Synthesis, crystal structures, and anti-convulsant activities of ternary [ZnII(3,5-diisopropylsalicylate)2], [ZnII(salicylate)2] and [ZnII(aspirinate)2] complexes

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Abstract

Following observations that bis(3,5-diisopropylsalicylato)diaquazincII, [ZnII(3,5-DIPS)2(H2O)2], had anti-convulsant activity, bis(acetylsalicylate)diaquazincII, [ZnII(aspirinate)2(H2O)2], and the ZnII ternary 1,10-phenanthroline (phen), 2,9-dimethyl-1,10-phenanthroline (neocuproine, NC) or dimethyl sulfoxide (DMSO) complexes of ZnII3,5-diisopropylsalicylate, salicylate, and acetylsalicylate were synthesized and spectroscopically characterized. Anti-convulsant and Rotorod toxicity activities of these complexes were determined to examine their anti-convulsant and undesirable central nervous stimulant or depressant activities of these ZnII non-steroidal anti-inflammatory agent complexes. Bis(3,5-diisopropylsalicylato)-1,10-phenanthorlinezincII, [ZnII(3,5-DIPS)2(phen)], (1) has one bidentate phen ligand and two mono-deprotonated 3,5-DIPS ligands. One of the carboxylates bonds in an asymmetric chelating mode. The ZnII atom exhibits a distorted bicapped rectangular pyramidal environment N2O2OO (4 + 1 + 1∗). In the neocuproine complex, bis(3,5-diisopropylsalicylato)-2,9-dimethyl-1,10-phenanthorlinezincII, [ZnII(3,5-DIPS)2(NC)] (2), the ZnII atom has a much more distorted bicapped rectangular pyramidal environment, N2O2O2 (4 + 2∗), compared to 1. The two carboxylate ligands exhibit the same asymmetric coordinating mode with longer metalloelement–oxygen bond distances compared to 1. The space group of [ZnII(aspirinate)2(H2O)2] (3), which has been reported as Cc is corrected to C2/c. The zinc atom exhibits a (4 + 2∗) bicapped square pyramidal environment. While the two ternary phenanthroline-containing complexes, 1 and 2, evidenced weak protection against maximal electroshock (MES)- and subcutaneous Metrazol (scMET) induced seizures, [ZnII(3,5-DIPS)2(DMSO)2], [ZnII(aspirinate)2(H2O)2], and bis(salicylato)-1,10-phenanthorlinezincII, [ZnII(salicylate)2(phen)], were found to be particularly useful in protecting against MES and scMET seizures and [ZnII(aspirinate)2(H2O)2] and [ZnII(salicylate)2(phen)] were found to have activity in protecting against Psychomotor seizures, without causing Rotorod toxicity. Activities of these and other ZnII complexes of non-steroidal anti-inflammatory agents are consistent with the well-known anti-inflammatory responses of ZnII-dependent enzymes. There was also some evidence of Rotorod toxicity consistent with a mechanism of action involving sedative-hypnotic activity of recognized anti-epileptic drugs.

Introduction

Zinc is an essential metalloelement required by all cells for activation of a large number of Zn-dependent enzymes [1] and cited references. These Zn-dependent enzymes have roles in normal metabolic processes involved in the multifaceted biochemical-mediated function and maintenance of all tissues. In addition, Zn-dependent enzymes have many specific key roles in overcoming tissue injury or inflammatory disease states.

Since the concentration of ionically bonded ZnII in blood is 10−9 M [2], [3] and the concentration of ionically bonded Zn in solid tissues is less than 10−9 M, due to the presence of many more functional groups capable of forming coordinate-covalent bonds with Zn, all measured Zn in tissues exists as complexes, which includes Zn-dependent enzymes. The use of small molecular mass chelates or complexes of Zn then constitutes the most propitious forms of Zn for the delivery of this metalloelement to required cellular sites enabling Zn-dependent enzyme syntheses and facilitation of Zn-dependent biochemical processes.

Irradiation injury of brain tissues causes seizures in response to inflammatory injury caused by irradiation. Following the observation that treatment with 60 μmol bis(3,5-diisopropylsalicylato)-1,10-phenanthorlinezincII, [ZnII(3,5-DIPS)2], per kg of body mass facilitated recovery from lethal whole body irradiation injury, increasing survival to 90% above vehicle-treated mice [4], [ZnII(3,5-DIPS)2] was examined for anti-seizure or anti-convulsant activity in recognised animal models of human seizures.

Electric current delivered with corneal electrodes to mice or rats in a maximal electroshock (MES) paradigm causes tonic seizures, which constitutes a model of human Grand Mal epilepsy. Treatment of mice or rats with a subcutaneous injection of pentalenetetrazol, Metrazol (scMET), a central nervous system stimulant, causes clonic seizures, which constitutes a model of human Petit Mal seizures. Both MES and scMET seizures are associated with inflammatory brain injury.

Treatment of the mouse MES seizure model with a series of intraperitoneally administered doses of [ZnII (3,5-DIPS)2] revealed that a dose of 107 μmol [ZnII(3,5-DIPS)2]/kg was an ED50 dose for the prevention of MES seizures. A dose of 96 μmol [ZnII(3,5-DIPS)2]/kg was found to be an ED50 dose for the prevention of scMET seizures. The time required for the production of the peak anti-convulsant effect of [ZnII(3,5-DIPS)2] ranged from 15 to 30 m, indicating a rapid onset of anti-convulsant action. However, a dose of 123 μmol [ZnII(3,5-DIPS)2]/kg produced sedation or sleep, Rotorod Toxicity, which is an undesirable side effect commonly associated with anti-epileptic drugs.

These observations lead to the synthesis of a number of ternary ZnII complexes in an effort to examine their anti-convulsant and central nervous system (CNS) stimulant or depressant activity relationships.

It has been suggested that bis(acetylsalicylato)diaquazincII, [ZnII(aspirinate)2(H2O)2], has a non-centrosymmetric Cc space-group [5]. This space-group assignment for the crystal structure of this ternary complex was based upon a refinement of the R index of 0.043 for 2302 reflections with I > 3σ(I). Cc structures comprise a special class of structural candidates that have led to incorrect space-group assignments. The correct imposition of a twofold axis of symmetry leads to a C2/c space-group assignment [6], which is supported by our results.

Section snippets

Materials and methods

Analytical grade DMA, DMSO and zinc(II) dichloride (Prolabo), salicylic acid, acetylsalicylic acid and 3,5-diisopropylsalicylic acid (Aldrich), 1,10-phenanthroline monohydrate and 2,9-dimethyl-1,10-phenanthroline (Sigma) were purchased and used without further purification.

X-ray crystallography of ternary ZnII non-steroidal anti-inflammatory drug complexes

The molecular structure of 1 and 2 are shown in Fig. 1, Fig. 2, respectively, and selected bond lengths and angles are given in Table 2. These compounds are monomeric complexes in which ZnII exhibits a highly irregular octahedral geometry. In 1, ZnII is coordinate-covalently bonded to two 3,5-DIPS carboxylate ligands and one bidentate phenanthroline ligand with one Zn–N bond significantly shorter than the other [Zn–N41: 2.056(3) Å; Zn–N50: 2.115(3) Å]. In 2, ZnII is coordinate-covalently bonded

Abbreviations

    3,5-DIPS acid

    3,5-diisopropylsalicylic acid

    3,5-DIPS

    3,5-diisopropylsalicylate

    3,5-DTBS

    3,5-ditertiarybutylsalicylate

    phen

    1,10-phenanthroline

    NC (neocuproine)

    2,9-dimethyl-1,10-phenanthroline

    DMSO

    dimethyl sulfoxide

    [ZnII(salicylate)2phen]

    bis(salicylato)-1,10-phenanthrolinezincII

    [ZnII(salicylate)2(py)2]

    bis(salicylato)dipyridinezincII

    [ZnII(salicylate)2(H2O)2]

    bis(salicylato)diaquazincII

    [ZnII(salicylate)2NC]

    bis(salicylato)-2,9-dimethyl-1,10-phenanthrolinezincII

    [ZnII(aspirinate)2NC]

Acknowledgements

We are indebted to the National Institute of Neurological Disorders and Stroke Antiepileptic Drug Development screening program and in particular Mr. James P. Stables, the Program Director for his assistance in obtaining the anti-convulsant and Rotorod Toxicity data presented in this manuscript.

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