Synthesis and biological activity of analogs of the antifungal antibiotic UK-2A. I. Impact of picolinamide ring replacement.

Autor: Owen WJ; Crop Protection Discovery-Biology, Dow AgroSciences LLC, 9330 Zionsville Rd., Indianapolis, IN 46268-1054, USA., Meyer KG; Crop Protection Discovery-Chemistry, Dow AgroSciences LLC, 9330 Zionsville Rd., Indianapolis, IN 46268-1054, USA., Slanec TJ; Crop Protection Discovery-Biology, Dow AgroSciences LLC, 9330 Zionsville Rd., Indianapolis, IN 46268-1054, USA., Wang NX; Crop Protection Discovery-Chemistry, Dow AgroSciences LLC, 9330 Zionsville Rd., Indianapolis, IN 46268-1054, USA., Meyer ST; Crop Protection Discovery-Biology, Dow AgroSciences LLC, 9330 Zionsville Rd., Indianapolis, IN 46268-1054, USA., Niyaz NM; Crop Protection Discovery-Chemistry, Dow AgroSciences LLC, 9330 Zionsville Rd., Indianapolis, IN 46268-1054, USA., Rogers RB; Department of Chemistry, University of South Alabama, 6040 USA South Drive, Mobile, AL 36688, USA., Bravo-Altamirano K; Crop Protection Discovery-Chemistry, Dow AgroSciences LLC, 9330 Zionsville Rd., Indianapolis, IN 46268-1054, USA., Herrick JL; Crop Protection Discovery-Chemistry, Dow AgroSciences LLC, 9330 Zionsville Rd., Indianapolis, IN 46268-1054, USA., Yao C; Crop Protection Discovery-Biology, Dow AgroSciences LLC, 9330 Zionsville Rd., Indianapolis, IN 46268-1054, USA.
Jazyk: angličtina
Zdroj: Pest management science [Pest Manag Sci] 2019 Feb; Vol. 75 (2), pp. 413-426. Date of Electronic Publication: 2018 Sep 03.
DOI: 10.1002/ps.5130
Abstrakt: Background: The antifungal antibiotic UK-2A strongly inhibits mitochondrial electron transport at the Q i site of the cytochrome bc1 complex. Previous reports have described semi-synthetic modifications of UK-2A to explore the structure-activity relationship (SAR), but efforts to replace the picolinic acid moiety have been limited.
Results: Nineteen UK-2A analogs were prepared and evaluated for Q i site (cytochrome c reductase) inhibition and antifungal activity. While the majority are weaker Q i site inhibitors than UK-2A (IC 50 , 3.8 nM), compounds 2, 5, 13 and 16 are slightly more active (IC 50 , 3.3, 2.02, 2.89 and 1.55 nM, respectively). Compared to UK-2A, compounds 13 and 16 also inhibit growth of Zymoseptoria tritici and Leptosphaeria nodorum more strongly, while 2 and 13 provide stronger control of Z. tritici and Puccinia triticina in glasshouse tests. The relative activities of compounds 1-19 are rationalized based on a homology model constructed for the Z. tritici Q i binding site. Physical properties of compounds 1-19 influence translation of intrinsic activity to antifungal growth inhibition and in planta disease control.
Conclusions: The 3-hydroxy-4-methoxy picolinic acid moiety of UK-2A can be replaced by a variety of o-hydroxy-substituted arylcarboxylic acids that retain strong activity against Z. tritici and other agriculturally relevant fungi. © 2018 Society of Chemical Industry.
(© 2018 Society of Chemical Industry.)
Databáze: MEDLINE
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