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

ABSTRACT 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 IC50 values 1.5‐ to 3.7‐fold higher than UK‐2A (IC50 0.86 nM). The cyclohexyl analog (38, IC50 1.23 nM) was the most intrinsically active derivative, and inhibited in vitro growth of Zymoseptoria tritici (EC50 2.8 ppb) and Leptosphaeria nodorum (EC50 6.2 ppb) more strongly than UK‐2A (EC50 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 This paper describes structure activity relationship studies off position 8 of the macrocycle of the antifungal antibiotic UK‐2A. Replacement by aryls and aliphatics lacking heteroatoms generated analogs with good activity against Zymoseptoria tritici and other fungi.