Strobilurin fungicides play a crucial role in protecting plants against different pathogens and securing food supplies. A series of 1,2,3-thiadiazole and thiazole-based strobilurins were rationally designed, synthesized, characterized, and tested against various fungi. Introduction of 1,2,3-thiadiazole greatly improved the fungicidal activity of the target molecules. Compounds 8a, 8c, 8d, and 10i exhibited a relatively broad spectrum of fungicidal activity. Compound 8a showed excellent activities against Gibberella zeae, Sclerotinia sclerotiorum, and Rhizoctonia cerealis with median effective concentrations (EC) of 2.68, 0.44, and 0.01 μg/mL, respectively; it was much more active than positive controls enestroburin, kresoxim-methyl, and azoxystrobin with EC between 0.06 and 15.12 μg/mL. Comparable or better fungicidal efficacy of compound 8a compared with azoxystrobin and trifloxystrobin against Sphaerotheca fuliginea and Pseudoperonspera cubensis was validated in cucumber fields at the same application dosages. Therefore, compound 8a is a promising fungicidal candidate worthy of further development.
A molecular design approach was used in our laboratory to guide the development of imidazole-based fungicides. Based on homology modeling and molecular docking studies targeting the cytochrome P450-dependent sterol 14α-demethylase, 3,4-dichloroisothiazole-based imidazoles showed great potential. Several such compounds were then rationally designed, synthesized, characterized, and their antifungal activities were evaluated. Bioassay results showed that compounds such as ( R)-11, ( R)-12, and ( S)-11 have commendable, broad-spectrum antifungal activities that are comparable to those of commercial products. Based on Q-PCR testing and microscopy observations, the imidazole derivatives affect fungal cell wall formation through the inhibition of the BcCYP51 expression system. These findings strongly suggest that the mode of action of these imidazole compounds is similar to that of tioconazole and imazalil. This report indicates that this molecular design strategy is not only practical but productive.
A series of 3,4-dichloroisothiazole based novel strobilurin analogs were synthesized, the compound8dwas discovered as a new fungicidal candidate with better efficacy than commercial standards.
Transketolase
(TK) has been regarded as a new target for the development
of novel herbicides. In this study, a series of 2-thioether-5-(thienyl/pyridyl)-1,3,4-oxadiazoles
were designed and synthesized based on TK as the new target. The preliminary
bioassay results indicated that compounds 4l and 4m displayed the best herbicidal activities against Amaranthus retroflexus (AR) and Digitaria sanguinalis (DS), with
the inhibition exceeding 90% at 100–200 mg/L in vitro. Moreover, they also displayed higher postemergence herbicidal activities
(90% control) against AR and DS than
all of the positive controls at 45–90 g [active ingredient
(ai)]/ha in a greenhouse. Notably, compounds 4l and 4m showed a broad spectrum of weed control at 90 g ai/ha.
More significantly, compound 4l exhibited good crop selectivity
against maize at 90 g ai/ha. Both fluorescent binding experiments
and molecular docking analyses indicated that compounds 4l and 4m exhibited strong TK inhibitory activities with
superior binding affinities than the others. Preliminary mechanism
studies suggested that they might exert their TK inhibitory effects
by occupying the active cavity of At TK and forming
more strong interactions with amino acids in the active site. Taken
together, these results suggested that compound 4l was
a potential herbicide candidate for weed control in maize fields targeting
TK.
To discover novel target-based fungicidal candidates, a molecular design model was established with a threedimensional (3D) structure of Rhizoctonia solani pyruvate kinase (RsPK) simulated with the AlphaFold 2 and YZK-C22 as a fungicidal lead. A series of novel [1,2,4]triazolo [3,4-b][1,3,4]thiadiazole derivatives were rationally designed, synthesized, evaluated for their fungicidal performance, and validated for their mode of action. The in vitro bioassays with R. solani indicated that compounds 5g, 5o, and 5z with an EC 50 value ranging from 1.01 to 1.54 μg/mL displayed higher fungicidal activity than the positive control YZK-C22 with its EC 50 of 3.14 μg/mL. Especially, 5o exhibited high potency and a broad spectrum against Alternaria solani, Botrytis cinerea, Cercospora arachidicola, Physalospora piricola, R. solani, and Sclerotinia sclerotiorum with its EC 50 value falling between 1.54 and 13.10 μg/mL. Like all positive controls, 5g, 5o, and 5z showed excellent in vivo growth inhibition against Pseudoperonospora cubensis at 200 μg/mL. Even though the PK enzymatic inhibition assay showed that 5o was approximately 2.6 times less active than YZK-C22 (IC 50 : 29.14 vs 11.15 μg/mL, respectively), the similar fluorescence quenching patterns of RsPK by 5o and YZK-C22, and the docking results of interactions between RsPK and 5o or YZK-C22 implied that they might share the similar binding site in the RsPK active pocket. Our studies suggested that 5o could be used as a potent fungicidal lead for further optimization. The results of comparative molecular field analysis (CoMFA) provided a direction for further molecular design.
A rational molecule design strategy based on scaffold hopping was applied to discover novel leads, and then a series of novel pyrazole amide derivatives were designed, synthesized, characterized, and evaluated for their antifungal activities. Bioassay results indicated that some target compounds such as S3, S12, and S26 showed good in vivo antifungal activities; among them, S26 exhibited commendable in vivo protective activity with an 89% inhibition rate against Botrytis cinerea on cucumber at 100 μg/mL that is comparable to positive controls boscalid, isopyrazam, and fluxapyroxad. Microscopy observations suggested that S26 affects the normal fungal growth. Fluorescence quenching analysis and SDH (succinate dehydrogenase) enzymatic inhibition studies validated that S26 may not be an SDH inhibitor. Based on induction of plant defense responses testing, S26 enhanced the accumulation of RBOH, WRKY6, WRKY30, PR1, and PAL defense-related genes expression and the defense-associated enzyme phenylalanine ammonia lyase (PAL) expression on cucumber. These findings support that S26 not only displayed direct fungicidal activity but also exhibited plant innate immunity stimulation activity, and it could be used as a promising plant defense-related fungicide candidate.
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