In vitro and in vivo antimalarial activity of amphiphilic naphthothiazolium salts with amine-bearing side chains

• Published in: The American journal of tropical medicine and hygiene Vol. 91; no. 4; pp. 824 - 832
• Main Authors: Ulrich, Peter, Gipson, Gregory R, Clark, Martha A, Tripathi, Abhai, Sullivan, Jr, David J, Cerami, Carla
• Format: Journal Article
• Language: English
• Published: United States The American Society of Tropical Medicine and Hygiene 01.10.2014
• Subjects: Amines - chemistry; Animals; Antimalarials - chemical synthesis; Antimalarials - pharmacology; Benzothiazoles - chemical synthesis; Benzothiazoles - pharmacology; Dose-Response Relationship, Drug; Humans; Inhibitory Concentration 50; Malaria, Falciparum - drug therapy; Malaria, Falciparum - parasitology; Mice; Mice, Inbred C57BL; Naphthoquinones - chemistry; Parasitic Sensitivity Tests; Plasmodium berghei - drug effects; Plasmodium falciparum; Plasmodium falciparum - drug effects; Surface-Active Agents - chemical synthesis; Surface-Active Agents - pharmacology; Thiourea - chemistry
• ISSN: 0002-9637; 1476-1645
• DOI: 10.4269/ajtmh.13-0565

Because of emerging resistance to existing drugs, new chemical classes of antimalarial drugs are urgently needed. We have rationally designed a library of compounds that were predicted to accumulate in the digestive vacuole and then decrystallize hemozoin by breaking the iron carboxylate bond in hemozoin. We report the synthesis of 16 naphthothiazolium salts with amine-bearing side chains and their activities against the erythrocytic stage of Plasmodium falciparum in vitro. KSWI-855, the compound with the highest efficacy against the asexual stages of P. falciparum in vitro, also had in vitro activity against P. falciparum gametocytes and in vivo activity against P. berghei in a murine malaria model.