Synthesis and biological activity of analogs of the antifungal antibiotic UK‐2A. I. Impact of picolinamide ring replacement

Abstract

The 3-hydroxy-4-methoxy picolinic acid moiety of UK-2A can be replaced by a variety of o-hydroxy-substituted arylcarboxylic acids that retain strong activity against Z. tritici and other agriculturally relevant fungi. © 2018 Society of Chemical Industry.

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

“…On this basis, we focused further SAR efforts on optimization of the more synthetically accessible macrocycle substituents, notably at the picolinamide, isobutyryl ester and benzyl substituents at positions 3, 7 and 8, respectively. The results of our SAR explorations at positions 3 and 8 were reported recently, substantially extending the preliminary efforts of Usuki et al . While the majority of the picolinic acid replacement analogs prepared were significantly less active than UK‐2A, two analogs (the 2‐OH phenyl & 3‐OH‐2‐pyridyl ring replacements) were more active than UK‐2A in controlling both Z. tritici and Puccinia triticina (wheat leaf rust) in 1‐day protectant greenhouse tests .…”

“…Also contained in Table are antifungal growth inhibition data, expressed as EC 50 values, for compounds 4–33 against the fungal pathogens Z. tritici and L. nodorum, while data for two additional pathogens, P. oryzae and U. maydis , is presented as Supplementary Information (Table 1(s)). As was the case for the previously reported SAR investigations focused on the picolinamide ring and the benzyl substituent at position 8 of the UK‐2A macrocycle, Z. tritici and L. nodorum are more sensitive to growth inhibition than are P. oryzae and U. maydis, mean EC 50 values across all analogs being 28.5 and 69.4 μg L −1 for Z. tritici and L. nodorum (Table ) compared to 190.3 and 228.2 μg L −1 for P. oryzae and U. maydis (Table 1(s)).…”

“…Procedures used for host plant propagation, test compound formulation and application as well as pathogen inoculation and treatment of disease assessment data were as previously described (Owen et al …”

Natural products: a strategic lead generation approach in crop protection discovery

“…). More than 250 analogs were prepared and evaluated for control of Z. tritici as well as for synthetic feasibility . Typical synthetic routes to these analogs are illustrated in Fig.…”

“…More than 250 analogs were prepared and evaluated for control of Z. tritici as well as for synthetic feasibility. 54,56 Typical synthetic routes to these analogs are illustrated in Fig. 10 and, although some structural replacements resulted in analogs with comparable or even slightly better in vitro potency relative to fenpicoxamid, the efficacy gains were not sufficient for consideration of development.…”