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

Abstract

To design new anmnyroid agents with less side ettecls. the electrotopological-state (E-siate) indexes of ihiourylene moiety 'SNAS* was Utilized as a guideline to develop five acyclic thio-urylene-typc compounds with reduced antioxidant property. Methods. These agents were synthesized and screened for antithy¬roid activity in rats using i:5l-thiocyanate discharge technique. In addition, chemiluminescence studies on the activated polymorpho¬nuclear leukocytes (PMNLs) were also conducted to reveal antiox¬idant 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 (Kc) and the SNAS was observed and utilized in designing those agents. At least one of the compounds (abouthiou/.ine) was found to have a potential value as an antithyroid agent. The relative efficacy of abouthiou/.ine | l-n-hutylO(isonicotinamido)-2-thiourea], utter equimolar dose, was 1029^ and 51.5% of that of propylthiouracil with respect to the rate of i:3l-discharge and ;:'l-uptake. respec¬tively. In addition. Chemiluminescence studies on PMNLs revealed that abouthiou/ine has slight oxidant property. Such properties may provide advantages in avoiding the iatrogenic hypothyroidism and antithyroid-induced immunological reactions. Conclusions. The F.-staie approach provides guidelines to economize efforts and cost of designing new antithyroid druRs.