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. 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 biological potency of anilino-triazine insecticides.

BACKGROUND: An insecticide screening effort identified N-(4-bromophenyl)-4,6-bis(2,2,2-trifluoroethoxy)-1,3,5-triazine-2-amine as having weak potency against two lepidopteran species, Helicoverpa zea and Spodoptera exigua. A structure-activity relationship study about the trifluoroethoxy substituents and the aniline of this compound was carried out in an effort to improve insecticidal potency. RESULTS: Initially, a series of analogs bearing various substituents on the aniline were prepared, and the insecticidal potency was evaluated against H. zea and S. exigua in greenhouse diet feeding assays. The results showed that electron-withdrawing substituents, such as Cl, Br and CF3 , were preferred over electron-donating substituents, such as methoxy, and that potency was significantly better when the substituent was in the para-position. Additional investigations showed that bis(anilino)trifluoroethoxytriazines were more potent. Replacement of the remaining trifluoroethyl group in the bis(anilino)triazine series with an alkyl amine lead to compounds of equal or superior efficacy. CONCLUSION: The work presented showed that electron-withdrawing substituents in the para-position of the aniline ring of the initial hit delivered the best levels of insecticidal potency against the two insect species tested. Further investigations showed that potency could be improved by replacing one of the two trifluoroethoxy groups with additional 4-substituted aniline. This level of potency was maintained or further improved when the remaining trifluoroethoxy was replaced with a substituted amine. © 2017 Society of Chemical Industry.

Desketoneoenactin-siderophore conjugates for Candida: evidence of iron transport-dependent species selectivity.

We investigated the inhibitory activity of synthetic isocyanurate-based as well as linear mono- and trihydroxamate siderophore-drug conjugates against Candida spp. The conjugated drug was 13C-desketoneoenactin (DE). The MICs of siderophore-drug conjugates were determined in the absence and presence of 2,2'-dipyridyl to restrict iron availability. The ability of various siderophore types to promote growth in an iron-restricted medium was also assayed. Addition of a siderophore portion to the drug strongly impaired the inhibitory activity of DE. However, the activity of the drug conjugates was increased by up to 16-fold in iron-depleted medium for species having their growth strongly promoted by most hydroxamate-type siderophores (C. albicans, C. stellatoidea, and C. pseudotropicalis). The uptake of (55)Fe from ferrichrome and from two siderophore-drug conjugates was improved when C. albicans cells were grown in a low-iron medium. In the same assay, unlabeled ferrichrome was able to compete with the uptake of (55)Fe from both conjugates, indicating a common mechanism of uptake. A C. albicans strain lacking the siderophore transporter CaSit1/CaArn1 was not able to use ferrichrome or the synthetic ornithine-based trihydroxamate siderophore for growth promotion and was much less susceptible to the siderophore-drug conjugates than its isogenic parent strain. In summary, the ability of some Candida spp. to use ferrichrome-like siderophores for growth promotion explains the selective activity of hydroxamate-drug conjugates, and this activity seems to be related to the presence, in C. albicans, of the siderophore transporter CaSit1/CaArn1. New conjugate designs are necessary to fully restore or improve the initial DE activity.