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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.

Phytopathogenic fungal infections have become a major threat to agricultural production, food security, and human health globally, and novel antifungal agents with simple chemical scaffolds and high efficiency are needed. In this study, we designed and synthesized 38 8-hydroxyquinoline metal complexes and evaluated their antifungal activities. The results showed that most of the tested compounds possessed remarkable in vitro antifungal activity. Especially, compound 1e exhibited the highest antifungal potency among all target compounds, with EC50 values of 0.0940, 0.125, 2.95, and 5.96 μg/mL, respectively, against Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum, and Magnaporthe oryzae. Preliminary mechanistic studies had shown that compound 1e might cause mycelial abnormalities of S. sclerotiorum, cell membrane permeability changes, leakage of cell contents, and inhibition of sclerotia formation and germination. Moreover, the results of in vivo antifungal activity of compound 1e against S. sclerotiorum showed that 1e possessed higher curative effects than that of the positive control azoxystrobin. Therefore, compound 1e is expected to be a novel leading structure for the development of new antifungal agents.

Isoquinoline alkaloids, an important class of N-based heterocyclic compounds, have attracted considerable attention from researchers worldwide since the early 19(th) 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 diseases caused by phytopathogenic fungi reduce the yield and quality of crops. To develop novel antifungal agents, we designed and synthesized eight series of quinazolinone derivatives and evaluated their anti-phytopathogenic fungal activity. The bioassay results revealed that compounds KZL-15, KZL-22, 5b, 6b, 6c, 8e, and 8f exhibited remarkable antifungal activity in vitro. Especially, compound 6c displayed the highest bioactivity against Sclerotinia sclerotiorum, Pellicularia sasakii, Fusarium graminearum, and Fusarium oxysporum, displaying appreciable IC50 values (50% inhibitory concentration) of 2.46, 2.94, 6.03, and 11.9 μg/mL, respectively. A further mechanism interrogation revealed abnormal mycelia, damaged organelles, and changed permeability of cell membranes in S. sclerotiorum treated with compound 6c. In addition, the in vivo bioassay indicated that compound 6c possessed comparable curative and protective effects (87.3 and 90.7%, respectively) to the positive control azoxystrobin (89.5 and 91.2%, respectively) at 100 μg/mL concentration against S. sclerotiorum. This work validated the potential of compound 6c as a new and promising fungicide candidate, contributing to the exploration of potent antifungal agents.

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.

Phytopathogenic fungi have become a serious threat to the quality of agricultural products, food security and human health globally, necessitating the need to discover new antifungal agents with de novo chemical scaffolds and high efficiency. A series of 8-hydroxyquinoline derivatives were designed and synthesized, and their antifungal activity was evaluated against five phytopathogenic fungi. In vitro assays revealed that most of the tested compounds remarkably impacted the five target fungi and their inhibitory activities were better than that of the positive control azoxystrobin. Compound 2, in particular, exhibited the highest potency among all the tested compounds, with an EC50 of 0.0021, 0.0016, 0.0124, 0.0059 and 0.0120 mM respectively against B. cinerea, S. sclerotiorum, F. graminearum, F. oxysporum and M. oryzae, followed by compound 5c. The morphological observations of optical microscopy and scanning electron microscopy revealed that compounds 2 and 5c caused mycelial abnormalities of S. sclerotiorum. Futhermore, the results of in vivo antifungal activity of compounds 2 and 5c against S. sclerotiorum showed that 5c possessed stronger protective and curative activity than that of 2, and the curative effects of 5c at 40 and 80 μg mL−1 (84.18% and 95.44%) were better than those of azoxystrobin (77.32% and 83.59%). Therefore, compounds 2 and 5c are expected to be novel lead structures for the development of new fungicides.

Objective To explore the effect of Wenshen Yangxue Recipe (WYR) on inhibin-ac- tivin-follistatin (INH-ACT-FS) system and gonadal hormone level in anovulatory rats. Methods Anovula- tory rat model was established in 76 rats (9 days old) by subcutaneous injecting testosterone propionate (1. 25 mg/0. 05 mL for each rat) from the nape. Totally 58 successfully modeled rats were divided into 5 groups according to random digit table, i.e., the model group (n =10), the Western medicine (WM) group (n =12), high, middle, and low dose WYR groups (n =12). Besides, another ten 22-day old rats were recruited as a normal group. Distilled water was daily administered to rats in the normal group and the model group by gastrogavage. Clomiphene citrate (0. 58 mg/100 g) was daily administered to rats in the WM group for 5 successive days. WYR at 5. 2, 2. 6, 1. 3 mg/100 g was daily administered to rats in high, middle, and low dose WYR groups for 21 successive days. Levels of follicular stimulating hormone (FSH) , luteinizing hormone (LH) , estradiol (E₂) , progesterone (P) , and prolactin (PRL) were detected using radioimmunoassay. Contents of inhibin (INH) , activin (ACT) , and follistatin (FS) were measured using ELISA. Results Compared with the normal group, serum levels of FSH and LH increased, and P level decreased in the model group (P0. 05) ; INH level decreased and FS level increased in the model group (P0. 05). Compared with the model group, serum FSH level decreased in the WM group and 3 WYR groups, P level decreased in the WM group (P0. 05); INH increased and FS levels decreased in the WM group and 3 WYR groups; ACT level increased in the high dose WYR group, with statistical differ- ence (P0. 05). Conclusion WYR promoted follicular development possibly through regulating INH- ACT-FS system and gonadal hormone level.

In an attempt to find the neonicotinoid insecticides, twenty novel dihydropyridine derivatives were designed, &ldquo, green&rdquo, synthesized via one pot facile three-component reaction and evaluated for their bioactivities against Tetranychus cinnabarinus, Myzus persicae, Brevicoryne brassicae, Fusarium oxysporum f. sp. vasinfectum, Magnaporthe oryzae, Sclerotinia sclerotiorum and Botrytis cinereal. All of the tested compounds showed potent insecticidal activity, and some were much better in comparison with imidacloprid (IMI). Especially, compounds 3d (LC50: 0.011 mM) and 5c (LC50: 0.025 mM) were 12.2- and 5.4-fold more active than IMI (LC50: 0.135 mM) against T. cinnabarinus, respectively. Moreover, out of all the derivatives, compound 3d (LC50: 0.0015 mM) exhibited the strongest insecticidal activity against B. brassicae and compound 3i (LC50: 0.0007 mM) displayed the strongest insecticidal activity against M. persicae. Surprisingly, when the concentration of compound 4 was 50 mg/L, the inhibition rate against F. oxysporum and S. sclerotiorum reached 45.00% and 65.83%, respectively. The present work indicated that novel dihydropyridine derivatives could be used as potential lead compounds for developing neonicotinoid insecticides and agricultural fungicides.