Synthesis and biological activity of analogs of the antifungal antibiotic UK‐2A. III. Impact of modifications to the macrocycle isobutyryl ester position
2020
Owen, W John | Meyer, Kevin G | Slanec, Thomas J | Meyer, Stacy T | Wang, Nick X | Fitzpatrick, Gina M | Niyaz, Noormohamed N | Nugent, Jaime | Ricks, Michael J | Rogers, Richard B | Yao, Chenglin
BACKGROUND: Fenpicoxamid (Inatreq™ active), a new fungicide under development by Corteva Agriscience™, Agriculture Division of DowDuPont, is an isobutyryl acetal derivative of the antifungal antibiotic UK‐2A. SAR studies around the picolinamide ring and benzyl substituents attached at positions 3 and 8, respectively, of the UK‐2A bislactone macrocycle have recently been documented. This study focuses on replacement of the isobutyryl ester group in the 7 position. RESULTS: Thirty analogs, predominantly esters and ethers, were prepared and evaluated for inhibition of mitochondrial electron transport and in vitro growth of Zymoseptoria tritici, Leptosphaeria nodorum, Pyricularia oryzae and Ustilago maydis. Aliphatic substituents containing four to six carbon atoms deliver strong intrinsic activity, the pivaloate ester (IC₅₀ 1.44 nM) and the n‐butyl, 1‐Me‐propyl, 3,3‐diMe‐propyl and 2‐c‐propyl propyl ethers (IC₅₀ values = 1.08, 1.14, 1.15 & 1.32 nM, respectively) being the most active derivatives. QSAR modelling identified solvation energy (Eₛₒₗᵥ) and critical packing parameters (vsurf_CP) as highly significant molecular descriptors for explaining relative intrinsic activity of analogs. Activity translation to fungal growth inhibition and disease control testing was significantly influenced by intrinsic activity and physical properties, the cyclopropanecarboxylate ester (log D 3.67, IC₅₀ 3.36 nM, Z. tritici EC₅₀ 12 μg L⁻¹) showing the strongest Z. tritici activity in protectant tests. CONCLUSIONS: Substitution of the isobutyryl ester group of UK‐2A generates analogs that retain strong antifungal activity against Z. tritici and other fungi. © 2019 Society of Chemical Industry
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