Tri-butyltin(IV)phenoxyacetohydroxamate: Synthesis,characterization,biological evaluation and molecular docking studies

Abstract

The tri-organotin(IV) complex of composition [n-Bu₃Sn(C₆H₅OCH₂CONHO)] has been synthesized by using Bu₃SnCl and potassium phenoxyacetohydroxamate ligand (KPAH) in pre-determined molar ratio of methanol and tetrahydrofuran. These are characterized by spectral techniques like FTIR, ¹ H NMR and mass spectrometry. Studies on electrochemical processes are carried out using cyclic voltammetry. The in vitro antibacterial and antifungal activities performed by using minimum inhibitory concentration (MIC) method has revealed complex as biologically active. Molecular docking of the ligand and complex has been performed against the fungal receptor (PDB ID: 1UKC) to study the interactions between compound and receptor.

Keywords

Tri-butyltin(IV)phenoxyacetohydroxamate complex spectral studies antimicrobial activity molecular docking

1 Introduction

Due to structural complexities, the organotin(IV) compounds have drawn more research interest among various organometallic compounds [1, 2]. In pharmaceutical industries, the synthesis of organotin(IV) compounds as an effective drug with low toxicity and high activity for the medicinal applications has continuously been increasing. The majority of applications of organotin compounds are in catalytic, biological, medicine and material science [3 –7].

Hydroxamic acids, R’(CO)N(OH)R” (R’ = alkyl/aryl; R” = H or alkyl/aryl); a class of weak organic acids have much biochemical interest as an active pharmacological agent as they exhibit wide variety of biological activities [8, 9]. Due to metal-binding property, the hydroxamic acids are used by micro-organisms and they substitute for antibacterial, anti-inflammatory, antihypertensive, antitumor, psychotropic and insecticidal [10 –12].

Thus, on account of biological importance of both organotin compounds and hydroxamic acids, we report herein the synthesis of tri-butyltin(IV) phenoxyacetohydroxamate [13 –16] by the reaction of Bu₃SnCl with biologically significant functionally substituted potassium phenoxyacetohydroxamate (KPAH) ligand. The antimicrobial potential against standard bacteria and fungi of potassium phenoxyacetohydroxamate (KPAH) ligand and tri-butyltin(IV) phenoxyacetohydroxamate [n-Bu₃Sn(C₆H₅OCH₂CONHO)] complex has been studied thoroughly.

2 Experimental

2.1 Materials and method

Before use, all the reagent and solvents were dried and distilled. The synthesis of potassium phenoxyhydroxamate (KPAH) was carried by reported method [13]. At 18±1°C, the molar conductance of the complex solution (10^-3 M) was measured using a CON510; Bench conductivity/ TDS meter.

The FTIR (Fourier Transform Infrared) spectra of ligand and complex were recorded on a Nicolet-5700 spectrophotometer using potassium bromide (KBr) pellets. The ¹ H NMR spectra of the complex was recorded on Bruker Avance II 400 spectrometer using DMSO-d6 as solvent and TMS as an internal standard. The mass spectrometer Waters QTOF-MICROMASS is used to record an Electrospray ionization mass spectrum (ESI-MS) of complex. Autolab Potentiostat 128 N electrochemical analyzer was used to perform cyclic voltammetric measurements. A negative scan was initiated in positive direction at a scan rate 100 mVs^-1 with the scan in –2 to +2 V range in 10^-4 M methanolic solution with 10^-2 M KCl as supporting electrolyte. The potentials were measured against reference electrode Ag/AgCl, Pt-working and auxiliary electrodes.

2.2 Synthesis of tri-butyltin(IV)phenoxyacetohydroxamate

The solution of n-Bu₃SnCl (0.006 mol) was added to potassium phenoxyacetohydroxamate (0.013 mol) solution. The reaction mixture was refluxed for 24 h where formation of a white solid (KCl) was observed. By distillation, the excess of solvent was removed from the filtrate and then by using distilled petroleum ether concentrate was treated. The petroleum ether addition immediately separates the solid cream which was recrystallized after drying appropriately under vacuum (Yield 78%).

2.3 Antimicrobial activity assay

The in vitro antibacterial and antifungal activities of potassium phenoxyhydroxamate (KPAH) and tri-butyltin(IV) phenoxyacetohydroxamate complex were evaluated by MIC method against bacteria and fungi using two fold serial dilution and Resazurin as oxidation-reduction colorimetric indicator [17]. For both ligand and complex, the stock solutions were prepared in DMSO (100μg/mL). The standard antibacterial drug: chloramphenicol for S. aureus, S. typhi, E. Coli and B. cereus and antifungal drug: Nystatin for A. niger and A. alternate were used for comparison of results [18]. These studies were performed in triplicate.

2.4 Molecular modelling study

To find suitable interactions of ligand and complex against crystal structure of fungal receptor A. niger (PDB ID: 1UKC), molecular docking study was performed. For docking, Autodock tool 4.2 was used and chain-A was selected. Gasteiger charges were assigned to the ligand and complex before docking. Most of the docking parameters were kept as default. The distance measurements among the interacting residues were completed on PyMol [19 –21].

3 Results and Discussion

The reaction of tri-n-butyltinchloride (Bu₃SnCl) with potassium phenoxyacetohydroxamate in pre-determined molar ratio 1:1 (metal:ligand) in anhydrous methanol and benzene under reflux at 68°C result in tri-butyltin(IV) phenoxyacetohydroxamate complex of composition [n-Bu₃Sn(C₆H₅OCH₂CONHO)] shown by the equation (Fig. 1).

Fig. 1

Synthesis of tri-butyltin(IV)phenoxyacetohydroxamate complex.

This complex is a cream colored solid with sharp melting point and easily soluble in nearly all usual organic solvents. The recorded molar conductance is 1.65 and 1.70 mathchar " 1356_mScm²mol^-1 in 1–3 M methanol for ligand and complex respectively (Table 1) representing their non-electrolytic nature [22]. The structure of complex [n-Bu₃Sn(C₆H₅OCH₂CONHO)] is shown in Fig. 2.

Table 1

The analytical data of the ligand and complex

Ligand/	Colour	Yield (%)	Melting	Elemental analysis				Mol.Wt	Molar
Complex			point °C)	% Found (Calc.)				Found	conductance
				C	H	N	Sn		(Λ_m S cm² mol^-1)
C₆H₅OCH₂CONHOK	Light Brown	86	107	46.54 (46.83)	3.48 (3.91)	6.53 (6.82)	–	207 (205)	1.65
[n-Bu₃Sn (C₆H₅OCH₂CONHO)]	Yellow	78	210	49.48 (52.66)	7.64 (7.73)	4.77 (3.07)	26.48 (26.02)	463 (457)	1.70

Fig. 2

Structure of tri-butyltin(IV) phenoxyacetohydroxamate complex.

3.1 IR Spectra

The synthesis of complex tri-butyltin(IV) phenoxyacetohydroxamate has been ascertained through carefully assessing its IR spectra with KPAH ligand recorded in 4500–450 cm^-1 region (Table 2 and Figures S1, S2). A sharp absorption band at ∼3178 cm^-1 in free ligand corresponds to ν(N-H) mode. The bands appearing at 1687 cm^-1, 1276 cm^-1 and 987 cm^-1 correspond to ν(C = O), ν(C-N) and ν(N-O) modes respectively and are in agreement with the reported literature [23]. The absorption band at 3211 cm^-1 in [n-Bu₃Sn(C₆H₅OCH₂CONHO)] indicates the characteristic ν(N-H) mode. The absorption bands due to ν(C = O), ν(C-N) and ν(N-O) modes have been obtained at 1682 cm^-1, 1247 and 998 cm^-1 respectively.

Table 2
IR spectral data for ligand and complex

Ligand/ Complex Bands (cm^-1)

Ligand [KPAH] 3178, 1687, 1454, 1351, 1276, 1195, 1167, 1088, 1020, 987, 937, 745, 709, 686, 593, 541, 525, 460

Complex [n-Bu₃Sn(C₆H₅OCH₂CONHO)] 3211, 1682, 1246, 1167, 1139, 1084, 998, 936, 802, 745, 709, 689, 584, 544, 523, 435, 442

Ligand/ Complex	Bands (cm^-1)
Ligand [KPAH]	3178, 1687, 1454, 1351, 1276, 1195, 1167, 1088, 1020, 987, 937, 745, 709, 686, 593, 541, 525, 460
Complex [n-Bu₃Sn(C₆H₅OCH₂CONHO)]	3211, 1682, 1246, 1167, 1139, 1084, 998, 936, 802, 745, 709, 689, 584, 544, 523, 435, 442

The retention of band due to ν(N-H) modes at 3211 cm^-1 in complex has indicated that nitrogen does not participate in bonding. The ν(C = O) absorption band has been shifted to lower frequency in tri-butyltin(IV) phenoxyacetohydroxamate complex. The shift observed in various modes such as ν(C = O), ν(C-N) and ν(N-O) has shown bonding by carbonyl and hydroxylamine oxygen atoms [O,O coordination] which signify that ligand is of bi-dentate nature. The complex formation and bonding by carbonyl oxygen and hydroxylamine group has further been assured by new band appeared at 435 cm^-1 which is assigned to ν(Sn-O) mode [13, 24].

3.2 ¹H NMR Spectra

The formation of tri-organotin(IV) phenoxyacetohydroxamate has further been validated by comparison of its room temperature ¹H NMR with free ligand [KPAH] (Table 3 and Figures S3, S4). The ligand [KPAH] show signals due to –NH proton, aromatic protons and –CH₂ at chemical shift (δ) values 10.69–10.95 ppm, 6.91–7.59 ppm and 3.37–3.75 ppm respectively. The complex of composition [n-Bu₃Sn(C₆H₅OCH₂CONHO)] exhibits –NH, aromatic proton and -CH₂ proton signals respectively at 11.89 ppm, 7.06–7.67 ppm and at 3.46–4.35 ppm. The aromatic protons has shown downfield shift in complex as compared to ligand. The N-H proton resonance in ligand as well as in complex has shown that nitrogen does not participate in coordination. The DMSO-d6 exhibits a sharp signal in 2.50–2.51 ppm range for both ligand and complex. The signal appeared in 1.13–1.35 ppm range due to n-butyl group in complex which is absent in free ligand has further substantiated the complex formation. The resonance observed in ¹H NMR spectra of the complex substantiated their formation.

Table 3
The chemical shift δ (in ppm) for ligand and complex obtained from ¹H NMR

Ligand/ Complex -NH- -CH₂- Aromatic Protons

Ligand [KPAH] 10.69–10.95 3.37–3.75 6.91–7.59

Complex [n-Bu₃Sn(C₆H₅OCH₂CONHO)] 11.89 3.46–4.35 7.06–7.67

Ligand/ Complex	-NH-	-CH₂-	Aromatic Protons
Ligand [KPAH]	10.69–10.95	3.37–3.75	6.91–7.59
Complex [n-Bu₃Sn(C₆H₅OCH₂CONHO)]	11.89	3.46–4.35	7.06–7.67

3.3 Mass spectra

The ESI mass spectrum of newly synthesized [n-Bu₃Sn(C₆H₅OCH₂CONHO)] complex has no molecular ion peak but it has shown di-tin fragment ions at m/z (%) 955 (2), 812 (12), 764 (10) and 634 (6.5) corresponding to [n-Bu₆Sn₂(C₆H₅OCH₂CONHO)₂ + K +]⁺, [n-Bu₆Sn₂(C₆H₅OCH₂CONHO) + K+ + Na⁺]⁺, [n-Bu₃Sn₂(C₆H₅OCH₂CONHO)₂ + Na⁺]⁺ and [n-Bu₄Sn₂(C₆H₅OCH₂CONHO) + Na⁺]⁺ respectively. The fragment ions at m/z (%) 523 (23), 485 (7) and 263 (21) have been accounted for [M+ + 3Na⁺]⁺, [M+ + Na⁺ + 6H⁺]⁺ and [LK + K+ + Na⁺ -5H⁺] respectively. The fragment ion corresponding to [C₆H₅OCH₂CON]⁺ has been appeared as a base peak at m/z (%) 150 (100). (Tables 4 and Figure S5).

Table 4
Mass spectral data of complex

Fragment ion m/z (%)

[n-Bu₆Sn₂(C₆H₅OCH₂CONHO)₂ + K +]⁺ 955 (2)

[n-Bu₆Sn₂(C₆H₅OCH₂CONHO) + K+ + Na⁺]⁺ 812 (12)

[n-Bu₃Sn₂(C₆H₅OCH₂CONHO)₂ + Na⁺]⁺ 764 (10)

[n-Bu₄Sn₂(C₆H₅OCH₂CONHO) + Na⁺]⁺ 634 (6.5)

[M+ + 3Na⁺]⁺ 523 (23)

[M+ + Na⁺ + 6H⁺]⁺ 485 (7)

[LK + K+ + Na⁺ -5H⁺] 263 (21)

[C₆H₅OCH₂CON]⁺ 150 (100)

Fragment ion	m/z (%)
[n-Bu₆Sn₂(C₆H₅OCH₂CONHO)₂ + K +]⁺	955 (2)
[n-Bu₆Sn₂(C₆H₅OCH₂CONHO) + K+ + Na⁺]⁺	812 (12)
[n-Bu₃Sn₂(C₆H₅OCH₂CONHO)₂ + Na⁺]⁺	764 (10)
[n-Bu₄Sn₂(C₆H₅OCH₂CONHO) + Na⁺]⁺	634 (6.5)
[M+ + 3Na⁺]⁺	523 (23)
[M+ + Na⁺ + 6H⁺]⁺	485 (7)
[LK + K+ + Na⁺ -5H⁺]	263 (21)
[C₆H₅OCH₂CON]⁺	150 (100)

3.4 Cyclic voltammetry (CV)

The cyclic voltammetric measurements for the ligand [KPAH] and respective tri-organotin(IV) hydroxamate of composition [n-Bu₃Sn(C₆H₅OCH₂CONHO)] has been carried out. The voltammetric scans are shown in (Figures S6, S7). The ligand [KPAH] has shown reduction wave at +0.643 V and oxidation wave at –0.514 V. The complex of composition [n-Bu₃Sn(C₆H₅OCH₂CONHO)] has shown reduction wave at +0.625 V and one oxidation wave at –0.576 V. The observed voltammograms are suggestive of electrochemically reversible reduction reaction which is herein seemed to be metal centered.

3.5 Antimicrobial activity

The biological potential of tri-organotin(IV) compounds have been affected by the hydroxamate ligand’s nature and the number of organic groups coupled with tin [25]. The organotin(IV) complexes have a large number of biological applications with different ligands [26 –29].

3.5.1 Antibacterial activity

The inhibitory effect of ligand [KPAH] against B. cereus and S. aureus has been observed at MIC 19.38 and 18.70μg/ml whereas for E. coli and S. typhi at 18.70 and 4.60μg/ml MIC respectively. The complex of composition [n-Bu₃Sn(C₆H₅OCH₂CONHO)] has shown MIC at 8.81, 8.81, 14.86 and 3.35μg/ml against B. cereus, S. aureus, E. coli and S. typhi respectively. The observed MIC values indicate that complex exhibit promising antibacterial activity against all tested bacteria which is even better than the free ligand [KPAH]. The commercial antibiotic Chloramphenicol has been chosen as a standard for comparing the results (Table 5 and Fig. 3).

Table 5
Antibacterial and Antifungal activity data for ligand, complex and standard antibiotic using MIC (in μg/mL) method

Bacteria/Fungi Ligand Complex Antibiotic

S. typhi 4.6±0.08 3.35±0.06 2.64±0.03

E. coli 18.7±0.1 14.86±0.1 10.90±0.08

B. cereus 19.38±0.3 8.81±0.05 5.27±0.07

S. aureus 18.7±0.09 8.81±0.09 2.64±0.09

A. alternate 5.83±0.05 3.23±0.08 1.36±0.05

A. niger 5.83±0.07 3.23±0.05 1.36±0.07

Bacteria/Fungi	Ligand	Complex	Antibiotic
S. typhi	4.6±0.08	3.35±0.06	2.64±0.03
E. coli	18.7±0.1	14.86±0.1	10.90±0.08
B. cereus	19.38±0.3	8.81±0.05	5.27±0.07
S. aureus	18.7±0.09	8.81±0.09	2.64±0.09
A. alternate	5.83±0.05	3.23±0.08	1.36±0.05
A. niger	5.83±0.07	3.23±0.05	1.36±0.07

Fig. 3

In vitro antibacterial, antifungal spectra of ligand [KPAH], tri-butyltin(IV) phenoxyacetohydroxamate complex (I) and antibiotic.

3.5.2 Antifungal activity

The inhibition effect against A. alternata and A. niger of the ligand [KPAH] has been observed respectively at MIC 5.83μg/ml and 5.83μg/ml. The complex of composition [n-Bu₃Sn(C₆H₅OCH₂CONHO)] has shown inhibitory activity at 3.23μg/ml against both A. alternata and A. niger. The Complex has shown increased inhibitory activity compared to the free ligand [KPAH] against both fungi. The chelation theory may explain the enhanced antimicrobial activity of the complex with respect to the ligand. Upon complexation, the polarity of central metal ion is partially reduced due to sharing of its positive charge with ligand, favoring complex permeation via lipid cell membrane [30].

3.6 Molecular docking study

The interactions between drug molecule and receptor have been predicted by Molecular docking study. The affinity of ligand [KPAH] and tri-butyltin(IV) phenoxyacetohydroxamate complex towards A. niger fungal receptor (PDB ID: 1UKC) has been evaluated by determining their binding energies, inhibition constant as well as bonding interactions. The estimated free binding energy of the ligand and complex has been found to be –2.59 kcal/mol and –3.94 kcal/mol whereas inhibition constant (Ki) values are 1.30 and 12.71 mM respectively (Table 6).

Table 6
The estimated binding energy and inhibition constant from docking of ligand and complex with A. niger fungal receptor

Ligand/Complex Receptor Binding free energy (kcal/mol) Inhibition constant (Ki) (mM) Internal Energy (U) Kcal/mol

Ligand [KPAH] 1UKC –2.59 1.30 –0.75

Complex [n-Bu₃Sn(C₆H₅OCH₂CONHO)] 1UKC –3.94 12.71 –3.76

Ligand/Complex	Receptor	Binding free energy (kcal/mol)	Inhibition constant (Ki) (mM)	Internal Energy (U) Kcal/mol
Ligand [KPAH]	1UKC	–2.59	1.30	–0.75
Complex [n-Bu₃Sn(C₆H₅OCH₂CONHO)]	1UKC	–3.94	12.71	–3.76

The amino acid residues Glu 338, Gly 339, Thr 401 and Asp 397 of A. niger fungal receptor have shown hydrogen bonding interactions with phenoxy -O, -CO, -NO and -NH of ligand (Table 7 and Fig. 4A). The residues Leu 298 and Asp 300 are hydrogen bonded with -NH of complex. The amino acid residue Tyr 344 (Phenol ring) is involved in π-interactions with phenyl ring of the complex. The van der waals interactions have been observed between tin and Asp 300 (Table 8 and Fig. 4B).

Table 7

Distances between the interacting residues of A. niger fungal receptor and Ligand

Interacting Residues of	Distance (Å)	Bond type
Receptor::Ligand
A: GLY339 NH::Phenoxy-O	3.45	Hydrogen Bond
A: GLU338NH::CO	1.80
A:THR401 OH::NO	1.93
A:ASP397 CO::NH	2.23

Fig. 4

(A) Secondary structure of A. niger fungal receptor (PDB ID: 1UKC) where interacting residues are represented by sticks (green colour) and ligand is shown by cyan colour sticks. The interactions of ligand with amino acid residues are shown by dotted lines. The interacting residues are named with their respective three letters code. (B) Secondary structure of A. niger fungal receptor (PDB ID: 1UKC) where interacting residues are represented by green colour sticks and complex is shown by cyan colour sticks. The interactions of amino acid residues (represented with three letters code) of receptor with complex are shown by dotted lines.

Table 8

Distances between the interacting residues of A. niger fungal receptor and Complex

Interacting Residues of	Distance (Å)	Bond type
Receptor:: Complex
A:ASP 300 γCO::Sn	4.81	van der wall Interactions
A: ASP 300 γCO:: NH	2.29	Hydrogen Bond
A: ASP 300 NH:: NH	3.95
A: LEU 298 CO:: NH	2.43
A: TYR344 Phenol ring::Phenyl ring	3.41, 4.58	Π-interactions

Thermal energy (Internal energy) of the molecule can be related with binding energy of the molecule. The molecule with lower internal energy has more binding ability with the receptor. The molecular docking study reveals that complex has lower internal energy as compare to the ligand which indicate that complex has more binding affinity.

4 Conclusion

The tri-butyltin(IV) phenoxyacetohydroxamate complex has been synthesized by reaction of Bu₃SnCl with potassium phenoxyacetohydroxamate [KPAH]. Various spectral techniques like FTIR, ¹H NMR and mass spectrometry are used for characterization purpose. The carbonyl and hydroxylamine oxygen atoms [O,O coordination] bonding is specified from IR spectra. From different spectral studies, geometry proposed around tin is five-coordinate distorted trigonal bi-pyramidal. Electrochemical properties studied using cyclic voltammetry suggest metal-centered, two electron quasi-reversible reductions.

The antimicrobial activity of ligand and complex studied using MIC method against bacteria and fungi has revealed complex [n-Bu₃Sn(C₆H₅OCH₂CONHO)] as biologically active. Molecular docking of ligand and complex against A. niger fungal receptor has shown more negative binding energy and increased inhibition constant value further establishing more strong binding (interactions) with complex.

Conflict of interest

The authors have declared no conflict of interest.

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Tri-butyltin(IV)phenoxyacetohydroxamate: Synthesis,characterization,biological evaluation and molecular docking studies

Abstract

Keywords

1 Introduction

2 Experimental

2.1 Materials and method

2.2 Synthesis of tri-butyltin(IV)phenoxyacetohydroxamate

2.3 Antimicrobial activity assay

2.4 Molecular modelling study

3 Results and Discussion

Table 3 The chemical shift δ (in ppm) for ligand and complex obtained from 1H NMR Ligand/ Complex -NH- -CH2- Aromatic Protons Ligand [KPAH] 10.69–10.95 3.37–3.75 6.91–7.59 Complex [n-Bu3Sn(C6H5OCH2CONHO)] 11.89 3.46–4.35 7.06–7.67

3.5 Antimicrobial activity

3.5.1 Antibacterial activity

3.6 Molecular docking study

Conflict of interest

References

Table 3
The chemical shift δ (in ppm) for ligand and complex obtained from ¹H NMR

Ligand/ Complex -NH- -CH₂- Aromatic Protons

Ligand [KPAH] 10.69–10.95 3.37–3.75 6.91–7.59

Complex [n-Bu₃Sn(C₆H₅OCH₂CONHO)] 11.89 3.46–4.35 7.06–7.67