Synthesis and evaluation of novel lidocaine sulfur analogs

In order to test whether the structural requirement for basic or quaternary nitrogen in antiarrhythmic drugs is essential, several sulfur-containing lidocaine analogs were synthesized and their metabolism investigated in human plasma, various esterase preparations, bovine liver microsomes, and in vivo in rats. Skin diffusion was measured through hairless mouse skin. Two of the compounds were found to have long-lasting antiarrhythmic activity in dogs, and in the case of the ethylthio analog, activity equivalent to that of lidocaine persisted without the presence of an ionized group to interact with the proposed anionic portion of membrane polypeptides. Thus, non-specific antiarrhythmic activity is possible when only the myocardial membrane phospholipids interact with the drug and charge attractions between the drug and membrane peptide groups are not necessary.