Synthesis and biological activity of analogs of the antifungal antibiotic UK‐2A. III. Impact of modifications to the macrocycle isobutyryl ester position

• Published in: Pest management science Vol. 76; no. 1; pp. 277 - 286
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-01-2020; Wiley Subscription Services, Inc
• Subjects: Agricultural development; Agricultural sciences; Aliphatic compounds; Analogs; Antibiotics; Antifungal activity; Antifungal Agents; Biological activity; Disease control; Electron transport; Esters; Ethers; Fungi; Fungicides; Lactones - chemistry; Macrocyclic Compounds; Mitochondria; Organic chemistry; Parameter identification; Physical properties; Pyridines - chemistry; Solvation; Structure-Activity Relationship; Structure-activity relationships; United Kingdom > UK
• ISSN: 1526-498X; 1526-4998
• DOI: 10.1002/ps.5511

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
This paper describes SAR studies off position 7 of the macrocycle of the antifungal antibiotic UK‐2A. Replacement of the isobutyryl ester with ethers, esters and other groups generated analogs with good activity v Zymoseptoria tritici and other fungi.