CRYSTAL-STRUCTURE AT 180-DEGREES-K OF -DIISOPROPYLSALICYLATOBISDIMETHYLSULFOXIDOZINC(II) AND THE INHIBITION OF SEIZURES AND POLYMORPHONUCLEAR LEUKOCYTE CHEMILUMINESCENCE

Dimethylsulfoxide (DMSO) formed a ternary complex when mixed with a Zn -3,5-diisopropylsalicylate complex of unknown structure. The structure of this new ternary complex was characterized in an initial effort to understand the nature of this compound. Since the original complex is known to have anticonvulsant activity, the new ternary complex was al so examined for anticonvulsant activity. The original complex was exam ined for inhibition of the polymorphonuclear leukocyte (PMNL) respirat ory burst in an effort to mechanistically account for zinc complex med iated anticonvulsant activity. Dissolving the structurally unknown com plex in DMSO gave crystals of a characterizable complex with an empiri cal formula C30H46O8S2Zn. Crystallographic data: P (1) over bar, Z = 2 , a = 8.063(1), b = 12.452(2), c = 17.951(2) Angstrom, alpha = 74.42(1 ), beta = 77.07(1), gamma = 89.50(1)degrees. The structure was refined to R = 0.03, R-w = 0.04 for 3815 independent reflections with I > 2 s igma(I). This complex is mononuclear, with two 3,5-diisopropylsalicyla te ligands and two bonded DMSO ligands, Zn(II)(3,5-DIPS)(2)(DMSO)(2). Zn(II) is coordinate covalently bonded to four O atoms in a strongly d istorted tetrahedral arrangement, Each DMSO ligates via its sulfoxide O atom while each 3,5-diisopropylsalicylate ligand is monodentate. The non-ligating carbonyl O atom of each 3,5-DIPS is free except for an i ntramolecular hydrogen bond from the hydroxy group of the same ligand. Both 3,5-DIPS acid and Zn(II)(3,5-DIPS)(2)(DMSO)(2) were examined for anticonvulsant activity in the Maximal Electroshock (MES) and Metrazo l (MET) models of seizures and found to prevent both types of seizures . The Zn complex was qualitatively and quantitatively more effective t han treatment with the free ligand. The influence of a Zn 3,5-DIPS com plex and of the ligand 3,5-DIPS on PMNL oxidative metabolism was also studied to help understand the mechanism of anticonvulsant activity of these compounds. A dose-related and significant decrease in chemilumi nescent (CL) response to opsonized Zymosan was observed, and the Zn co mplex was significantly more effective than the free ligand,It is conc luded that mononuclear Zn complexes have anticonvulsant activity in Gr and Mal and Petit Mal models of seizure possibly due to inhibition of the synthesis of superoxide or down-regulation of Nitric Oxide Synthas e in activated phagocytic cells of the central nervous system. (C) 199 8 Elsevier Science Inc. All rights reserved.