Inspired by quinine and its analogues,
we designed, synthesized,
and evaluated two series of quinoline small molecular compounds (a and 2a) and six series of quinoline derivatives
(3a–f) for their antifungal activities.
The results showed that compounds 3e and 3f series exhibited significant fungicidal activities. Significantly,
compounds 3f-4 (EC50 = 0.41 μg/mL) and 3f-28 (EC50 = 0.55 μg/mL) displayed the superior
in vitro fungicidal activity and the potent in vivo curative effect
against Sclerotinia sclerotiorum. Preliminary
mechanism studies showed that compounds 3f-4 and 3f-28 could cause changes in the cell membrane permeability,
accumulation of reactive oxygen species, loss of mitochondrial membrane
potential, and effective inhibition of germination and formation of S. sclerotiorum sclerotia. These results indicate
that compounds 3f-4 and 3f-28 are novel
potential fungicidal candidates against S. sclerotiorum derived from natural products.
Plant pathogenic fungi seriously
affect agricultural production
and are difficult to control. The discovery of new leads based on
natural products is an important way to innovate fungicides. In this
study, 30 natural-product-based magnolol derivatives were synthesized
and characterized on the basis of NMR and mass spectroscopy. Bioactivity
tests on phytopathogenic fungi (Rhizoctonia solani, Fusarium graminearum, Botrytis cinerea, and Sclerotinia
sclerotiorum) in vitro of these compounds were performed
systematically. The results showed that 11 compounds were active against
four kinds of phytopathogenic fungi with EC50 values in
the range of 1.40–20.00 μg/mL, especially compound L5 that exhibited excellent antifungal properties against B. cinerea with an EC50 value of 2.86
μg/mL, approximately 2.8-fold more potent than magnolol (EC50 = 8.13 μg/mL). Moreover, compound L6 showed
the highest antifungal activity against F. graminearum and Rhophitulus solani with EC50 values of 4.39 and 1.40 μg/mL, respectively, and compound L7 showed good antifungal activity against S. sclerotiorum. Then, an in vivo experiment of compound L5 against B. cinerea was further
investigated in vivo using infected tomatoes (curative effect, 50/200
and 36%/100 μg/mL). The physiological and biochemical studies
illustrated that the primary action mechanism of compound L5 on B. cinerea might change the mycelium
morphology, increase cell membrane permeability, and destroy the function
of mitochondria. Furthermore, structure–activity relationship
(SAR) studies revealed that hydroxyl groups play a key role in antifungal
activity. To sum up, this study provides a reference for understanding
the application of magnolol-based antifungal agents in crop protection.
Inspired
by the widely antiphytopathogenic application of diversified
derivatives from natural sources, cryptolepine and its derivatives
were subsequently designed, synthesized, and evaluated for their antifungal
activities against four agriculturally important fungi Rhizoctonia solani, Botrytis cinerea, Fusarium graminearum, and Sclerotinia sclerotiorum. The results obtained from in vitro assay indicated that compounds a1–a24 showed great fungicidal property against B. cinerea (EC50 < 4 μg/mL); especially, a3 presented significantly prominent inhibitory activity with an EC50 of 0.027 μg/mL. In the pursuit of further expanding
the antifungal spectrum of cryptolepine, ring-opened compound f1 produced better activity with an EC50 of 3.632
μg/mL against R. solani and an
EC50 of 5.599 μg/mL against F. graminearum. Furthermore, a3 was selected to be a candidate to
investigate its preliminary antifungal mechanism to B. cinerea, revealing that not only spore germination
was effectively inhibited and the normal physiological structure of
mycelium was severely undermined but also detrimental reactive oxygen
was obviously accumulated and the normal function of the nucleus was
fairly disordered. Besides, in vivo curative experiment
against B. cinerea found that the therapeutic
action of a3 was comparable to that of the positive control
azoxystrobin. These results suggested that compound a3 could be regarded as a novel and promising agent against B. cinerea for its valuable potency.
Enlightened from our previous work
of structural simplification
of quinine and innovative application of natural products against
phytopathogenic fungi, lead structure 2,8-bis(trifluoromethyl)-4-quinolinol
(3) was selected to be a candidate and its diversified
design, synthesis, and antifungal evaluation were carried out. All
of the synthesized compounds Aa1–Db1 were evaluated
for their antifungal activity against four agriculturally important
fungi, Botrytis cinerea, Fusarium graminearum, Rhizoctonia
solani, and Sclerotinia sclerotiorum. Results showed that compounds Ac3, Ac4, Ac7, Ac9, Ac12, Bb1, Bb10, Bb11, Bb13, Cb1. and Cb3 exhibited a good antifungal effect,
especially Ac12 had the most potent activity with EC50 values of 0.52 and 0.50 μg/mL against S. sclerotiorum and B. cinerea, respectively, which were more potent than those of the lead compound 3 (1.72 and 1.89 μg/mL) and commercial fungicides azoxystrobin
(both >30 μg/mL) and 8-hydroxyquinoline (2.12 and 5.28 μg/mL).
Moreover, compound Ac12 displayed excellent in
vivo antifungal activity, which was comparable in activity
to the commercial fungicide boscalid. The preliminary mechanism revealed
that compound Ac12 might cause an abnormal morphology
of cell membranes, an increase in membrane permeability, and release
of cellular contents. These results indicated that compound Ac12 displayed superior in vitro and in vivo fungicidal activities and could be a potential fungicidal
candidate against plant fungal diseases.
Rhizoctonia solani causes serious plant diseases.
Neocryptolepine presented the significant antifungal activity against R. solani, however the mode of action is
unclear. In this paper, we investigated the potential mode of action
of neocryptolepine against R. solani integrated the proteomics and transcriptomics. Results showed that
after treatment with neocryptolepine, 1012 differentially expressed
proteins and 10 920 differentially expressed genes of R. solani were found, most of them were
enriched in mitochondrial respiratory chain. It affected oxidative
phosphorylation led to the enrichment of ROS and the decrease of MMP,
and inhibited complex III activity with the inhibition rate of 63.51%
at 10 μg/mL. The mitochondrial structural and function were
damaged. Cytochrome b-c1 complex subunit Rieske (UQCRFS1)
with the high binding score to neocryptolepine was found as a potential
target. In addition, it inhibited the sclerotia formation and presented
antifungal efficacy by decreasing the diameter of a wound in potato
in a concentration-dependent manner. Above results indicated that
neocryptolepine inhibited the complex III activity by binding UQCRFS1
and blocked the ion transfer to cause the death of R. solani mycelia. This study laid the foundation
for the future development of neocryptolepine as an alternative biofungicide.
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