title: Human p38 mitogen-activated protein kinase inhibitor drugs inhibit Plasmodium falciparum replication.
abstract: We recently demonstrated that human p38 mitogen-activated protein kinase (MAPK) inhibitors reduced in vitro and in vivo replication of the protozoan parasites Toxoplasma gondii and Encephalitozoon cuniculi. In this study, we assessed the efficacy of five p38 MAPK inhibitors to block the replication of Plasmodium falciparum in human erythrocytes cultured ex vivo and demonstrate that the pyridinylimidazole RWJ67657 and the pyrrolobenzimidazole RWJ68198 reduced P. falciparum replication, yielded trophozoites that were greatly diminished in size at 24h, and that these two agents interfered with stage differentiation. Interestingly, the chloroquine-resistant strain W2 was significantly more sensitive to these drugs than was the chloroquine-sensitive strain HB3. These results suggest that pyridinylimidazoles and pyrrolobenzimidazoles designed to inhibit human p38 MAPK activation can be developed to treat malaria.
authors.affiliation: Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, 2040 Babcock Rd., Suite 201, San Antonio, TX 78229, USA. brumlik@UTHSCSA.edu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Brumlik
authors.forename: Standwell
authors.initials: S
authors.lastname: Nkhoma
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kious
authors.forename: George R
authors.initials: GR
authors.lastname: Thompson
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Patterson
authors.forename: John J
authors.initials: JJ
authors.lastname: Siekierka
authors.forename: Tim J C
authors.initials: TJ
authors.lastname: Anderson
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015767:Mefloquine / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000962:Antimalarials; D007093:Imidazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C465539:SB202494; C514526:indole-5-carboxamide; D002738:Chloroquine; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D015767:Mefloquine