<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>BACKGROUND</jats:title><jats:p>UK‐2A is an antifungal antibiotic produced by <jats:italic>Streptomyces</jats:italic> 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.</jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Of 34 analogs prepared, the most active had mitochondrial electron transport IC<jats:sub>50</jats:sub> values 1.5‐ to 3.7‐fold higher than UK‐2A (IC<jats:sub>50</jats:sub> 0.86 nM). The cyclohexyl analog (38, IC<jats:sub>50</jats:sub> 1.23 nM) was the most intrinsically active derivative, and inhibited <jats:italic>in vitro</jats:italic> growth of <jats:italic>Zymoseptoria tritici</jats:italic> (EC<jats:sub>50</jats:sub> 2.8 ppb) and <jats:italic>Leptosphaeria nodorum</jats:italic> (EC<jats:sub>50</jats:sub> 6.2 ppb) more strongly than UK‐2A (EC<jats:sub>50</jats:sub> 5.3 and 11.3 ppb for <jats:italic>Z. tritici</jats:italic> and <jats:italic>L. nodorum</jats:italic>, respectively). Heterocyclic ring systems and polar linker functionalities resulted in substantial activity loss. Several analogs (20, 22, 23, 24, 36 and 38) translated <jats:italic>Z. tritici in vitro</jats:italic> growth inhibition activity to <jats:italic>in planta</jats:italic> disease control more effectively than did UK‐2A, with log <jats:italic>D</jats:italic> being a key factor in this regard<jats:bold>.</jats:bold></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>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</jats:sec>