Synthesis of novel brassinosteroid biosynthesis inhibitors based on the ketoconazole scaffold

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 4; pp. 1625 - 1628
• Main Authors: Oh, Keimei, Yamada, Kazuhiro, Asami, Tadao, Yoshizawa, Yuko
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.02.2012; Elsevier
• Subjects: agronomic traits; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Arabidopsis; Arabidopsis - drug effects; Arabidopsis - growth & development; bioactive properties; Biological and medical sciences; biosynthesis; brassinolide; Brassinosteroid biosynthesis inhibitor; Brassinosteroids - antagonists & inhibitors; Dioxolanes - chemistry; Dioxolanes - pharmacology; gibberellins; hypocotyls; Inhibitory Concentration 50; ketoconazole; Ketoconazole - chemical synthesis; Ketoconazole - chemistry; Ketoconazole - pharmacology; Medical sciences; Molecular Structure; mutants; Pharmacology. Drug treatments; plant architecture; Plant hormone; plant hormones; seed yield; seedlings; stem elongation; stress tolerance; Structure-Activity Relationship; structure-activity relationships; Triazole derivatives; triazoles; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Triazole derivatives; BRs; Plant hormone; GA; Brassinosteroid biosynthesis inhibitor; Brz; Hormone; Steroid; Imidazole derivatives; Ketoconazole; Azole derivatives; Chemical structure; Biosynthesis; Antifungal agent; Brassinosteroid; Plant; Inhibitor; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.12.120

Brassinosteroids (BRs) are steroidal plant hormones that control several important agronomic traits such as plant architecture, seed yield, and stress tolerance. Inhibitors that target BR biosynthesis are candidate plant growth regulators. We synthesized novel triazole derivatives, based on the ketoconazole scaffold, that function as inhibitors of BR biosynthesis. The biological activity of the test compounds was evaluated by determining their ability to induce dwarfism in Arabidopsis seedlings grown in the dark. The chemically induced dwarfism of Arabidopsis seedlings was further evaluated by a rescue experiment using the co-application of brassinolide and/or gibberellins (GA). The structure–activity relationship studies revealed a potent BR biosynthesis inhibitor, 2RS, 4RS-1-{2-(4-chlorophenyl)-4-[2-(2-ethoxyphenyl)-ethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole (7m), with an IC50 value of 0.10±0.03μM for retardation of Arabidopsis seedling stem elongation. The compound-induced hypocotyl dwarfism was counteracted by the co-application of 10nM brassinolide, but not 1μM GA3, which produced seedlings that resembled BR-deficient mutants. This result suggests that 7m is a potent and specific inhibitor of BR biosynthesis.