title: Analogues of thiolactomycin as potential anti-malarial and anti-trypanosomal agents.
abstract: A series of analogues of the naturally occurring antibiotic thiolactomycin (TLM) have been synthesised and evaluated for their ability to inhibit the growth of the malaria parasite, Plasmodium falciparum. Thiolactomycin is an inhibitor of Type II fatty acid synthase which is found in plants and most prokaryotes, but not an inhibitor of Type I fatty acid synthase in mammals. A number of the analogues showed inhibition equal to or greater than TLM. The introduction of hydrophobic alkyl groups at the C3 and C5 positions of the thiolactone ring lead to increased inhibition, the best showing a fourteenfold increase in activity over TLM. In addition, some of the analogues showed activity when assayed against the parasitic protozoa, Trypanosoma cruzi and Trypanosoma brucei.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, Wales, UK.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Jones
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Urch
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: John L
authors.initials: JL
authors.lastname: Harwood
authors.forename: Colin
authors.initials: C
authors.lastname: Berry
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D004912:Erythrocytes / Q000187:drug effects / Q000473:pathology; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development; D017434:Protein Structure, Tertiary; D051381:Rats; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014345:Trypanosoma / Q000187:drug effects / Q000254:growth & development
chemical_list: D000962:Antimalarials; D013876:Thiophenes; D014344:Trypanocidal Agents; C035068:thiolactomycin; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase