polluted with carbon atoms.

0

.01

.00

A

100

0

-0.01

-0.02

-0.03

-0.04

-0.05

-0.06

-0.07

-0.08

80

60

40

20

TG

DTG

0

100

200

300

400

500

600

700

800

900

o

Temp. [ C]

1

3

ACCEPTED MANUSCRIPT

110

B

0.00

100

90

80

70

60

50

40

30

-0.02

-

0.04

0.06

-

-0.08

TG

DTG

-0.10

0

100

200

300

400

500

600

700

800

900

o

Temp. [ C]

C

00

1

0

90

80

70

60

50

40

30

-

2

4

-

-6

TG

DTG

0

100

200

300

400

500

600

700

800

o

Temp. [ C]

1

4

ACCEPTED MANUSCRIPT

D

100

0.00

-0.05

-0.10

-0.15

-0.20

-0.25

80

60

40

20

0

TG

DTG

0

100

200

300

400

500

600

700

800

900

o

Temp. [ C]

Fig. 5AE: TGADrTGA curves of AMX complexes 14

Table 3: Thermo gravimetric assignments of AMX complexes 14

Complex

Steps

DTG_m_a_x/ (°C)

Assignments

Weight loss, %

Found (Calcd.)

st

1

2

46, 138

205, 434

4H

2

O

7.39(7.34)

nd

Cl +AMX-Na (dec.)

75.10(74.77)

17.51(17.89)

3.81(3.83)

60.55(60.14)

35.64(36.03)

1.74(1.95)

59.76(60.03)

38.50(38.02)

88.45(88.49)

11.55(11.51)

2

residue

CuO+8C

2H O

st

2

3

4

1

2

56

2

nd

233, 394, 506, 782 Cl +AMX-Na (dec.)

2

residue

CoO+22C

st

1

2

80

H O

2

nd

242, 529, 780

Cl +AMX-Na (dec.)

2

residue

NiO+23C

1½Cl +AMX-Na (dec.)

FeO+3C

st

1

176, 453

2

residue

The thermodynamic parameters were calculated theoretically based on the

integral Coats & Redfern and Horowitz-Metzger method [63, 64]. The ∆H, ∆S and

G parameters were calculated using the relationships; ∆H = E – RT, ∆S = R

ln(Ah/kT)] and ∆G = ∆H - T∆S, where, k is the Boltzmann‟s constant and h is the

∆

[

Planck‟s constant. The thermodynamic parameters are listed in Table 4.

Table 4: Kinetic parameters using the Coats–Redfern (CR) and Horowitz-Metzger

(HM) methods for the AMX complexes 14

Complexes DTG_m_a_x

Thermodynamic parameters

Parameters Methods

CR

HM

1

5

ACCEPTED MANUSCRIPT

-

1

4

E (Jmol )

7.99*10₂

8.34*10₇

-1

A (s )

2.61*10

1.31*10

-1

2

o

ΔS (Jmol K )

ΔH (Jmol )

ΔG (Jmol )

^-²^.⁰³^*¹⁰4

^-¹^.¹³^*¹⁰4

Complex 1

Complex 2

Complex 3

Complex 4

205 C

-1

3.19*10

9.40*10

7.94*10

1.33*10

-

1

4

5

r

0.989

0.968

-

1

4

E (Jmol )

A (s )

ΔS (Jmol K )

ΔH (Jmol )

ΔG (Jmol )

r

E (Jmol )

A (s )

ΔS (Jmol K )

ΔH (Jmol )

ΔG (Jmol )

r

E (Jmol )

A (s )

ΔS (Jmol K )

ΔH (Jmol )

1.41*10₃

1.89*10₇

-

1

1.89*10

9.35*10

-

1

-1

2

o

^-³^.⁰⁵^*¹⁰3

^-³^.⁸⁶^*¹⁰3

233 C

-1

6.36*10

6.48*10

-

1

4

2.32*10

0.991

1.99*10

4.34*10

0.999

-1

4

1.93*10₇

-1

15

1.03*10 ₂

8.92*10

-1

o

^-³^.⁴²^*¹⁰3

^-³^.⁶⁹^*¹⁰3

242 C

-1

6.51*10

6.69*10

-

1

4

3.41*10

0.999

2.91*10

0.999

-1

4

1.98*10₁

1.34*10₇

-1

2.50*10

2.31*10

-1

2

o

^-²^.²⁶^*¹⁰3

^-¹^.¹¹^*¹⁰4

176 C

-1

5.94*10

1.28*10

-

1

4

ΔG (Jmol )

1.61*10

2.10*10

r

0.979

The activation thermodynamic parameters, such as, energy of activation, enthalpy,

entropy and free energy change of the complexes were evaluated and the stabilities of

the thermal decomposition of the complexes are discussed. From the kinetic point of

view, it is found that the thermal stability of the complexes follows the order

Cu(II)>Ni(II)> Fe(III)>Co(II). The reactions for which ΔG is positive and ΔS is

negative considered as unfavorable or non spontaneous reactions [65, 66]. The

correlation coefficients of the Arrhenius plots of the thermal decomposition steps

were found to lie in the range 0.999 to 0.968, showing a good fit with linear functions.

3

-5- Theoretical and molecular docking calculation

The molecular structures of the AMX drug and their Cu(II), Co(II), Ni(II) and

Fe(III) complexes 14 are optimized by an HF method with a 3-21G basis set. The

molecules were built with the Perkin Elmer ChemBio Draw and optimized using

Perkin Elmer ChemBio3D software [67]. The calculated of internal coordinates of

molecular structures for AMX and complexes 14 are shown in Figs. 1 and 2.

Selected geometric parameters,bond lengths and bond angles are summarized in

Tables 5-8.

The docking process in which the ligand–protein interaction energies are

calculated using a Docking Server [68]. The MMFF94 Force field was used for

energy minimization of the ligand molecule using Docking Server. Gasteiger partial

charges were added to the ligand atoms. Non-polar hydrogen atoms were merged, and

rotatable bonds were defined. Docking calculations were carried out on 2q7k-

hormone protein model. Essential hydrogen atoms, Kollman united atom type

1

6

ACCEPTED MANUSCRIPT

charges, and solvation parameters were added with the aid of AutoDock tools [69].

Affinity (grid) maps of 20×20×20 Å grid points and 0.375 Å spacing were generated

using the Autogrid program [67]. Auto Dock parameter set- and distance-dependent

dielectric functions were used in the calculation of the van der Waals and the

electrostatic terms, respectively. The molecular docking is a key tool in computational

drug design [68]. The focus of molecular docking is to simulate the molecular

recognition process. Molecular docking aims to achieve an optimized conformation

for both the protein and drug with a relative orientation between them such that the

free energy of the overall system is minimized [68]. The results of molecular docking

between AMX drug and receptor of prostate cancer mutant 2q7k-hormone showed a

possible arrangement between AMX drug and receptor 2q7k. On a docking study

showing a favorable interaction between AMX drug and the receptor 2q7k and the

calculated of energy are listed in Table 9 and Fig. 6. The 2D plot curves of docking

with ligands are shown in Fig. 7. This interaction could activate apoptosis in cancer

cells, energy of interactions with drugs. Binding energies are most widely used mode

of measuring binding affinity of drugs. Thus, a decrease in binding energy due to

mutation will increase the binding affinity of the AMX drug towards the receptor. The

characteristic feature of AMX represents in presence of several active sites available

for hydrogen bonding. According to our results, (Fig. 8), HB plot curve indicates that,

the AMX drug compound binds to the 2q7k protein with hydrogen bond interactions

and decomposed interactions energies in Kcal/mole exist of AMX drug with 2q7k.

Table 5: Internal coordinates parameters of AMX drug

nd

Atom

Bond

Atom

Bond

Length

Angle

Atom

Angle (o)

2

2 Angle

Angle

Atom

(o)

Type

(

A)

C(15)

N(19)

C(18)

C(16)

C(13)

C(17)

N(11)

S(14)

O(20)

C(23)

H(37)

C(9)

C(21)

C(22)

O(25)

H(35)

H(36)

C(8)

C(15)

N(19)

C(15)

C(16)

C(13)

C(15)

C(18)

C(16)

N(11)

C(17)

C(23)

C(13)

C(15)

C(9)

C(8)

C(4)

C(3)

C(2)

C(5)

C(1)

1.450

1.369

1.450

1.523

1.448

1.450

1.815

1.208

1.509

1.113

1.369

1.523

1.338

1.113

1.509

1.497

1.395

1.355

C(15)

N(19)

C(15)

C(13)

C(17)

C(13)

S(14)

C(16)

N(11)

C(13)

N(11)

C(9)

90.000

107.700

90.000

C(18)

C(16)

C(15)

C(18)

N(19)

C(15)

C(16)

C(17)

C(15)

S(14)

C(13)

N(11)

C(9)

118.400

130.638

50.973

Pro-R

Dihedral

Pro-S

Pro-R

Pro-S

Pro-R

Pro-S

Dihedral

Pro-S

Pro-R

112.161

115.566

109.000

132.532

108.773

107.906

120.000

112.806

117.399

120.000

96.389

119.594

120.000

109.442

119.998

120.003

120.000

119.997

119.999

115.566

104.000

132.532

108.773

107.906

-94.678

112.806

117.399

-0.000

124.021

108.464

180.000

119.964

120.000

119.998

0.001

Dihedral

Pro-R

Dihedral

Pro-S

Dihedral

Pro-R

C(4)

C(3)

C(5)

C(2)

C(1)

C(6)

O(7)

C(8)

C(3)

C(4)

C(3)

C(4)

C(2)

C(8)

C(5)

C(4)

C(3)

-0.006

0.003

119.999

C(6)

1

7

ACCEPTED MANUSCRIPT

N(10)

O(12)

O(24)

H(26)

H(27)

H(28)

H(29)

H(31)

H(30)

H(32)

H(33)

H(34)

H(38)

H(39)

H(40)

H(41)

H(42)

H(43)

H(44)

C(8)

C(9)

C(23)

C(2)

C(3)

C(5)

C(6)

C(8)

O(7)

N(10)

N(11)

C(21)

C(22)

O(25)

1.438

1.208

1.100

1.113

0.972

1.020

1.034

1.012

1.113

1.114

1.113

1.111

1.114

0.972

C(4)

C(8)

C(16)

C(1)

C(2)

C(4)

C(1)

C(4)

C(1)

C(8)

109.442

120.000

120.002

120.000

120.001

120.000

109.520

108.000

109.470

110.022

120.000

109.500

110.414

112.171

109.500

112.271

111.379

106.100

C(9)

N(11)

O(25)

C(3)

C(4)

C(6)

C(5)

C(9)

C(2)

C(4)

H(32)

C(13)

S(14)

H(38)

S(14)

H(41)

C(16)

109.500

120.000

120.002

120.000

120.001

120.000

109.462

180.000

104.757

120.000

73.115

107.607

107.438

113.028

107.992

107.051

180.000

Pro-S

Pro-R

Pro-S

Pro-R

Pro-S

Pro-R

Dihedral

Pro-S

Dihedral

Pro-S

Pro-R

Dihedral

Pro-S

Pro-R

Dihedral

C(8)

C(9)

C(17)

C(23)

Table 6: Internal coordinates parameters of complex 1

O

nd

Atom

Bond

Atom

Bond

Length

Angle

Atom

Angle ( ) 2 Angle 2 Angle

2 Angle

O

Atom

( )

Type

(

A)

C(15)

N(19)

C(18)

C(16)

C(23)

C(17)

O(24)

Cu(26)

O(25)

O(50)

O(51)

C(49)

C(42)

N(45)

C(41)

C(44)

C(43)

C(13)

S(14)

C(39)

S(40)

N(11)

C(21)

C(22)

N(37)

C(47)

C(48)

O(20)

O(46)

C(9)

C(15)

N(19)

C(16)

C(23)

O(24)

Cu(26)

O(50)

C(49)

C(42)

N(45)

C(42)

C(15)

C(41)

C(13)

C(17)

C(39)

C(43)

C(18)

C(44)

N(11)

N(37)

1.448

1.355

1.447

1.505

1.547

1.206

1.810

1.849

1.811

1.849

1.205

1.503

1.439

1.447

1.352

1.551

1.599

1.823

1.599

1.817

1.460

1.537

1.541

1.467

1.540

1.199

1.364

1.368

C(15)

N(19)

C(16)

C(23)

O(24)

O(25)

Cu(26)

O(50)

C(49)

C(42)

C(41)

N(45)

N(19)

C(13)

N(45)

C(39)

C(15)

S(14)

C(41)

S(40)

C(13)

C(39)

C(13)

C(39)

100.468

119.429

121.032

102.921

140.518

107.421

64.022

C(18)

C(15)

C(23)

C(17)

C(16)

C(23)

O(25)

O(51)

O(50)

C(49)

C(42)

C(49)

C(16)

N(19)

C(42)

N(45)

C(18)

C(16)

C(44)

C(42)

N(19)

N(45)

C(15)

C(41)

129.648

175.674

115.023

-77.270

164.380

2.073

Pro-R

Dihedral

Pro-R

Dihedral

Pro-R

Dihedral

Pro-S

Pro-R

Dihedral

Pro-R

Dihedral

Pro-R

Pro-S

Pro-R

Pro-S

Pro-R

Pro-S

88.790

129.888

71.676

122.061

107.459

143.099

116.656

121.761

102.064

102.937

83.496

-125.857

123.062

-135.301

173.105

132.240

118.016

-148.556

100.917

-161.616

97.529

110.136

111.566

111.864

118.121

110.864

113.180

132.642

131.640

73.283

116.903

82.323

119.755

114.702

109.936

108.270

117.360

108.740

108.771

138.087

140.619

122.075

124.632

Pro-S

Dihedral

C(35)

-75.687

1

8

ACCEPTED MANUSCRIPT

C(8)

C(4)

C(3)

C(5)

C(2)

C(1)

C(6)

O(7)

C(9)

C(8)

C(4)

C(3)

C(2)

C(5)

C(1)

C(8)

1.517

1.514

1.345

1.344

1.340

1.343

1.342

1.360

1.470

1.205

1.520

1.512

1.345

1.344

1.342

1.343

1.341

1.361

1.469

1.204

1.103

1.102

1.101

1.103

1.102

1.109

1.110

1.119

1.113

1.117

1.020

1.117

1.020

0.971

1.035

1.034

1.114

1.113

1.111

1.114

1.112

0.974

1.034

1.114

1.111

1.112

1.114

N(11)

C(9)

C(8)

C(3)

C(4)

C(3)

C(4)

C(2)

C(4)

114.047

113.165

120.071

117.564

121.436

121.044

120.866

121.483

111.354

123.443

113.476

112.852

120.869

117.875

121.071

121.262

120.736

121.629

110.130

123.222

119.411

118.626

120.821

119.079

119.206

118.863

120.522

119.168

116.314

116.787

114.826

108.421

110.704

109.051

109.692

118.885

110.093

116.585

108.931

110.108

110.526

111.549

110.811

111.919

111.579

111.736

112.338

108.067

110.497

109.830

111.559

110.607

112.082

112.184

111.443

111.794

C(13)

N(11)

C(9)

C(8)

C(5)

C(4)

C(3)

C(6)

C(9)

N(11)

C(39)

N(37)

C(35)

C(34)

C(31)

C(30)

C(29)

C(32)

C(35)

N(37)

C(3)

-168.892

-39.482

85.370

122.364

-0.499

Dihedral

Pro-R

Dihedral

Pro-R

-0.208

1.048

120.982

109.995

122.471

174.161

176.497

101.828

121.215

0.259

N(10)

O(12)

C(34)

C(30)

C(29)

C(31)

C(28)

C(27)

C(32)

O(33)

N(36)

O(38)

H(52)

H(53)

H(54)

H(55)

H(70)

H(71)

H(72)

H(73)

H(62)

H(80)

H(61)

H(63)

H(79)

H(81)

H(57)

H(60)

H(75)

H(78)

H(56)

H(58)

H(59)

H(64)

H(65)

H(66)

H(67)

H(68)

H(69)

H(74)

H(76)

H(77)

H(82)

H(83)

H(84)

H(85)

H(86)

H(87)

Pro-S

Pro-R

C(9)

C(8)

C(35)

C(34)

C(30)

C(29)

C(28)

C(31)

C(27)

C(34)

C(35)

C(2)

N(37)

C(35)

C(34)

C(29)

C(30)

C(29)

C(30)

C(28)

C(30)

C(34)

C(1)

Dihedral

Pro-S

Dihedral

Pro-S

Pro-R

Pro-S

Pro-R

Pro-S

Pro-R

Pro-S

Pro-R

Pro-S

Pro-R

Dihedral

Pro-S

Dihedral

Pro-S

Pro-R

Dihedral

Pro-S

-0.615

0.068

120.851

109.786

123.299

119.538

119.935

118.310

119.370

119.519

120.043

118.722

119.189

119.259

118.952

115.469

105.515

111.825

105.628

105.655

118.763

106.557

118.661

174.395

-179.954

104.250

64.818

107.629

107.675

178.773

106.969

106.318

-142.906

-60.142

104.758

63.503

107.499

107.493

70.791

107.028

107.894

C(3)

C(5)

C(6)

C(2)

C(4)

C(1)

C(4)

C(6)

C(5)

C(28)

C(29)

C(31)

C(32)

C(15)

C(41)

C(13)

C(16)

C(39)

C(42)

C(8)

C(27)

C(28)

C(30)

C(27)

C(13)

C(39)

N(11)

C(17)

N(37)

C(43)

C(4)

C(29)

C(30)

C(32)

C(31)

S(14)

S(40)

C(15)

N(19)

C(41)

N(45)

C(9)

N(11)

C(34)

N(37)

O(7)

C(9)

C(13)

C(35)

C(39)

C(2)

C(30)

C(35)

C(1)

C(8)

N(10)

C(21)

C(22)

O(33)

N(36)

C(47)

C(48)

C(4)

H(58)

S(14)

H(64)

S(14)

H(67)

C(28)

C(30)

H(76)

S(40)

H(82)

S(40)

H(85)

C(17)

C(27)

C(34)

C(43)

Pro-R

Dihedral

Pro-S

Dihedral

Pro-S

Pro-R

Dihedral

Pro-S

Pro-R

1

9

ACCEPTED MANUSCRIPT

Table 7: Internal coordinates parameters of complex 2

O

nd

Atom

Bond

Atom

Bond

Length(A)

Angle

Atom

Angle ( )

2

2 Angle

O

Angle

Atom

( )

Type

C(15)

N(19)

C(18)

C(16)

C(13)

C(23)

N(11)

S(14)

C(17)

O(20)

C(9)

C(21)

C(22)

O(24)

H(61)

H(62)

H(63)

Co(51)

O(25)

O(49)

O(50)

C(48)

C(41)

N(44)

C(40)

C(43)

C(42)

C(38)

S(39)

N(36)

C(46)

C(47)

O(45)

C(34)

C(8)

C(4)

C(3)

C(5)

C(2)

C(1)

C(6)

O(7)

N(10)

O(12)

C(33)

C(29)

C(28)

C(30)

C(27)

C(26)

C(31)

C(15)

N(19)

C(15)

C(16)

C(13)

C(15)

C(16)

C(18)

N(11)

C(17)

C(23)

C(13)

C(15)

C(16)

O(24)

Co(51)

O(49)

C(48)

C(41)

N(44)

C(41)

C(40)

C(38)

C(42)

C(43)

N(36)

C(9)

1.450

1.369

1.450

1.523

1.509

1.450

1.815

1.448

1.208

1.369

1.523

1.208

1.113

0.600

0.925

1.037

1.208

1.509

1.450

1.369

1.448

1.523

1.815

1.450

1.523

1.208

1.369

1.509

1.497

1.395

1.355

1.438

1.208

1.509

1.497

1.395

C(15)

N(19)

C(15)

C(13)

N(19)

C(13)

S(14)

C(16)

N(11)

C(13)

C(17)

C(23)

O(24)

O(25)

Co(51)

O(49)

C(48)

C(41)

C(40)

N(44)

C(38)

C(40)

S(39)

C(38)

N(11)

C(9)

C(8)

C(3)

C(4)

C(3)

C(4)

C(2)

C(4)

C(8)

N(36)

C(34)

C(33)

C(28)

C(29)

C(28)

C(29)

90.000

107.700

90.000

C(18)

C(16)

C(15)

C(18)

N(19)

C(23)

N(19)

C(15)

C(16)

C(17)

C(15)

S(14)

N(19)

C(16)

C(23)

O(25)

O(50)

O(49)

C(48)

C(41)

C(48)

C(41)

N(44)

C(43)

C(41)

N(44)

C(40)

C(13)

N(11)

C(9)

C(8)

C(5)

C(4)

C(3)

C(6)

C(9)

N(11)

C(38)

N(36)

C(34)

C(33)

C(30)

C(29)

C(28)

118.400

-130.638

171.335

115.566

104.000

108.773

132.532

-94.678

112.806

117.399

-118.783

124.021

108.464

107.906

180.000

0.000

Pro-R

Dihedral

Pro-S

Pro-R

Pro-S

Dihedral

Pro-S

Pro-R

Dihedral

Pro-R

108.773

115.566

109.000

112.161

132.532

120.000

112.806

117.399

157.690

96.389

119.594

107.906

90.000

Pro-R

Pro-S

Dihedral

Pro-R

Dihedral

Pro-S

Pro-R

Dihedral

Pro-R

Pro-S

90.000

115.957

108.504

90.000

157.595

108.773

107.700

90.000

135.374

-117.441

90.000

157.595

118.783

171.335

118.400

108.773

-130.638

104.000

115.566

112.806

117.399

132.532

-94.678

180.000

119.964

120.000

119.998

0.001

112.161

90.000

109.000

115.566

112.806

117.399

132.532

120.000

109.442

119.998

120.003

120.000

119.997

119.999

109.442

120.000

109.442

119.998

120.003

120.000

119.997

Pro-R

Pro-S

Dihedral

Pro-R

Dihedral

Pro-S

C(8)

C(4)

C(3)

C(2)

C(5)

C(1)

C(8)

-0.006

0.003

119.999

109.500

120.000

-180.000

119.964

120.000

119.998

0.001

Pro-S

C(9)

C(34)

C(33)

C(29)

C(28)

C(27)

C(30)

Dihedral

Pro-S

Dihedral

-0.006

0.003

2

0

ACCEPTED MANUSCRIPT

O(32)

N(35)

O(37)

H(52)

H(53)

H(54)

H(55)

H(70)

H(71)

H(72)

H(73)

H(80)

H(79)

H(81)

H(57)

H(75)

H(78)

H(56)

H(58)

H(59)

H(60)

H(64)

H(65)

H(66)

H(67)

H(68)

H(69)

H(74)

H(76)

H(77)

H(82)

H(83)

H(84)

H(85)

H(86)

H(87)

C(26)

C(33)

C(34)

C(2)

C(3)

C(5)

1.355

1.438

1.208

1.100

1.113

1.012

0.972

1.020

1.035

1.012

1.113

1.111

1.113

0.972

1.020

1.034

1.113

1.114

1.113

1.114

C(27)

C(29)

C(33)

C(1)

C(2)

C(4)

119.999

109.442

120.000

120.002

120.000

120.001

120.000

120.002

120.000

120.001

120.000

119.594

96.389

107.906

109.520

120.000

108.000

109.470

110.086

120.000

109.500

110.991

112.155

109.500

113.432

111.325

108.000

109.470

109.666

109.500

110.582

112.426

109.500

110.903

111.384

C(31)

C(34)

N(36)

C(3)

C(4)

C(6)

119.999

109.500

120.000

120.002

120.000

120.001

120.000

120.002

120.000

120.001

120.000

108.464

124.021

107.906

109.462

120.000

180.000

-180.000

104.799

120.000

73.115

107.231

107.442

113.028

107.924

107.669

-180.000

104.850

73.115

Pro-S

Pro-R

Pro-S

Pro-R

Pro-S

Pro-R

Pro-S

Pro-R

Dihedral

Pro-S

Dihedral

Pro-S

Pro-R

Dihedral

Pro-S

Pro-R

Dihedral

Pro-S

C(6)

C(1)

C(5)

C(27)

C(28)

C(30)

C(31)

C(40)

C(38)

C(41)

C(8)

C(26)

C(27)

C(29)

C(26)

C(38)

N(36)

C(42)

C(4)

C(29)

C(34)

C(1)

C(8)

C(28)

C(29)

C(31)

C(30)

S(39)

C(40)

N(44)

C(9)

C(33)

N(36)

O(7)

C(34)

C(38)

C(2)

N(10)

N(11)

C(21)

C(22)

O(32)

N(35)

C(46)

C(47)

C(4)

H(58)

C(13)

S(14)

H(64)

S(14)

H(67)

C(27)

C(29)

H(76)

S(39)

H(82)

S(39)

H(85)

C(9)

C(17)

C(26)

C(33)

C(42)

Dihedral

Pro-S

Pro-R

Dihedral

Pro-S

107.183

107.462

113.028

108.222

106.508

Pro-R

Table 8: Internal coordinates parameters of complex 4

o

nd

Atom

Bond

Atom

Bond

Length

Angle

Atom

Angle ( )

2 Angle

o

Atom

( )

Type

(

A)

C(15)

N(19)

C(18)

C(16)

C(13)

C(23)

N(11)

S(14)

C(17)

O(20)

C(9)

C(15)

N(19)

C(15)

C(16)

C(13)

C(15)

C(16)

C(18)

N(11)

C(17)

C(23)

C(13)

1.450

1.369

1.450

1.523

1.509

1.450

1.815

1.448

1.208

1.369

1.523

1.208

1.113

C(15)

N(19)

C(15)

C(13)

N(19)

C(13)

S(14)

C(16)

N(11)

90.000

107.700

90.000

C(18)

C(16)

C(15)

C(18)

N(19)

C(23)

N(19)

C(15)

C(16)

C(17)

C(15)

118.400

-130.638

171.335

115.566

104.000

108.773

132.532

-94.678

112.806

117.399

-118.783

124.021

Pro-R

Dihedral

Pro-S

Pro-R

Pro-S

Dihedral

Pro-S

Pro-R

Dihedral

Pro-R

108.773

115.566

109.000

112.161

132.532

120.000

112.806

117.399

125.802

96.389

C(21)

C(22)

O(24)

H(86)

2

1

ACCEPTED MANUSCRIPT

H(87)

H(88)

Fe(76)

O(25)

O(49)

O(50)

O(74)

O(75)

C(48)

C(41)

N(44)

C(40)

C(43)

C(42)

C(73)

C(66)

N(69)

C(65)

C(68)

C(67)

C(38)

S(39)

C(63)

S(64)

N(36)

C(46)

C(47)

N(61)

C(71)

C(72)

O(45)

O(70)

C(34)

C(59)

C(8)

C(4)

C(3)

C(5)

C(2)

C(1)

C(6)

O(7)

N(10)

O(12)

C(33)

C(29)

C(28)

C(30)

C(27)

C(26)

C(31)

O(32)

N(35)

O(37)

C(58)

C(54)

C(53)

C(55)

C(15)

C(16)

O(24)

Fe(76)

O(49)

C(48)

C(41)

N(44)

C(41)

O(74)

C(73)

C(66)

N(69)

C(66)

C(40)

C(65)

C(38)

C(42)

C(63)

C(67)

C(43)

C(68)

N(36)

N(61)

C(9)

1.113

1.810

1.809

1.846

1.810

1.208

1.509

1.450

1.369

1.448

1.208

1.509

1.450

1.369

1.448

1.523

1.815

1.523

1.815

1.450

1.523

1.450

1.523

1.208

1.369

1.509

1.497

1.395

1.355

1.438

1.208

1.509

1.497

1.395

1.355

1.438

1.208

1.509

1.497

1.395

C(13)

C(17)

C(23)

O(24)

O(25)

Fe(76)

O(49)

C(48)

C(41)

C(40)

N(44)

Fe(76)

O(74)

C(73)

C(66)

C(65)

N(69)

N(44)

C(38)

N(69)

C(63)

C(40)

S(39)

C(65)

S(64)

C(38)

C(63)

C(38)

C(63)

N(11)

C(9)

C(8)

C(3)

C(4)

C(3)

C(4)

C(2)

C(4)

C(8)

N(36)

C(34)

C(33)

C(28)

C(29)

C(28)

C(29)

C(27)

C(29)

C(33)

N(61)

C(59)

C(58)

C(53)

119.594

107.906

90.000

127.710

99.315

90.000

144.227

108.773

107.700

90.000

112.161

90.000

144.227

108.773

107.700

90.000

112.161

90.000

S(14)

N(19)

C(16)

C(23)

O(50)

O(25)

O(50)

O(49)

C(48)

C(41)

C(48)

O(25)

O(75)

O(74)

C(73)

C(66)

C(73)

C(41)

N(44)

C(66)

N(69)

C(43)

C(41)

C(68)

C(66)

N(44)

N(69)

C(40)

C(65)

C(13)

N(11)

C(9)

108.464

107.906

180.000

0.000

-119.785

177.129

180.000

0.000

Pro-R

Pro-S

Dihedral

Pro-R

Dihedral

Pro-S

Dihedral

Pro-S

Pro-R

Dihedral

Pro-S

Dihedral

Pro-S

Pro-R

Dihedral

Pro-R

Dihedral

Pro-R

Pro-S

Pro-R

90.000

144.227

118.783

171.335

118.400

108.773

-90.000

144.227

-55.603

171.335

118.400

108.773

-130.638

104.000

-130.638

104.000

115.566

112.806

117.399

115.566

112.806

117.399

132.532

-94.678

180.000

119.964

120.000

119.998

0.001

109.000

90.000

109.000

115.566

112.806

117.399

115.566

112.806

117.399

132.532

120.000

109.442

119.998

120.003

120.000

119.997

119.999

109.442

120.000

109.442

119.998

120.003

120.000

119.997

119.999

109.442

120.000

109.442

119.998

120.003

Pro-S

Pro-R

Pro-S

Dihedral

Pro-R

Dihedral

Pro-R

C(8)

C(4)

C(3)

C(2)

C(5)

C(1)

C(8)

C(5)

C(4)

C(3)

C(6)

C(9)

-0.006

0.003

119.999

109.500

120.000

180.000

119.964

120.000

119.998

0.001

Pro-S

Pro-R

C(9)

N(11)

C(38)

N(36)

C(34)

C(33)

C(30)

C(29)

C(28)

C(31)

C(34)

N(36)

C(63)

N(61)

C(59)

C(58)

C(34)

C(33)

C(29)

C(28)

C(27)

C(30)

C(26)

C(33)

C(34)

C(59)

C(58)

C(54)

Dihedral

Pro-S

Dihedral

Pro-R

Pro-S

Pro-R

Dihedral

Pro-S

-0.006

0.003

119.999

109.500

120.000

180.000

119.964

120.000

119.998

2

ACCEPTED MANUSCRIPT

C(52)

C(51)

C(56)

O(57)

N(60)

O(62)

H(77)

H(78)

H(79)

H(80)

H(95)

H(96)

H(97)

C(53)

C(52)

C(55)

C(51)

C(58)

C(59)

C(2)

C(3)

C(5)

C(6)

C(27)

C(28)

C(30)

C(31)

C(52)

C(53)

C(55)

C(56)

C(40)

C(65)

C(38)

C(41)

C(63)

C(66)

C(8)

1.395

1.355

1.438

1.208

1.100

1.113

1.012

1.113

1.012

0.972

1.020

1.034

1.012

1.113

1.110

1.113

0.972

1.020

1.035

1.113

1.114

1.113

1.112

1.114

0.972

1.020

1.035

1.113

1.114

C(54)

C(53)

C(54)

C(52)

C(54)

C(58)

C(1)

C(2)

C(4)

C(1)

C(26)

C(27)

C(29)

C(26)

C(51)

C(52)

C(54)

C(51)

C(38)

C(63)

N(36)

C(42)

N(61)

C(67)

C(4)

120.000

119.997

119.999

109.442

120.000

120.002

120.000

120.001

120.000

120.002

120.000

120.001

120.000

120.002

120.000

120.001

120.000

119.594

96.389

C(55)

C(54)

C(53)

C(56)

C(59)

N(61)

C(3)

C(4)

C(6)

C(5)

C(28)

C(29)

C(31)

C(30)

C(53)

C(54)

C(56)

C(55)

S(39)

S(64)

C(40)

N(44)

C(65)

N(69)

C(9)

0.001

-0.006

0.003

Dihedral

Pro-S

Pro-R

Pro-S

Pro-R

Pro-S

Pro-R

Pro-S

Pro-R

Pro-S

Pro-R

Pro-S

Pro-R

Pro-S

Dihedral

Pro-S

Pro-R

Dihedral

Pro-S

119.999

109.500

120.000

120.002

120.000

120.001

120.000

120.002

120.000

120.001

120.000

120.002

120.000

120.001

120.000

108.464

124.021

107.906

124.021

107.906

109.462

120.000

109.462

120.000

180.000

105.325

120.000

73.115

106.868

106.885

113.028

107.715

107.390

180.000

-180.000

105.528

73.115

107.188

107.526

113.028

107.209

107.307

-180.000

180.000

105.504

73.115

H(98)

H(113)

H(114)

H(115)

H(116)

H(105)

H(123)

H(104)

H(106)

H(122)

H(124)

H(82)

H(100)

H(103)

H(118)

H(121)

H(81)

H(83)

H(84)

H(85)

H(89)

H(90)

H(91)

H(92)

H(93)

107.906

96.389

107.906

109.520

120.000

109.520

120.000

108.000

109.470

109.865

120.000

109.500

110.784

112.154

109.500

112.751

110.973

108.000

109.470

109.839

109.500

111.133

111.919

109.500

111.454

111.370

108.000

109.470

109.836

109.500

110.846

112.000

109.500

111.260

111.531

C(33)

N(36)

C(58)

N(61)

O(7)

C(29)

C(34)

C(54)

C(59)

C(1)

C(8)

C(9)

C(34)

C(38)

C(59)

C(63)

C(2)

N(10)

N(11)

C(21)

C(22)

O(32)

N(35)

C(46)

C(47)

O(57)

N(60)

C(71)

C(72)

C(4)

H(83)

C(13)

S(14)

H(89)

S(14)

H(92)

C(27)

C(29)

H(101)

S(39)

H(107)

S(39)

H(110)

C(52)

C(54)

H(119)

S(64)

H(125)

S(64)

H(128)

C(17)

C(26)

C(33)

C(42)

C(51)

C(58)

C(67)

Pro-R

Dihedral

Pro-S

H(94)

H(99)

Pro-R

Dihedral

Pro-S

Dihedral

Pro-S

Pro-R

Dihedral

Pro-S

H(101)

H(102)

H(107)

H(108)

H(109)

H(110)

H(111)

H(112)

H(117)

H(119)

H(120)

H(125)

H(126)

H(127)

H(128)

H(129)

H(130)

Pro-R

Dihedral

Pro-S

Dihedral

Pro-S

Pro-R

Dihedral

Pro-S

106.860

107.095

113.028

107.679

107.192

Pro-R

2

3

ACCEPTED MANUSCRIPT

Table 9: Energy data produced from molecular docking calculations of AMX drug

with receptor prostate cancer mutant 2q7khormone

Est. Free energy

of binding

Est. inhibition

Electrostatic

Total

intermolecular

energy (kcal/mol)

4.73

Interact surface

constant, K (μM) energy (kcal/mol)

i

(

kcal/mol)

-

4.712

443.18

-1.464

360.777

Fig. 6: The AMX drug (green in (A) and blue in (B)) in the interaction with receptor

prostate cancer mutant 2q7khormone. (For interpretation of the references to color in

this figure legend, the reader is referred to the web version of this article).

2

4

ACCEPTED MANUSCRIPT

Fig. 7: The 2D plot of interaction between AMX with receptor prostate cancer mutant

2

q7khormone.

Fig. 8: HB plot of interaction between AMX drug and 2q7k receptor mutant.

2

5

ACCEPTED MANUSCRIPT

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Highlights



Preparation of of Cu(II), Co(II), Ni(II) and Fe(III) chelates of

amoxicillin antibiotic drug.



Spectroscopic and thermal analyses were performed.

The stoichiometry of 1:2 (Metal : AMX) complexes was explained

.



The values of molar conductance for the AMX complexes led to

electrolytic behavior.

2

9

Article Doi

Spectroscopic and molecular structure characterization of Cu(II), Co(II), Ni(II) and Fe (III) amoxicillin antibiotic drug complexes in alcoholic media

DOI: 10.1016/j.molliq.2016.05.050

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