Contribution of dithiol ligands to in vitro and in vivo trypanocidal activities of dithiaarsanes and investigation of ligand exchange in an aqueous solution

Twelve new dithiaarsanes were evaluated for their in vitro and in vivo tryp anocidal properties In regard to their three parent molecules, 4-amino-phen ylarsenoxide, melarsenoxide, and 4-dansylamino-phenylarsenoxide, The most p otent dithiaarsane, compound 2b, had a minimum effective concentration of 1 .5 mM after 48 h of incubation and at a dose of 0.39 mu mol/kg of body weig ht (0.2 mg/kg) administered subcutaneously cured 100% of mice acutely infec ted with Trypanosoma brucei brucei CMP. With this model, the chemotherapeut ic index of compound 2b was 512, compared to 256 for melarsamine dihydrochl oride (Cymelarsan) under the same conditions. With a chronic infection prod uced by T, brucei brucei GVR, compound 2b cured 100% of mice after treatmen t at a dose of 25 mu mol/kg (12.5 mg/kg) for 4 consecutive days, whereas me larsamine dihydrochloride and potassium melarsonyl (Trimelarsan) cured less than 50% mice at this dose. For both acute and Late-stage infections, dith iaarsanes having a melaminophenyl ring exhibited the most-potent trypanocid al activity. Compound 2b is thus one of the most active organoarsenicals de scribed in a mouse trypanosomiasis model. Considering that the main intrace llular targets of organoarsenicals are thiol groups, we studied the possibi lity of ligand exchange between Cymelarsan and several dithiols. In aqueous solution, we observed a rapid exchange of cysteamine from melarsamine with free cysteamine and also with various dithiols always in favor of more sta ble cyclic derivatives. These ligand exchanges suggest the ability of triva lent organoarsenicals to react with targets such as trypanothione and dihyd rolipoic acid. Among several ligands, a 1,3-dimercaptopropane moiety appear ed the most suitable for trypanocidal activity.