title: Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity.
abstract: Pantothenamides are N-substituted pantothenate derivatives which are known to exert antimicrobial activity through interference with coenzyme A (CoA) biosynthesis or downstream CoA-utilizing proteins. A previous report has shown that replacement of the ProR methyl group of the benchmark N-pentylpantothenamide with an allyl group (R-anti configuration) yielded one of the most potent antibacterial pantothenamides reported so far (MIC of 3.2 μM for both sensitive and resistant Staphylococcus aureus). We describe herein a synthetic route for accessing the corresponding R-syn diastereomer using a key diastereoselective reduction with Baker's yeast, and report on the scope of this reaction for modified systems. Interestingly, whilst the R-anti diastereomer is the only one to show antibacterial activity, the R-syn isomer proved to be significantly more potent against the malaria parasite (IC50 of 2.4±0.2 μM). Our research underlines the striking influence that stereochemistry has on the biological activity of pantothenamides, and may find utility in the study of various CoA-utilizing systems.
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Hoegl
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Hamed
authors.initials: H
authors.lastname: Darabi
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Elisa
authors.initials: E
authors.lastname: Tran
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Emelia
authors.initials: E
authors.lastname: Awuah
authors.affiliation: Research School of Biology, College of Medicine, Biology and Environment, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
authors.forename: Eleanor S C
authors.initials: ES
authors.lastname: Kerdo
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Habib
authors.affiliation: Research School of Biology, College of Medicine, Biology and Environment, The Australian National University, Canberra, Australian Capital Territory 0200, Australia; Medical School, College of Medicine, Biology and Environment, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Saliba
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada. Electronic address: karine.auclair@mcgill.ca.
authors.forename: Karine
authors.initials: K
authors.lastname: Auclair
mesh_terms: D000498:Allyl Compounds / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010205:Pantothenic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000498:Allyl Compounds; D000900:Anti-Bacterial Agents; D010205:Pantothenic Acid
keywords: Antibacterial; Antiplasmodial; Baker’s yeast; Coenzyme A; Pantothenamides