Atom level electrotopological state indexes in QSAR: Designing and testing antithyroid agents

Purpose. To design new antithyroid agents with less side effects, the electrotopological-state (E-state) indexes of thiourylene moiety (S-N&S) was utilized as a guideline to develop five acyclic thiourylene-type compounds with reduced antioxidant property. Methods. These agents were synthesized and screened for antithyroid activity in rats using I-125-thiocyanate discharge technique. In addition, chemiluminescence studies on the activated polymorphonuclear leukocytes (PMNLs) were also conducted to reveal antioxidant properties of the tested compounds. Results. A linear relationship between the in vitro literature value of the formation constants of thiourylene-type compounds with iodine (K-c) and the S-N&S was observed and utilized in designing those agents. At least one of the compounds (abouthiouzine) was found to have a potential value as an antithyroid agent. The relative efficacy of abouthiouzine [1-n-butyl-3(isonicotinamido)-2-thiourea], after equimolar dose, was 102% and 51.5% of that of propylthiouracil with respect to the rate of I-125-discharge and I-125-uptake, respectively. In addition, Chemiluminescence studies on PMNLs revealed that abouthiouzine has slight oxidant property. Such properties may provide advantages in avoiding the iatrogenic hypothyroidism and antithyroid-induced immunological reactions. Conclusions. The E-state approach provides guidelines to economize efforts and cost of designing new antithyroid drugs.