Anti-Drug Antibodies (Topas Therapeutics)

The acidobasic and complexing properties of 1-methyl-2-mercaptoimidazole (Methimazole, an anti-thyroid drug) were investigated. The pK_a 11.49 ± 0.03 was estimated by molecular absorption spectroscopy (I = 0.10 M NaCl, t = 25.0 ± 0.1 °C). This value is in good agreement with the value 11.58 ± 0.05, obtained using the solvent-extraction technique. Theoretical (LFER and quantum chemical calculations) and experimental (¹H/¹³C NMR spectroscopy) methods confirmed that the ligand prefers to be in the thion form, and the proton dissociation takes place on the nitrogen atom. Using glass electrode potentiometry, the complexation of the Pd(II) ion by the methimazole ligand occurs without the participation of protons. The best chemical model considers the [Pd(HL)]²⁺, [Pd(HL)₂]²⁺ and [Pd(HL)₃]²⁺ complex species, whose stability constants were also determined using spectroscopy and capillary zone electrophoretic (CZE) measurements. The metal complexes dissociate at -log [H⁺] > 7, where an uncharged palladium(II) hydroxide is formed. The formation kinetics of the palladium(II) complex with methimazole were studied in perchloric and hydrochloric acids (I = 1.00 M, t = 15-40 °C) and the determined rate constants and activation parameters are consistent with literature values determined for the reactions of the Pd(II) ion with thiourea derivatives. The rate constants decrease by two orders of magnitude in both media, which can be assigned to a lower tendency of the chloride ion to dissociate from the [PdCl₄]^2- complex species than the water molecule from the [Pd(H₂O)₄]²⁺ ion. The presented results can be utilized for the design of new Pd and Pt metallodrugs.