Isoquinoline alkaloids, an important class of N-based heterocyclic compounds, have attracted considerable attention from researchers worldwide since the early 19th century. Over the past 200 years, many compounds from this class were isolated, and most of them and their analogs possess various bioactivities. In this review, we survey the updated literature on bioactive alkaloids and highlight research achievements of this alkaloid class during the period of 2014-2018. We reviewed over 400 molecules with a broad range of bioactivities, including antitumor, antidiabetic and its complications, antibacterial, antifungal, antiviral, antiparasitic, insecticidal, anti-inflammatory, antioxidant, neuroprotective, and other activities. This review should provide new indications or directions for the discovery of new and better drugs from the original naturally occurring isoquinoline alkaloids.
Neocryptolepine is an alkaloid isolated
from traditional African herbal medicine Cryptolepis
sanguinolenta, and its broad spectrum of biological
activities has been illuminated in past decades. In this study, neocryptolepine
and its derivatives (1–49) were designed
and synthesized from economical and readily available starting materials.
Their structures were confirmed by proton nuclear magnetic resonance,
carbon nuclear magnetic resonance, and mass spectrometry. The synthesized
compounds were screened for their antifungal profile against six agriculturally
important fungi Rhizoctonia solani, Botrytis cinerea (B. cinerea), Fusarium graminearum, Mycosphaerella melonis, Sclerotinia
sclerotiorum, and Magnaporthe oryzae. The results of in vitro assay revealed that compounds 5, 21, 24, 35, 40, 45, and 47 presented remarkable antifungal
activity against the fungi tested with EC50 values lower
than 1 μg/mL. Significantly, compound 24 displayed
the most effective inhibitory potency against B. cinerea (EC50 = 0.07 μg/mL), and the data from in vivo
experiments revealed that compound 24 demonstrated comparable
protective activity with the positive control boscalid. Preliminary
mechanism studies indicated that compound 24 showed impressive
spore germination inhibitory effectiveness and lower cytotoxicity
than azoxystrobin, imparted on normal function of the cell membrane
and cell wall, and arrested the normal function of the nucleus. Besides
the excellent inhibitory activity against agriculturally important
phytopathogenic fungi tested, the designed assemblage possesses several
benefits with a high profile of variation in synthesized molecules,
the ease of synthesis, and good cost-effectiveness of commercially
available synthetic reagents, all of these have highlighted the potential
worth of compound 24 as a new and highly efficient agricultural
fungicide.
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.
Based on the structural characteristics
of the cryptolepine alkaloid,
a series of new quindoline derivatives bearing various substituents
were prepared and evaluated for their fungicidal and antibacterial
activities. Bioassay results showed that compound D7 displayed
superior in vitro fungicidal activities against Sclerotinia sclerotiorum, Botrytis
cinerea, Fusarium graminearum, and Rhizoctonia solani with EC50 values of 0.780, 3.62, 1.59, and 2.85 μg/mL, respectively.
Compound A7 showed apparent antibacterial activities
toward Xanthomonas oryzae
pv.
oryzae with a minimum inhibitory concentration (MIC) value
of 3.12 μg/mL. Significantly, in vivo antifungal
activity suggested that the curative effect (98.3%) of compound D7 was comparable to that of the positive control azoxystrobin
(96.7%) at 100 μg/mL. Preliminary mechanistic studies showed
that compound D7 might cause mycelial abnormality of S. sclerotiorum, cell membrane breakage, accumulation
of reactive oxygen species (ROS), and inhibition of sclerotia formation.
Therefore, compound D7 could be a novel broad-spectrum
fungicidal candidate against plant fungal diseases.
Crop diseases caused by fungi threaten food security and exacerbate the food crisis. Inspired by the application of fungicide candidates from natural products in agrochemical discovery, a series of luotonin A derivatives were designed, synthesized, and evaluated for their antifungal activities against five plant fungi. Most of these compounds exhibited significant fungicidal activity against Botrytis cinerea in vitro with EC 50 values less than 1 μg/mL. Among them, compounds w7, w8, w12, and w15 showed superior antifungal activity against B. cinerea with EC 50 values of 0.036, 0.050, 0.042, and 0.048 μg/mL, respectively, which were more potent than boscalid (EC 50 = 1.790 μg/mL). Preliminary mechanism studies revealed that compound w7 might pursue its antifungal activity by disrupting the fungal cell membrane and cell wall. Moreover, in vivo bioassay also indicated that compound w7 could be effective for the control of B. cinerea. The above results evidenced the potential of luotonin A derivatives as novel and promising candidate fungicides.
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