Fungicide Candidate Research Articles

Primary Study on Mode of Action for Macrocyclic Fungicide Candidates (7B3, D1) against Rhizoctonia solani Kühn

A novel macrolactam fungicide candidate (7B3) and a novel aza-macrolactone fungicide candidate (D1) were designed and synthesized, and the bioassay showed that both displayed excellent fungicidal activity against Rhizoctonia solani Kuhn. To elucidate the biochemical mode of action of the two compounds against R. solani and illustrate the similarities and differences of action mechanism resulting from subtle differences in structure of the two compounds, the effects of the two compounds on the ultrastructure of hyphae, electrolyte leakage, and respiration of mycelia cell suspension caused by 7B3 or D1 were studied. The results showed that the two compounds had very similar modes of action. Both induced irregular swelling of hyphae, vacuolation of cytoplasm, and thickening of cell wall. The conductivity of mycelia cell suspension increased in the presence of 7B3 or D1, which indicated that the two compounds had a similar effect on cell membrane permeability. In addition, both 7B3 and D1 were insufficient in inhibiting the respiration of mycelia.

Subnanomolar Inhibitor of Cytochrome bc1 Complex Designed by Optimizing Interaction with Conformationally Flexible Residues

Cytochrome bc(1) complex (EC 1.10.2.2, bc(1)), an essential component of the cellular respiratory chain and the photosynthetic apparatus in photosynthetic bacteria, has been identified as a promising target for new drugs and agricultural fungicides. X-ray diffraction structures of the free bc(1) complex and its complexes with various inhibitors revealed that the phenyl group of Phe274 in the binding pocket exhibited significant conformational flexibility upon different inhibitors binding to optimize respective pi-pi interactions, whereas the side chains of other hydrophobic residues showed conformational stability. Therefore, in the present study, a strategy of optimizing the pi-pi interaction with conformationally flexible residues was proposed to design and discover new bc(1) inhibitors with a higher potency. Eight new compounds were designed and synthesized, among which compound 5c, with a K(i) value of 570 pM, was identified as the most promising drug or fungicide candidate, significantly more potent than the commercially available bc(1) inhibitors, including azoxystrobin (AZ), kresoxim-methyl (KM), and pyraclostrobin (PY). To our knowledge, this is the first bc(1) inhibitor discovered from structure-based design with a potency of subnanomolar K(i) value. For all of the compounds synthesized and assayed, the calculated binding free energies correlated reasonably well with the binding free energies derived from the experimental K(i) values, with a correlation coefficient of r(2) = 0.89. The further inhibitory kinetics studies revealed that 5c is a noncompetitive inhibitor with respect to substrate cytochrome c, but it is a competitive inhibitor with respect to substrate ubiquinol. Due to its subnanomolar K(i) potency and slow dissociation rate constant (k(-0) = 0.00358 s(-1)), 5c could be used as a specific probe for further elucidation of the mechanism of bc(1) function and as a new lead compound for future drug discovery.

Fungicidal activity of 12-propoxyimino-1, 15-pentadecanlactam on selected crops

Fungicide candidate 7B3, featuring a structure of macrolactam with an oxime side chain, was evaluated through pot culture test and field efficacy trials. The results showed that 7B3 has excellent fungicidal activity against Rhizoctonia solani and Botrytis cinerea. In the pot culture test 7B3 showed good control against R. solani on cucumber and B. cinerea on tomato. In two-year four-place field efficacy trials the control of R. solani on cotton by 7B3 reached 64–92% at a rate of 140 g ai ha −1 and was better than or comparable to the commercial fungicide, carbendazin at the same dose. In a one-year one-place field efficacy trial the control effect of 7B3 against B. cinerea on cucumber reached 95% at a rate of 450 g ai ha −1 and was comparable to the commercial fungicide, huimeike at a rate of 504 g ai ha −1. Study on the dynamic distribution in cotton plants showed that 7B3 has almost no acropetal translocation or systemic activity in cotton plants. The toxicological profile of 7B3 indicated that it is a low toxicological compound and safe to humans, i.e. teratogenesis, mutagenesis and carcinogenesis tests were negative. All of the results suggested that 7B3 may be expected to be further developed as a practical fungicide.

Global Antifungal Profile Optimization of Chlorophenyl Derivatives against Botrytis cinerea and Colletotrichum gloeosporioides

Twenty-two aromatic derivatives bearing a chlorine atom and a different chain in the para or meta position were prepared and evaluated for their in vitro antifungal activity against the phytopathogenic fungi Botrytis cinerea and Colletotrichum gloeosporioides. The results showed that maximum inhibition of the growth of these fungi was exhibited for enantiomers S and R of 1-(4'-chlorophenyl)-2-phenylethanol (3 and 4). Furthermore, their antifungal activity showed a clear structure-activity relationship (SAR) trend confirming the importance of the benzyl hydroxyl group in the inhibitory mechanism of the compounds studied. Additionally, a multiobjective optimization study of the global antifungal profile of chlorophenyl derivatives was conducted in order to establish a rational strategy for the filtering of new fungicide candidates from combinatorial libraries. The MOOP-DESIRE methodology was used for this purpose providing reliable ranking models that can be used later.

In vitro inhibition of postharvest pathogens of fruit and control of gray mold of strawberry and green mold of citrus by aureobasidin A

Aureobasidin A (AbA), an antifungal cyclic depsipeptide antibiotic produced by Aureobasidium pullulans R106, has previously been shown to be effective against a wide range of fungi and protozoa. Here we report the inhibitory effects of AbA on spore germination, germ tuber elongation and hyphal growth of five pathogenic fungi including Penicillium digitatum, P. italicum, P. expansum, Botrytis cinerea and Monilinia fructicola, which are major pathogens causing postharvest diseases of a variety of fruits. AbA inhibited five pathogenic fungi by reducing conidial germination rates, delaying conidial germination initiation, restricting elongation of germ tuber and mycelium, as well as inducing abnormal alternations of morphology of germ tubes and hyphae of these fungi. The sensitivity of these fungi to AbA was pathogen species-dependent. P. digitatum was the most sensitive and M. fructicola the least. Importantly, AbA at 50 μg/ml was effective in controlling the citrus green mold and in reducing the strawberry gray mold incidence and severity, caused by P. digitatum and B. cinerea, respectively, after artificial inoculation. AbA and/or its analogs, therefore, hold promise as relatively safe and promising fungicide candidates to control postharvest decays of fruits, because AbA targets the inositol phosphorylceramide (IPC) synthase, an enzyme essential for fungi but absent from mammals.

The radiolabelled synthesis of N-Ethyl-2-chloro-6-trimethylsilylbenzamide[Ring-14C(U)], a fungicide candidate for wheat take-all disease

N-Ethyl-2-chloro-6-trimethylsilylbenzamide [Ring-14C(U)], 61, was synthesized in five steps from [U-14C]-benzoic acid 1 in an overall yield of 71%. Two key steps in the synthesis involve directed ortho metalation reactions2 on the aromatic ring. Purification by Silica gel Flash Column Chromatography produced 6 with a radiochemical purity of 99%. © 1997 John Wiley & Sons, Ltd.

The radiolabelled synthesis of N-Ethyl-2-chloro-6-trimethylsilylbenzamide[Ring-14C(U)], a fungicide candidate for wheat take‐all disease

The radiolabelled synthesis of N-Ethyl-2-chloro-6-trimethylsilylbenzamide[Ring-14C(U)], a fungicide candidate for wheat take‐all disease