title: Structure-activity relationship of cytochrome bc1 reductase inhibitor broad spectrum antifungal ilicicolin H.
abstract: Ilicicolin H is a broad spectrum antifungal agent showing sub micro g/mL MICs against Candida spp., Aspergillus fumigatus and Cryptococcus spp. It is a potent inhibitor (C50 2-3ng/mL) of the mitochondrial cytochrome bc1 reductase with over 1000-fold selectivity against rat liver cytochrome bc1 reductase. Structure-activity relationship of semisynthetic derivatives by chemical modification of ilicicolin H and its 19-hydroxy derivative produced by biotransformation have been described. Basic 4'-esters and moderately polar N- and O-alkyl derivatives retained antifungal and the cytochrome bc1 reductase activities. 4',19-Diacetate and 19-cyclopropyl acetate retained antifungal and enzyme activity and selectivity with over 20-fold improvement of plasma protein binding.
authors.affiliation: Departments of Medicinal Chemistry and Infectious Disease, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. sheo.singh@merck.com
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.forename: Weiguo
authors.initials: W
authors.lastname: Liu
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.forename: Tom
authors.initials: T
authors.lastname: Chen
authors.forename: Ali
authors.initials: A
authors.lastname: Shafiee
authors.forename: Sarah
authors.initials: S
authors.lastname: Dreikorn
authors.forename: Viktor
authors.initials: V
authors.lastname: Hornak
authors.forename: Maria
authors.initials: M
authors.lastname: Meinz
authors.forename: Janet C
authors.initials: JC
authors.lastname: Onishi
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001547:Benzaldehydes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008928:Mitochondria / Q000201:enzymology; D008968:Molecular Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D001547:Benzaldehydes; D004791:Enzyme Inhibitors; C433880:ilicicolin H; D014450:Electron Transport Complex III