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1.
Molecules ; 27(9)2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35566241

RESUMO

Six new diterpenoids, blusamiferoids A-F (1-6), including four pimarane-type diterpenoids, one rosane-type diterpenoid (3), and one rearranged abietane-type diterpenoid (6), were isolated from the dry aerial parts of Blumea balsamifera. Their structures were characterized by spectroscopic and computational methods. In particular, the structures of 1 and 4 were confirmed by X-ray crystallography. Compounds 5 and 6 were found to dose-dependently inhibit the production of TNF-α, IL-6, and nitrite oxide, and compound 5 also downregulated NF-κB phosphorylation in lipopolysaccharide (LPS)-induced RAW 264.7 cells.

2.
Biochem Pharmacol ; 200: 115049, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35469784

RESUMO

A series of new 7-ethyl-10-fluoro-20-O-(cinnamic acid ester)-camptothecin derivatives were synthesized and evaluated for cytotoxicity against four human tumor cell lines including HepG2 (hepatocellular carcinoma), SW480 (colorectal cancer), A2780 (ovarian cancer), and Hucct1 (intrahepatic cholangiocarcinoma). The results of cytotoxic activities in vitro showed that most of the camptothecin derivatives harbor promising cytotoxic activity against tested tumor cell lines. Among them, compound XJS-11 exhibited broad-spectrum inhibitory activities against HepG2, SW480, A2780, and Hucct1 cell lines with IC50 values of 0.03, 0.09, 0.22, and 0.32 µM, respectively. Further investigation demonstrated that compound XJS-11 exhibited more effective growth inhibition against a variety of human hepatoma cells (Sk-hep-1, Hep3B and Huh7) and lower cytotoxicity against immortalized normal human liver cell line L02 than the positive control topotecan. Especially, XJS-11 showed higher selective toxicity in two kinds of human hepatoma cells and immortalized normal human liver cell line (IC50(L-02)/IC50(HepG2) = 113.20; IC50(L-02)/IC50(Hep3B) = 85.60) than topotecan (IC50(L-02)/IC50(HepG2) = 9.45; IC50(L-02)/IC50(Hep3B) = 8.52). Mechanistically, XJS-11 induced cell cycle arrest and cell apoptosis in HepG2 and Hep3B cells by inhibiting Top I activity in a manner similar to that of topotecan. Meanwhile, XJS-11 could attenuate the tumor growth in both xenograft and primary HCC mouse models. In addition, the acute toxicity assay showed that XJS-11 did not cause lethality or significant body weight loss with a single intraperitoneal dose at 100 mg/kg or with an intraperitoneal dose at 25 mg/kg for 7 days. Moreover, unlike topotecan, XJS-11 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the C57BL/6 mice. Taken together, XJS-11 merits further development as a new generation of the camptothecin-derived drug candidate.

3.
Bioorg Chem ; 122: 105747, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35338969

RESUMO

Based on the structural skeleton of natural products boeravinones, two types of 6H-chromeno[3,4-b]quinoline derivatives were designed and synthesized by nitrogen atom substitution strategy. Then, their cytotoxic activities were evaluated against six human tumor cell lines including HepG2 (hepatocellular carcinoma), A2780 (ovarian cancer), Hela (cervical cancer), HCT116 (colorectal cancer), SW1990 (pancreatic cancer), and MCF7 (breast cancer). The results showed that compounds ZML-8 and ZML-14 exhibited robust inhibitory activities against HepG2 cells with IC50 values of 0.58 and 1.94 µM, respectively. In addition, ZML-8 and ZML-14 showed higher selectivity against HepG2 and L-02 cells than Topotecan. Mechanistically, ZML-8 and ZML-14 not only induced cell cycle arrest in the G2/M phase and cell apoptosis, but also dose-dependently inhibited topoisomerase I activity and induced DNA damage in HepG2 cells. Molecular docking showed that ZML-8 and ZML-14 could interact with topoisomerase I-DNA complex with a similar binding mode to Topotecan. Inhibitory activities of these two compounds on topoisomerase I were then confirmed in both cell-free systems and in whole-cell lysates. Taken together, compounds ZML-8 and ZML-14 merit further development as a new generation of non-camptothecin topoisomerase I inhibitors for the treatment of cancer.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Simulação de Acoplamento Molecular , Inibidores da Topoisomerase I , Inibidores da Topoisomerase II/farmacologia
4.
Alkaloids Chem Biol ; 88: 1-47, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35305754

RESUMO

Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted scientific and popular interest worldwide since the 19th century. More than 600 compounds have been isolated from nature to date. To build on our two prior reviews, we reexamined the promising molecules described in previous reports and provided updated literature on novel quinoline and quinazoline alkaloids isolated over the past 5 years. This chapter reviews and discusses 205 molecules with a broad range of bioactivities, including antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, and other effects. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.


Assuntos
Alcaloides , Quinolinas , Alcaloides/farmacologia , Anti-Inflamatórios , Biologia , Quinazolinas/farmacologia , Quinolinas/farmacologia
5.
J Nat Prod ; 85(4): 963-971, 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35191714

RESUMO

Neocryptolepine derivatives have attracted great interest because of their unique cytotoxic activity. 8-Fluoroneocryptolepine (8FNC) was synthesized, and its cytotoxicity was evaluated by MTT assay in AGS gastric cancer cells and gastric mucosa GES-1 cells. 8-Fluoroneocryptolepine showed greater selectivity and cytotoxicity to AGS cells than the cisplatin (CIS) and fluorouracil (5-Fu) commonly used in clinical treatment of gastric cancer. Most importantly, we significantly improved the cytotoxic effect of 8FNC against AGS cells by structural modification and reduced the cytotoxicity against GES-1 cells compared with neocryptolepine. We further evaluated the activity of 8FNC against AGS cells in vitro. Our results indicate that 8FNC arrests the AGS cell cycle in the G2/M phase, reduces the mitochondrial membrane potential of AGS cells, and drives the initiation of apoptotic body formation in 8FNC-induced apoptosis. Moreover, 8FNC exhibits strong inhibitory effects on AGS cell migration. Studies on the molecular mechanisms of the cytotoxic activities of 8FNC revealed that it may play a significant role in the inhibitory effect on AGS human gastric cancer cells through the PI3K/AKT signaling pathway. In conclusion, 8FNC may become a promising lead compound in the development of potential clinical drug candidates for the treatment of gastric cancer.


Assuntos
Antineoplásicos , Neoplasias Gástricas , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Fluoruracila/farmacologia , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Gástricas/tratamento farmacológico
6.
J Agric Food Chem ; 70(9): 2851-2863, 2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35226498

RESUMO

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.


Assuntos
Fungicidas Industriais , Alcaloides Indólicos , Alcaloides , Antifúngicos/química , Fungicidas Industriais/química , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Indóis , Estrutura Molecular , Quinolinas , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 227: 113937, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34710744

RESUMO

Evodiamine and rutaecarpine are two alkaloids isolated from traditional Chinese herbal medicine Evodia rutaecarpa, which have been reported to have various biological activities in past decades. To explore the potential applications for evodiamine and rutaecarpine alkaloids and their derivatives, various kinds of evodiamine and rutaecarpine derivatives were designed and synthesized. Their antifungal profile against six phytopathogenic fungi Rhizoctonia solani, Botrytis cinerea, Fusarium graminearum, Fusarium oxysporum, Sclerotinia sclerotiorum, and Magnaporthe oryzae were evaluated for the first time. Furthermore, a series of modified imidazole derivatives of rutaecarpine were synthesized to investigate the structure-activity relationship. The results of antifungal activities in vitro showed that imidazole derivative of rutaecarpine A1 exhibited broad-spectrum inhibitory activities against R. solani, B. cinerea, F. oxysporum, S. sclerotiorum, M. oryzae and F. graminearum with EC50 values of 1.97, 5.97, 12.72, 2.87 and 16.58 µg/mL, respectively. Preliminary mechanistic studies showed that compound A1 might cause mycelial abnormalities of S. sclerotiorum, mitochondrial distortion and swelling, and inhibition of sclerotia formation and germination. Moreover, the curative effects of compound A1 were 94.7%, 81.5%, 80.8%, 65.0% at 400, 200, 100, 50 µg/mL in vivo experiments, which was far more effective than the positive control azoxystrobin. Significantly, no phytotoxicity of compound A1 on oilseed rape leaves was observed obviously even at a high concentration of 400 µg/mL. Therefore, compound A1 is expected to be a novel leading structure for the development of new antifungal agents.


Assuntos
Antifúngicos/farmacologia , Desenho de Fármacos , Alcaloides Indólicos/farmacologia , Quinazolinas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Ascomicetos/efeitos dos fármacos , Botrytis/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fusarium/efeitos dos fármacos , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Rhizoctonia/efeitos dos fármacos , Relação Estrutura-Atividade
8.
J Agric Food Chem ; 69(48): 14467-14477, 2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34843231

RESUMO

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 EC50 values less than 1 µg/mL. Among them, compounds w7, w8, w12, and w15 showed superior antifungal activity against B. cinerea with EC50 values of 0.036, 0.050, 0.042, and 0.048 µg/mL, respectively, which were more potent than boscalid (EC50 = 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.


Assuntos
Antifúngicos , Fungicidas Industriais , Antifúngicos/farmacologia , Botrytis , Fungos , Fungicidas Industriais/farmacologia , Pirróis , Quinonas , Relação Estrutura-Atividade
9.
Chem Biodivers ; 18(12): e2100633, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34643056

RESUMO

The increasing resistance of plant diseases caused by phytopathogenic fungi highlights the need for highly effective and environmentally benign agents. The antifungal activities of Cnidium monnieri fruit extracts and five isolated compounds as well as structurally related coumarins against five plant pathogenic fungi were evaluated. The acetone extract, which contained the highest amount of five coumarins, showed strongest antifungal activity. Among the coumarin compounds, we found that 4-methoxycoumarin exhibited stronger and broader antifungal activity against five phytopathogenic fungi, and was more potent than osthol. Especially, it could significantly inhibit the growth of Rhizoctonia solani mycelium with an EC50 value of 21 µg mL-1 . Further studies showed that 4-methoxycoumarin affected the structure and function of peroxisomes, inhibited the ß-oxidation of fatty acids, decreased the production of ATP and acetyl coenzyme A, and then accumulated ROS by damaging MMP and the mitochondrial function to cause the cell death of R. solani mycelia. 4-Methoxycoumarin presented antifungal efficacy in a concentration- dependent manner in vivo and could be used to prevent the potato black scurf. This study laid the foundation for the future development of 4-methoxycournamin as an alternative and friendly biofungicide.


Assuntos
Antifúngicos/farmacologia , Cnidium/química , Cumarínicos/farmacologia , Frutas/química , Rhizoctonia/efeitos dos fármacos , Acetilcoenzima A/antagonistas & inibidores , Acetilcoenzima A/biossíntese , Trifosfato de Adenosina/antagonistas & inibidores , Trifosfato de Adenosina/biossíntese , Antifúngicos/química , Antifúngicos/isolamento & purificação , Cumarínicos/química , Cumarínicos/isolamento & purificação , Ácidos Graxos/antagonistas & inibidores , Ácidos Graxos/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Rhizoctonia/crescimento & desenvolvimento
10.
Int J Mol Sci ; 22(19)2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34639194

RESUMO

Humulus lupulus Linn. is a traditional medicinal and edible plant with several biological properties. The aims of this work were: (1) to evaluate the in vitro antifungal activity of H. lupulus ethanolic extract; (2) to study the in vitro and in vivo antifungal activity of isoxanthohumol, an isoprene flavonoid from H. lupulus, against Botrytis cinerea; and (3) to explore the antifungal mechanism of isoxanthohumol on B. cinerea. The present data revealed that the ethanolic extract of H. lupulus exhibited moderate antifungal activity against the five tested phytopathogenic fungi in vitro, and isoxanthohumol showed highly significant antifungal activity against B. cinerea, with an EC50 value of 4.32 µg/mL. Meanwhile, it exhibited moderate to excellent protective and curative efficacies in vivo. The results of morphologic observation, RNA-seq, and physiological indicators revealed that the antifungal mechanism of isoxanthohumol is mainly related to metabolism; it affected the carbohydrate metabolic process, destroyed the tricarboxylic acid (TCA) cycle, and hindered the generation of ATP by inhibiting respiration. Further studies indicated that isoxanthohumol caused membrane lipid peroxidation, thus accelerating the death of B. cinerea. This study demonstrates that isoxanthohumol can be used as a potential botanical fungicide for the management of phytopathogenic fungi.


Assuntos
Trifosfato de Adenosina/metabolismo , Antifúngicos/farmacologia , Botrytis/efeitos dos fármacos , Humulus/química , Peroxidação de Lipídeos/efeitos dos fármacos , Xantonas/farmacologia , Botrytis/crescimento & desenvolvimento
11.
J Agric Food Chem ; 69(41): 12156-12170, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34623798

RESUMO

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.


Assuntos
Fungicidas Industriais , Fusarium , Hidroxiquinolinas , Quinolinas , Antifúngicos/farmacologia , Ascomicetos , Botrytis , Fungos , Fungicidas Industriais/farmacologia , Estrutura Molecular , Quinina , Rhizoctonia , Relação Estrutura-Atividade
12.
J Agric Food Chem ; 69(40): 11781-11793, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34582205

RESUMO

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.


Assuntos
Antifúngicos , Fungicidas Industriais , Animais , Antifúngicos/farmacologia , Ascomicetos , Compostos de Bifenilo , Botrytis , Fungicidas Industriais/farmacologia , Fusarium , Lignanas , Estrutura Molecular , Rhizoctonia , Relação Estrutura-Atividade
13.
J Agric Food Chem ; 69(30): 8347-8357, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34288693

RESUMO

Inspired by natural 2-quinolinecarboxylic acid derivatives, a series of quinoline compounds containing acylhydrazine, acylhydrazone, sulfonylhydrazine, oxadiazole, thiadiazole, or triazole moieties were synthesized and evaluated for their fungicidal activity. Most of these compounds exhibited excellent fungicidal activity in vitro. Significantly, compound 2e displayed the superior in vitro antifungal activity against Sclerotinia sclerotiorum, Rhizoctonia solani, Botrytis cinerea, and Fusarium graminearum with the EC50 values of 0.39, 0.46, 0.19, and 0.18 µg/mL, respectively, and were more potent than those of carbendazim (EC50, 0.68, 0.14, >100, and 0.65 µg/mL, respectively). Moreover, compound 2e could inhibit spore germination of F. graminearum. Preliminary mechanistic studies showed that compound 2e could cause abnormal morphology of cell walls and vacuoles, loss of mitochondrion, increases in membrane permeability, and release of cellular contents. These results indicate that compound 2e displayed superior fungicidal activities and could be a potential fungicidal candidate against plant fungal diseases.


Assuntos
Fungicidas Industriais , Quinolinas , Antifúngicos/farmacologia , Ascomicetos , Botrytis , Fungicidas Industriais/farmacologia , Fusarium , Estrutura Molecular , Quinolinas/farmacologia , Rhizoctonia , Relação Estrutura-Atividade
14.
J Agric Food Chem ; 69(23): 6455-6464, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34075744

RESUMO

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.


Assuntos
Alcaloides , Rhizoctonia , Alcaloides/farmacologia , Antifúngicos/farmacologia , Doenças das Plantas , Proteômica , Quinolinas , Rhizoctonia/genética , Transcriptoma
15.
Bioorg Chem ; 114: 105065, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34174631

RESUMO

29 novel 20(S)-aminophosphonate derivatives of camptothecin were synthesized via a FeCl3 - catalyzed one-pot reaction. All of these compounds displayed similar or superior cytotoxic activity in comparison with that of Irinotecan against Hep3B, MCF-7, A-549, MDA-MB-231, KB, and multidrug-resistant (MDR) KB-vin cell lines. Out of them, compound B07 exhibited significant cytotoxicity and 10-fold improvement in activity compared to Irinotecan. Mechanistically, B07 not only induced cell apoptosis and cell cycle arrest in Hep3B and MCF-7 cells, but also inhibited Topoisomerase I activity in the cell and cell-free system in a manner similar to that of Irinotecan. In both xenograft and primary HCC mouse models, B07 showed significant anti-tumor activity and was more potent than Irinotecan. Additionally, the acute toxicity assay showed that B07 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the FVB/N mice. Therefore, these findings indicate that compound B07 could be a potential Topoisomerase I poison drug candidate for further clinical trial.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Desenho de Fármacos , Organofosfonatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Camptotecina/síntese química , Camptotecina/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Organofosfonatos/síntese química , Organofosfonatos/química , Relação Estrutura-Atividade
16.
J Agric Food Chem ; 69(16): 4604-4614, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33872004

RESUMO

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.


Assuntos
Fungicidas Industriais , Antifúngicos/farmacologia , Ascomicetos , Fungicidas Industriais/farmacologia , Fusarium , Quinazolinonas/farmacologia , Relação Estrutura-Atividade
17.
J Agric Food Chem ; 69(4): 1259-1271, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33496176

RESUMO

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.


Assuntos
Fungicidas Industriais/síntese química , Fungicidas Industriais/farmacologia , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ascomicetos/efeitos dos fármacos , Ascomicetos/crescimento & desenvolvimento , Desenho de Fármacos , Fungicidas Industriais/química , Fusarium/efeitos dos fármacos , Fusarium/crescimento & desenvolvimento , Doenças das Plantas/microbiologia , Rhizoctonia/efeitos dos fármacos , Rhizoctonia/crescimento & desenvolvimento , Relação Estrutura-Atividade
18.
Med Res Rev ; 41(2): 928-960, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33128409

RESUMO

Indolizidine alkaloids are chemical constituents isolated from various marine and terrestrial plants and animals, including but not limited to trees, fungi, ants, and frogs, with a myriad of important biological activities. In this review, we discuss the biological activity and pharmacological effects of indolizidine alkaloids and offer new avenues toward the discovery of new and better drugs based on these naturally occurring compounds.


Assuntos
Alcaloides , Indolizidinas , Alcaloides/farmacologia , Animais , Fungos , Indolizidinas/farmacologia , Plantas
19.
J Adv Res ; 34: 149-158, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-35024187

RESUMO

Introduction: Eugenol is a major component of essential oils of several plants, it exhibits significant antiparasitic and acaricidal activities, yet its molecular targets remain unknown. Objectives: We aimed to systematically investigate the mechanism of action and the potential targets of eugenol against P. cuniculi, and evaluate the safety for laying the theoretical foundation for clinical application as an acaricide. Methods: Using RNA-Seq analysis, surface plasmon resonance analysis and RNA interference assay, the mode of action of eugenol against Psoroptes cuniculi was investigated. The effect on the mitochondrial membrane potential and complex I of PC12 cells and C6/36 cells was assayed to investigate the species specificity of eugenol in insects and mammals. Finally, a safety evaluation of eugenol in vivo was performed. Results: Eugenol inhibited complex I activity of the mitochondrial respiratory chain in the oxidative phosphorylation pathway by binding to NADH dehydrogenase chain 2 and resulted in the death of mites. The inhibition rates were 37.89% for 50 µg/mL and 60.26% for 100 µg/mL, respectively. Further experiments indicated that the difference in the complex I sequence between insects and mammals led to the different affinity of eugenol to specific peptide, resulting in species specificity. Eugenol exhibited significant inhibitory effects against the mitochondrial membrane potential and complex I in Aedes albopictus C6/36 cells but was not active in rat PC12 cells. Insect cells were particularly sensitive to eugenol. In contrast to the known inhibitor rotenone, eugenol had better safety and did not result in Parkinson's disease or other diseases in rats. Conclusion: This is the first report on acaricidal eugenol targeting complex I of the mitochondrial respiratory chain. This work lays the foundation for the development of eugenol as an environmentally alternative acaricidal agent.


Assuntos
Acaricidas , Óleos Voláteis , Psoroptidae , Acaricidas/farmacologia , Animais , Eugenol/farmacologia , Extratos Vegetais , Ratos
20.
J Pharm Biomed Anal ; 190: 113547, 2020 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-32866747

RESUMO

Discovering acetylcholinesterase (AChE) inhibitors is one of the important ways to develop new drugs for the treatment of Alzheimer's disease. In this work, a simple strategy was developed for screening AChE inhibitors from traditional Chinese medicines (TCMs) by capillary electrophoresis (CE) analysis combined with enzymatic assay, in which immobilized AChE was employed. For AChE immobilization, cellulose filter paper (CFP) was used as the carrier material and physically coated with chitosan owing to moderate viscosity of chitosan to be introduced into amino groups, and then AChE was covalently bonded to the amino-functionalized CFP through a Schiff base reaction using glutaraldehyde (GA) as a cross-linking agent. The CFP-immobilized AChE exhibited enhanced endurance to pH and temperature, improved storage stability, excellent repeatability and reusability. More remarkably, CFP-immobilized AChE can be instantly separated from enzyme reaction mixture thus greatly simplifying the operational process. For immobilized AChE, the Michaelis-Menten constant, inhibition constant and IC50 were determined using huperzine A as a model inhibitor. Finally, CFP-immobilized AChE was applied to inhibitor screening from 17 TCMs, among which Chebulae Fructus (ripe fruits of Terminalia chebula) exhibited the strongest inhibitory effect on AChE. The positive results indicated that such a screening strategy may open up a new avenue to discover active components from TCMs.


Assuntos
Inibidores da Colinesterase , Enzimas Imobilizadas , Acetilcolinesterase , China , Eletroforese Capilar , Medicina Tradicional Chinesa
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