Development of new antithyroid compounds with reduced antioxidant property

ABSTRACT

Based on literature evaluation, we hypothesize that in order to control graves disease and the onset of drug induced agranulocytosis the trends in antithyroid therapy should be modified to include acyclic thiourea with reduced anioxidant property. A linear relationship was developed between percentage of inhibition of luminol enhanced chemiluminescence [%CL] of stimulated polymorphonuclear leucocytes [PMNLs] obtained from Imamura et al. [Acta Endocrinological, 1986; 112210-216.] data of currently used antithyroids and related compounds and their atom level electrotopological state [E-state] indexes of their thiourylene moiety [S[N AND S]]. The resulted relationship [% CL inhibition = 349.254 [ +/- 8.52] -37.692 [ +/- 1.13] [S[N AND S]; = 0.999; SEM = 0.47; F= 1108.1; P = 0.019] was utilized as a guideline for the rational selection of thiourylene type compounds [with S[N and S] >8] with reduced antioxidant property. The compounds selected were evaluated for their antioixdant property utilizing their influence on luminol-enhanced chemiluminescence [CL] of phorbol myristate acetate [PMA] induced human PMNLs and was found to agree with the guideline extracted from Imamura et al data. The formation of the selected compounds of their charge transfer complex with iodine was determined spectroscopically and utilized as a primary criteria for their potential antithyroid activity. In addition, these agents were screened for antithyroid activity in rats using [125] I-thiocyanate discharge technique. The relative efficacy [in relation to equimolar dose of propylthiouracil] of the tested agents with respect to both [125] I-uptake and the rate of [125] I-discharge were determined and proved that at least one of the three investigated compounds [abouthiouline] has higher antithyroidal activity than propylthiouracil with respect to the rate of [125] I-discharge. The relative efficacy of abouthiouline [1-cyclohexy1-3[3-quinoly1]-2-thiourea], after equimolar dose was 131.13% and 51.72% of that of propylthiouracil with respect to the rate of [125] I-discharge and [125] I-uptake respectively. The importance of the thyroid [125] I-discharge in antithyroid therapy in reducing the dose and the duration of treatment is discussed. Since the ratio of the percent efficacy with respect to the rate of [125] I-discharge to [125] I-uptake of abouthiouline is 2.54, it is perceived that abouthiouline is of potential value as antithyroid agent after adjusting the dose with respect to the therapeutic dose of propylthiouracil. In conclusion, abouthiouline has lower toxicity [LD[50] >800 mg/kg] reduced antioxidant property as well as higher antithyroidal efficacy than propylthiouracil with respect to the rate of 125I discharge. In view of the toxic omplications of the antioxidant property of the currently used antithyroid agents it is suggested that abouthiouline will be beneficial in reducing the severity of the immune reaction of both the Graves disease and the drug induced agranulocytosis. Further supportive investigations are in progress