title: Synthesis and antifungal activity of novel sclerotiorin analogues.
abstract: Sclerotiorin 1, first isolated from Penicillium sclerotiorum, has weak antifungal activity and belongs to the azaphilone-type family of natural products. Several series of sclerotiorin analogues were designed and synthesized with the aim of discovering novel fungicides with improved activity. The syntheses involved two key steps, cycloisomerization and then oxidation, and used a simple and efficient Sonogashira cross-coupling reaction to construct the required functionalized precursor. With sclerotiorin as a control, the activities of the newly synthesized analogues were evaluated against seven fungal pathogens, and several promising candidates (compounds 3a₁, 3d₂, 3e₂, 3f₂ and 3k₂) with greater activity and simpler structures than sclerotiorin were discovered. In addition, preliminary structure-activity relationships were studied, which revealed that not only the chlorine or bromine substituent at the 5-position of the nucleus but also the phenyl group at the 3-position and the substituent pattern on it contributed crucially to the observed antifungal activity. Analogues with a methyl substituent at the 1-position have reduced levels of activity, while those with a free hydroxyl group in place of acetoxy at the quaternary center of the bicyclic ring system retain activity.
authors.affiliation: Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.
authors.forename: Long
authors.initials: L
authors.lastname: Lin
authors.forename: Nick
authors.initials: N
authors.lastname: Mulholland
authors.forename: Qiong-You
authors.initials: QY
authors.lastname: Wu
authors.forename: David
authors.initials: D
authors.lastname: Beattie
authors.forename: Shao-Wei
authors.initials: SW
authors.lastname: Huang
authors.forename: Dianne
authors.initials: D
authors.lastname: Irwin
authors.forename: John
authors.initials: J
authors.lastname: Clough
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Gu
authors.forename: Guang-Fu
authors.initials: GF
authors.lastname: Yang
mesh_terms: D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D005517:Foodborne Diseases / Q000517:prevention & control; D005659:Fungicides, Industrial / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005874:Gibberella / Q000187:drug effects; D003904:Mitosporic Fungi / Q000187:drug effects; D011775:Pythium / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000977:Antiparasitic Agents; D001578:Benzopyrans; D005659:Fungicides, Industrial; C101449:sclerotiorin