Synthesis and pharmacochemical study of new Cu(II) complexes with thiophen-2-yl saturated and α,β-unsaturated substituted carboxylic acids

Abstract

Copper complexes with thiophen-2-yl saturated and α,β-unsaturated carboxylic acids as ligands were prepared, characterized and pharmacochemically studied. The available evidence supports a dimeric structure for the complexes of the general formula [Cu 2(L) 4(MeOH) 2] where L are the anions of thiophene 2-carboxylic acid (HL 1), 2-(thiophen-2-yl)-acetic acid (HL 2), 3-thiophen-2-yl-acrylic acid (HL 3), 2-phenyl-3-thiophen-2-yl-acrylic acid (HL 4) respectively. The crystal structure of [Cu 2(L 1) 4(MeOH) 2] ( 2) was determined while preliminary X-ray analysis of the copper complex with L 4 isolated from MeOH/DMSO solution proved to contain three crystallographically independent dimers of the formula [Cu 2(L 4) 4(MeOH)( dmso)][Cu 2(L 4) 4(MeOH) 2][Cu 2(L 4) 4( dmso) 2] · 8MeOH ( 9). Since lipophilicity is a significant physicochemical property determining distribution, bioavailability, metabolic activity and elimination, we tried to measure experimentally their lipophilicity from RPTLC method. The copper complexes and the ligands (thiophen-2-yl saturated and α,β-unsaturated carboxylic acids) were tested in vitro on: (a) soybean lipoxygenase inhibition, (b) interaction with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical, (c) the HO mediated oxidation of DMSO, (d) inhibition of lipid peroxidation, (e) scavenging of superoxide anion radicals and in vivo for the inhibition of carrageenin-induced rat paw edema. The compounds have shown important antioxidant activity, significant anti-inflammatory activity and potent inhibition of soybean lipoxygenase as a result of their physichochemical features. Complex [Cu 2(L 1) 4(MeOH) 2] (2) presents the higher in vivo activity (77.4%) followed by complex [Cu 2(L 2) 4(MeOH) 2] ( 4) (51%). Both complexes are more potent anti-inflammatory agents compared to their respective ligands. Moreover we have performed in vitro studies upon their effect on dsDNA, using adsorptive transfer stripping voltammetry and a dsDNA modified carbon paste electrode. Our conclusions were mainly based upon the effect of the studied compounds on the oxidation signal of guanine and adenine. From the given data it seems that complexes show similarities in their behaviour.