title: Novel inhibitors of Plasmodium falciparum based on 2,5-disubstituted furans.
abstract: Phenotypic HTS campaigns with a blood stage malaria assay have been used to discover novel chemotypes for malaria treatment with potential alternative mechanisms of action compared to existing agents. N1-(5-(3-Chloro-4-fluorophenyl)furan-2-yl)-N3,N3-dimethylpropane-1,3-diamine, 1 was identified as a modest inhibitor of P. falciparum NF54 (IC50= 875 nM) with an apparent long plasma half-life after high dose oral administration to mice, although the compound later showed poor metabolic stability in liver microsomes through ring- and side chain-oxidation and N-dealkylation. We describe here the synthesis of derivatives of 1, exploring the influence of substitution patterns around the aromatic ring, variations on the alkyl chain and modifications in the core heterocycle, in order to probe potency and metabolic stability, where 4k showed a long half-life in rats.
authors.affiliation: Instituto de Química, Universidade Estadual de Campinas, Barão Geraldo, PO Box 6154, Campinas, SP 13084-971, Brazil.
authors.forename: Susann H
authors.initials: SH
authors.lastname: Krake
authors.affiliation: Instituto de Química, Universidade Estadual de Campinas, Barão Geraldo, PO Box 6154, Campinas, SP 13084-971, Brazil.
authors.forename: Pablo David G
authors.initials: PDG
authors.lastname: Martinez
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Jenna
authors.initials: J
authors.lastname: McLaren
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Karen
authors.initials: K
authors.lastname: White
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Campbell
authors.affiliation: Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Willis
authors.affiliation: Instituto de Química, Universidade Estadual de Campinas, Barão Geraldo, PO Box 6154, Campinas, SP 13084-971, Brazil. Electronic address: ldias@iqm.unicamp.br.
authors.forename: Luiz Carlos
authors.initials: LC
authors.lastname: Dias
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D004355:Drug Stability; D005663:Furans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000962:Antimalarials; D005663:Furans
keywords: Diamines; Furan; Malaria; Synthesis; nM inhibitors