title: In vitro and in vivo antimalarial activity of amphiphilic naphthothiazolium salts with amine-bearing side chains.
abstract: 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.
authors.affiliation: The Kenneth S. Warren Institute, Ossining, New York; University of North Carolina, Chapel Hill, North Carolina; Johns Hopkins Malaria Institute, Baltimore, Maryland.
authors.forename: Peter
authors.initials: P
authors.lastname: Ulrich
authors.affiliation: The Kenneth S. Warren Institute, Ossining, New York; University of North Carolina, Chapel Hill, North Carolina; Johns Hopkins Malaria Institute, Baltimore, Maryland.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Gipson
authors.affiliation: The Kenneth S. Warren Institute, Ossining, New York; University of North Carolina, Chapel Hill, North Carolina; Johns Hopkins Malaria Institute, Baltimore, Maryland.
authors.forename: Martha A
authors.initials: MA
authors.lastname: Clark
authors.affiliation: The Kenneth S. Warren Institute, Ossining, New York; University of North Carolina, Chapel Hill, North Carolina; Johns Hopkins Malaria Institute, Baltimore, Maryland.
authors.forename: Abhai
authors.initials: A
authors.lastname: Tripathi
authors.affiliation: The Kenneth S. Warren Institute, Ossining, New York; University of North Carolina, Chapel Hill, North Carolina; Johns Hopkins Malaria Institute, Baltimore, Maryland.
authors.forename: David J
authors.initials: DJ
authors.lastname: Sullivan
authors.affiliation: The Kenneth S. Warren Institute, Ossining, New York; University of North Carolina, Chapel Hill, North Carolina; Johns Hopkins Malaria Institute, Baltimore, Maryland ccerami@unc.edu.
authors.forename: Carla
authors.initials: C
authors.lastname: Cerami
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D009285:Naphthoquinones / Q000737:chemistry; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects*; D013501:Surface-Active Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D013890:Thiourea / Q000737:chemistry
chemical_list: C000596029:2-(cyclohexylimino)-1,2-dihydro-4-methyl-1-(3-(dimethylamino)propyl)naphtho(1,2-d)thiazol-5-ol; D000588:Amines; D000962:Antimalarials; D052160:Benzothiazoles; D009285:Naphthoquinones; D013501:Surface-Active Agents; D013890:Thiourea