Interactions of metal ions with a 2,4-diaminopyrimidine derivative (trimethoprim)

Abstract

The interaction of copper (II), zinc(II) and cadmium(II) with Trimethoprim (2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl) pyrimidine) has been studied. The crystal structures of [Zn(Trim)₂Cl₂] (2) and [Cd(Trim)Cl₂(CH₃OH)]_n (4) are reported. Compound (2) exhibits a distorted tetrahedral environment around the metal center and crystallizes in the triclinic space group P1̄ with a=10.2397(6), b=10.4500(6), c=16.3336(16) Å, α=96.141(8), β=106.085(5), γ=96.551(5)° and Z=2. In complex (4), the Cd(II) centers are bridged sequentially by two chlorine ions to form infinite chains and present a six-coordinated environment; the compound crystallizes in the monoclinic P2₁/C space group with a=13.958(5), b=7.532(2), c=18.390(2) Å, α=90, β=97.32(5), γ=90° and Z=4. In both structures the Trimethoprim acts as a monodentate ligand through the pyrimidinic nitrogen N(1) atom. The characterization of the Cu(Trim)₂(CH₃O)(ClO₄) complex through EPR and magnetic measurements suggests a binuclear or polinuclear nature, with bridging methoxo groups. The complexes were screened for their activity against several bacteria, showing activity similar to that of trimethoprim.

Introduction

Compounds containing pyrimidine rings play a significant role in many biological systems [1]. The pyrimidine ring system, present in nucleic acids, several vitamins, coenzymes and antibiotics, provides potential binding sites for metal ions, and any information on their coordinating properties is important as a means of understanding the role of the metal ions in biological systems.

Many compounds of therapeutic importance contain the pyrimidine ring system. So, substituted 2,4 diaminopyrimidines are widely employed as metabolic inhibitors of pathways leading to the synthesis of proteins and nucleic acids. Among these kind of ligands, trimethoprim (Trim=2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl) pyrimidine) is a well known biological agent, also employed as a potent metabolic inhibitor of bacterial dihydrofolic acid reductase. This drug is an antibacterial agent highly active against strains resistant to other antibiotics frequently used, e.g. β-lactam antibiotics [2].

Trimethoprim has potential binding sites for metal ions. Several authors have studied the interaction of this ligand with biological metal ions and the coordination of trimethoprim via a NH₂ nitrogen atom was inferred on the basis of IR and visible measurements [3], [4]. However, other authors have shown by X-ray diffraction methods that the coordination site of the Trimethoprim molecule is the N₁ of the pyrimidine ring [5], [6], [7], [8], [9]. On the other hand, more recently, Seekhon et al. [10] have prepared and characterized complexes of trimethoprim with Ag(I), Zn(II), Cd(II), Hg(II) and Ni(II) and the infrared data show that the ligand acts as a monodentate through the 4-NH₂ group.

In order to enhance the information on the coordination properties of this drug we report here the synthesis and characterization of new metal complexes of trimethoprim and the crystal structures of the complexes [Zn(Trim)₂Cl₂] and [Cd(Trim)Cl₂(CH₃OH)]_n. On the other hand, many drugs modify their pharmacological and toxicological properties when administered in the form of metallic complexes [11], this is the reason for us to investigate the activity of all complexes synthesized against several bacteria strains; we intend to compare it with that of the ligand.