Synthesis and biological activity of analogs of the antifungal antibiotic UK-2A. II. Impact of modifications to the macrocycle benzyl position.

Autor: Owen WJ; Dow AgroSciences LLC, Crop Protection Discovery Biology, Indianapolis, IN, USA., Meyer KG; Dow AgroSciences LLC, Crop Protection Discovery Chemistry, Indianapolis, IN, USA., Meyer ST; Dow AgroSciences LLC, Crop Protection Discovery Biology, Indianapolis, IN, USA., Li F; Dow AgroSciences LLC, Process Chemistry, Indianapolis, IN, USA., Slanec TJ; Dow AgroSciences LLC, Crop Protection Discovery Biology, Indianapolis, IN, USA., Wang NX; Dow AgroSciences LLC, Crop Protection Discovery Chemistry, Indianapolis, IN, USA., Yao C; Dow AgroSciences LLC, Crop Protection Discovery Biology, Indianapolis, IN, USA.
Jazyk: angličtina
Zdroj: Pest management science [Pest Manag Sci] 2019 Jul; Vol. 75 (7), pp. 1831-1846. Date of Electronic Publication: 2019 Mar 10.
DOI: 10.1002/ps.5329
Abstrakt: Background: UK-2A is an antifungal antibiotic produced by Streptomyces sp. 517-02. Derivatization of its picolinamide OH to form the isobutyryl acetal led to the discovery of fenpicoxamid (InatreqTM active), which is currently under development as a fungicide by Dow AgroSciences LLC. This paper documents efforts to achieve additional efficacy enhancements through semi-synthetic modification of the benzyl substituent of the UK-2A macrocycle.
Results: Of 34 analogs prepared, the most active had mitochondrial electron transport IC 50 values 1.5- to 3.7-fold higher than UK-2A (IC 50 0.86 nM). The cyclohexyl analog (38, IC 50 1.23 nM) was the most intrinsically active derivative, and inhibited in vitro growth of Zymoseptoria tritici (EC 50 2.8 ppb) and Leptosphaeria nodorum (EC 50 6.2 ppb) more strongly than UK-2A (EC 50 5.3 and 11.3 ppb for Z. tritici and L. nodorum, respectively). Heterocyclic ring systems and polar linker functionalities resulted in substantial activity loss. Several analogs (20, 22, 23, 24, 36 and 38) translated Z. tritici in vitro growth inhibition activity to in planta disease control more effectively than did UK-2A, with log D being a key factor in this regard.
Conclusions: UK-2A is amenable to further modification at the benzyl position on the macrocycle, which provides opportunities for manipulation of physical properties while retaining strong intrinsic and antifungal activity. © 2019 Society of Chemical Industry.
(© 2019 Society of Chemical Industry.)
Databáze: MEDLINE
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