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Synthesis and biological activity of analogs of the antifungal antibiotic UK‐2A. I. Impact of picolinamide ring replacement
Author(s) -
Owen W John,
Meyer Kevin G,
Slanec Thomas J,
Wang Nick X,
Meyer Stacy T,
Niyaz Noormohamed M,
Rogers Richard B,
BravoAltamirano Karla,
Herrick Jessica L,
Yao Chenglin
Publication year - 2019
Publication title -
pest management science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.296
H-Index - 125
eISSN - 1526-4998
pISSN - 1526-498X
DOI - 10.1002/ps.5130
Subject(s) - antifungal , antibiotics , ring (chemistry) , chemistry , biological activity , biology , microbiology and biotechnology , pharmacology , toxicology , stereochemistry , biochemistry , organic chemistry , in vitro
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