title: Synthesis and evaluation of 1-amino-6-halo-β-carbolines as antimalarial and antiprion agents.
abstract: Malaria is one of the world's most devastating parasitic diseases, causing almost one million deaths each year. Growing resistance to classical antimalarial drugs, such as chloroquine, necessitates the discovery of new therapeutic agents for successful control of this global disease. Here, we report the synthesis of some 6-halo-β-carbolines as analogues of the potent antimalarial natural product, manzamine A, retaining its heteroaromatic core whilst providing compounds with much improved synthetic accessibility. Two compounds displayed superior activity to chloroquine itself against a resistant Plasmodium falciparum strain, identifying them as promising leads for future development. Furthermore, in line with previous reports of similarities in antimalarial and antiprion effects of aminoaryl-based antimalarial agents, the 1-amino-β-carboline libraries were also found to possess significant bioactivity against a prion-infected cell line.
authors.affiliation: Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S7 3HF, UK. m.j.thompson@sheffield.ac.uk
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Thompson
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Louth
authors.forename: Susan M
authors.initials: SM
authors.lastname: Little
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jackson
authors.forename: Yohan
authors.initials: Y
authors.lastname: Boursereau
authors.forename: Beining
authors.initials: B
authors.lastname: Chen
authors.forename: Iain
authors.initials: I
authors.lastname: Coldham
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D002227:Carbazoles / Q000737:chemistry; D002243:Carbolines / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004352:Drug Resistance, Microbial; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D011328:Prions / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D002227:Carbazoles; D002243:Carbolines; D011328:Prions; C078290:manzamine A; D002738:Chloroquine