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

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.

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

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.

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

BACKGROUND: The antifungal antibiotic UK-2A strongly inhibits mitochondrial electron transport at the Qi site of the cytochrome bc1 complex. Previous reports have described semi-synthetic modifications of UK-2A to explore the structure-activity relationship (SAR), but efforts to replace the picolinic acid moiety have been limited. RESULTS: Nineteen UK-2A analogs were prepared and evaluated for Qi site (cytochrome c reductase) inhibition and antifungal activity. While the majority are weaker Qi site inhibitors than UK-2A (IC50 , 3.8 nM), compounds 2, 5, 13 and 16 are slightly more active (IC50 , 3.3, 2.02, 2.89 and 1.55 nM, respectively). Compared to UK-2A, compounds 13 and 16 also inhibit growth of Zymoseptoria tritici and Leptosphaeria nodorum more strongly, while 2 and 13 provide stronger control of Z. tritici and Puccinia triticina in glasshouse tests. The relative activities of compounds 1-19 are rationalized based on a homology model constructed for the Z. tritici Qi binding site. Physical properties of compounds 1-19 influence translation of intrinsic activity to antifungal growth inhibition and in planta disease control. CONCLUSIONS: 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 antifungal activity of 3-aryl-1,2,4-triazin-6-one derivatives.

BACKGROUND: As a result of resistance development in many plant-pathogenic fungi to agricultural fungicides, there is an ongoing need to discover novel antifungal chemistries to help sustain efficient crop production. A fungicide screening program identified 3-phenyl-1-(2,2,2-trifluoroethyl)-1,2,4-triazin-6(1H)-one (5) as a promising new starting point for further activity optimization. A series of analogs were designed, prepared and evaluated in growth inhibition assays using four plant-pathogenic fungi. RESULTS: Thirty nine analogs (compounds 5 to 43) were prepared to explore structure-activity relationships at R1 and R2, and all targeted structures were characterized by (1)H NMR and MS. All compounds were in vitro tested against three ascomycetes [Leptosphaeria nodorum, Magnaporthe grisea and Zymoseptoria tritici (syn. Mycosphaerella graminicola)] and one basidiomycete (Ustilago maydis) pathogen. When R2 was trifluoroethyl, fungicidal activity was enhanced by a single electron-withdrawing substitution, such as Br, Cl and CF3 in the 3-position at R1 (compounds 9, 10 and 12), of which the 3-bromo compound (10) was the most active (EC50 = 0.08, averaged across four pathogens). More subtle activity improvement was found by addition of a second halogen substituent in the 4-position, with the 3-Br-4-F analog (20) being the most active against the commercially important cereal pathogen Z. tritici. Replacement of the R2 haloalkyl group with benzyl, alkyl (e.g. n-butyl, i-butyl, n-pentyl) and, particularly, CH2 -cycloalkyls (e.g. CH2-cyclopropyl, CH2-cyclobutyl) resulted in further activity enhancements against the ascomycete fungi, but was either neutral or detrimental to activity against U. maydis. One of the most active compounds in this series (41) gave control of Z. tritici, with an EC50 of 0.005 ppm, comparable with that of the commercial strobilurin fungicide azoxystrobin (EC50 0.002 ppm). CONCLUSIONS: The present work demonstrated that the 3-phenyl-1,2,4-triazin-6-ones are a novel series of compounds with highly compelling levels of antifungal activity against agriculturally relevant plant-pathogenic fungi.