Synthesis, antibacterial, antifungal activity and interaction of CT-DNA with a new benzimidazole derived Cu(II) complex

doi:10.1016/j.ejmech.2005.05.005

European Journal of Medicinal Chemistry

Volume 40, Issue 11, November 2005, Pages 1103-1110

https://doi.org/10.1016/j.ejmech.2005.05.005 Get rights and content

Abstract

The ligand [C₁₆H₁₀O₂N₄S₂] L has been synthesized by the condensation reaction of 2-mercaptobenzimidazole and diethyloxalate. The ligand L was allowed to react with bis(ethylenediamine)Cu^II/Ni^II complexes to yield [C₂₀H₂₂N₈S₂Cu]Cl₂ 1 and [C₂₀H₂₂N₈S₂Ni]Cl₂ 2 complexes. The Ni(II) complex was synthesized only to elucidate the structure of the complex. The complexes 1 and 2 were characterized by elemental analyses, IR, NMR, EPR, UV–vis spectroscopy and molar conductance measurements. Both the complexes are ionic in nature and possess square–planar geometry. The binding of the complex 1 to calf thymus DNA was investigated spectrophotometrically. The absorption spectra of complex 1 exhibits a slight red shift with “hyperchromic effect” in presence of CTDNA. Electrochemical analysis and viscosity measurements were also carried out to ascertain the mode of binding. The complex 1 in the absence and in presence of CT DNA in aqueous solution exhibits one quasi-reversible redox wave corresponding to Cu^II/Cu^I redox couple at a scan rate of 0.2 V s⁻¹. The shift in ΔE_p, E_1/2 and I_pa/I_pc values ascertain the interaction of calf thymus DNA with copper(II) complex. There is decrease in viscosity of CTDNA which indicates that the complex 1 binds to CTDNA through a partial intercalative mode. The antibacterial and antifungal studies of the [C₇H₆N₂S], [C₄H₁₆N₄Cu]Cl_2, [C₁₆H₁₀N₄S₂O₂] and [C₂₀H₂₂N₈S₂Cu]Cl₂ were carried out against S. aureus, E. coli and A. niger. All the results reveal that the complex 1 is highly active against the bacterial strains and also inhibits fungal growth.

Introduction

There is a considerable interest in the pharmacology of heterocyclic ligands and their metal chelates [1], [2]. In general, nitrogen and sulfur containing organic compounds and their metal complexes display a wide range of biological activity [3], [4], [5], [6], as antitumor, antibacterial, antifungal and antiviral agents. Benzimidazole substituted derivatives are inhibitors of cyclin-dependent kinase and useful for inhibiting cell proliferation, in for the treatment of cancer. The activity of these compounds have been determined by cyclin-dependent kinase (CDK) 4/cyclin D1 and CDK2/cyclin E flashplate assays [7].

Bis-benzimidazoles have potent activity against a number of microorganisms including those that lead to AIDS-related infections [8]. These compounds bind to DNA in AT-rich sequences [9] Recently, benzimidazole derived drugs have received much attention owing to the fact that benzimidazole residue is a constituent of vitamin B₁₂ [9] which supports their potential use as therapeutics [10]. Benzimidazole, sometimes called 1,3-dideazapurine and its derivatives can serve as model compounds for purine due to the structural similarity [11], [12].

Copper complexes have been extensively utilized in metal-mediated DNA cleavage for the generation of activated oxygen species [13], [14]. It has been reported that tetraaza macrocyclic copper complexes have shows anti-HIV activities, furthermore copper accumulates in tumors due to the selective permeability of cancer cell membranes to copper compounds. For this reason, a number of copper complexes were screened for anticancer activity and some of them were found active both in vivo and in vitro [15], [16].

To design improved drugs that target the cellular DNA and to understand the mechanism of action at the molecular level, we have synthesized new benzimidazole ligand [C₁₆H₁₀O₂N₄S₂] and its metal complexes [C₂₀H₂₂N₈S₂Cu]·Cl₂ and [C₂₀H₂₂N₈S₂Ni]·Cl_2. Binding studies of the potential drug complex [C₂₀H₂₂N₈S₂Cu]·Cl₂ with calf thymus DNA (CTDNA) were studied by electronic absorption spectroscopy, cyclic voltammetric and viscosity measurements. Antibacterial and antifungal activities of the complex [C₂₀H₂₂N₈S₂Cu]Cl₂ were screened against S. aureus and E. coli (bacteria) and A. niger (fungus).

Section snippets

Reagents

2-Mercaptobenzimidazole (Fluka), diethyl oxalate, NiCl₂·6H₂O and CuCl₂·2H₂O ethylenediamine (Merck) were used as received.

Other physical measurements

Microanalyses of the complexes were obtained on a Carlo Erba Analyzer Model 1106. Molar conductances were measured at room temperature on a Digisun Electronic Conductivity Bridge. IR spectra (200–4000 cm⁻¹) were recorded on a Carl Ziess specord M-80 spectrophotometer in Nujol mull. ¹H and ¹³C NMR spectra were recorded on an amx-500 spectrometer. The EPR spectra were obtained

IR spectra

The ligand L shows a medium intensity band at 2474 cm⁻¹ assigned to –SH group, which remains unaltered suggesting the noninvolvement of this group in coordination with diethyl oxalate [20]. The characteristic bands at 3100 and 1490 cm⁻¹ due to υ(NH) stretching and bending vibration [21], respectively, were not observed in IR spectrum of ligand indicating the ligand formation take place through –NH group of imidazole ring.

In the complexes, the characteristic band at ca. 1688 cm⁻¹ attributed to υ

Electrochemistry

The cyclic voltammetry of the complex 1 was recorded in DMSO/H₂O (5:95) at room temperature at a scan rate of 0.2 V s⁻¹ in the potential range 1.0 to –0.8 V (Fig. 2). The cyclic voltammogram of the complex 1 in absence of CTDNA exhibits a quasireversible redox wave for one electron transfer process corresponding to Cu^II/Cu^I redox couple with E_1/2 = 0.27 V and ΔE_p value of 288 mV. The ratio of the anodic and cathodic peak currents I_pa/I_pc is 1.33 implying quasi-reversible electron transfer. At

Kinetics studies

The absorption spectrum of the complex 1 (in absence of CTDNA) in DMSO reveals one intense well resolved MLCT band at 282 nm attributed to Cu(II) → π* of the benzimidazole ring and a broad band in the visible region at 657 nm assigned to d–d transition on addition of CTDNA to the complex 1 in Tris–HCl buffer/DMSO there is an increase in the absorbance (hyperchromism) in both CT band and the d–d band in the visible region and it is accompanied by a slight red shit. A similar hyperchromism was

Viscosity measurements

To further clarify the nature of the interaction between the complex and DNA, viscosity measurements were carried out and the results are presented in Fig. 7. The experiment involves the measurement of the flow rate of DNA solution through a capillary viscometer. Hydrodynamic measurement that are sensitive to length change (i.e. viscosity and sedimentation) are regarded as the least ambiguous and most critical tests of a binding model in solution in the absence of crystallographic structural

Acknowledgments

Thanks to RSIC, CDRI Lucknow for providing C,H,N analysis data, NMR, and IIT Bombay for EPR measurements. The authors gratefully acknowledge Dr. Sartaj Tabassum, AMU, Aligarh for providing cyclic voltammetry facility.

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Original articleSynthesis, antibacterial, antifungal activity and interaction of CT-DNA with a new benzimidazole derived Cu(II) complex

Abstract

Introduction

Section snippets

Reagents

Other physical measurements

IR spectra

Electrochemistry

Kinetics studies

Viscosity measurements

Acknowledgments

J. Inorg. Biochem.

J. Inorg. Biochem.

Chem.

Indian J. Chem.

Dalton Trans.

Chem.

Org. Biomol. Chem.

Inorg. Chem.

Curr. Opin. Investig. Drugs

Antimicrob. Agents Chemother.

J. Med. Chem.

Helv. Chim. Acta

Inorg. Chem.

Dalton Trans.

Metal Based Drugs

Curr. Sci.

Biopolymers

J. Pharm. Sci.

“Comprehensive Coordination Chemistry”

J. Chem. Soc., Dalton Trans.

Transition Met. Chem.

Original article
Synthesis, antibacterial, antifungal activity and interaction of CT-DNA with a new benzimidazole derived Cu(II) complex