Mast cell derived leukotrienes (LT's) play a vital role in pathophysiology of allergy and asthma. We synthesized various analogues of indolyl, naphthyl and phenylethyl substituted halopyridyl, thiazolyl and benzothiazolyl thioureas and examined their in vitro effects on the high affinity IgE receptor/FcERI-mediated mast cell leukotriene release. Of the 22 naphthylethyl thiourea compounds tested, there were seven active compounds and N-[1-(1-naphthyl)ethyl]-N'-[2-(ethyl-4-acetylthiazolyl)]thiourea (17 and 16) (IC(50)=0.002 microM) and N-[1-(1R)-naphthylethyl]-N'-[2-(5-methylpyridyl)]thiourea (5) (IC(50)=0.005 microM) were identified as the lead compounds. Among the 11 indolylethyl thiourea compounds tested, there were seven active compounds and the halopyridyl compounds N-[2-(3-indolylethyl)]-N'-[2-(5-chloropyridyl)]thiourea and N-[2-(3-indolylethyl)]-N'-[2-(5-bromopyridyl)]thiourea were the most active agents and inhibited the LTC(4) release with low micromolar IC(50) values of 4.9 microM and 6.1 microM, respectively. The hydroxylphenyl substituted compounds N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea (IC(50)=12.6 microM), N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (IC(50)=16.8 microM) and N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(pyridyl)]thiourea (IC(50)=8.5 microM) were the most active pyridyl thiourea agents. Notably, the introduction of electron withdrawing or donating groups had a marked impact on the biological activity of these thiourea derivatives and the Hammett sigma values of their substituents were identified as predictors of their potency. In contrast, experimentally determined partition coefficient values did not correlate with the biological activity of the thiourea compounds which demonstrates that their liphophilicity is not an important factor controlling their mast cell inhibitory effects.