Antitrypanosomal, Antileishmanial, and Antimalarial Activities of Quaternary Arylalkylammonium 2-Amino-4-Chlorophenyl Phenyl Sulfides, a New Class of Trypanothione Reductase Inhibitor, and of N -Acyl Derivatives of 2-Amino-4-Chlorophenyl Phenyl Sulfide

Quaternization of the nitrogen atom of 2-amino-4-chlorophenyl phenyl sulfide analogues of chlorpromazine improved inhibition approximately 40-fold (3',4'-dichlorobenzyl-[5-chloro-2-phenylsulfanyl-phenylamino)-propyl]-dimethylammonium chloride inhibited trypanothione reductase from Trypanosoma cruzi with a linear competitive Ki value of 1.7 +/- 0.2 microM). Molecular modelling explained docking orientations and energies by: (i) involvement of the Z-site hydrophobic pocket (roughly bounded by F396', P398', and L399'), (ii) ionic interactions for the cationic nitrogen with Glu-466' or -467'. A series of N-acyl-2-amino-4-chlorophenyl sulfides showed mixed inhibition (Ki, Ki' = 11.3-42.8 microM). The quaternized analogues of the 2-chlorophenyl phenyl sulfides had strong antitrypanosomal and antileishmanial activity in vitro against T. brucei rhodesiense STIB900, T. cruzi Tulahuan, and Leishmania donovani HU3. The N-acyl-2-amino-4-chlorophenyl sulfides were active against Plasmodium falciparum. The phenothiazine and diaryl sulfide quaternary compounds were also powerful antimalarials, providing a new structural framework for antimalarial design.