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1.
J Agric Food Chem ; 72(38): 20882-20891, 2024 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-39262056

RESUMO

Naturally derived compounds show promise as treatments for microbial infections. Polyphenols, abundantly found in various plants, fruits, and vegetables, are noted for their physiological benefits including antimicrobial effects. This study introduced a new set of acylated phloroglucinol derivatives, synthesized and tested for their antifungal activity in vitro against seven different pathogenic fungi. The standout compound, 3-methyl-1-(2,4,6-trihydroxyphenyl) butan-1-one (2b), exhibited remarkable fungicidal strength, with EC50 values of 1.39 µg/mL against Botrytis cinerea and 1.18 µg/mL against Monilinia fructicola, outperforming previously screened phenolic compounds. When tested in vivo, 2b demonstrated effective antifungal properties, with cure rates of 76.26% for brown rot and 83.35% for gray mold at a concentration of 200 µg/mL, rivaling the commercial fungicide Pyrimethanil in its efficacy against B. cinerea. Preliminary research suggests that 2b's antifungal mechanism may involve the disruption of spore germination, damage to the fungal cell membrane, and leakage of cellular contents. These results indicate that compound 2b has excellent fungicidal properties against B. cinerea and holds potential as a treatment for gray mold.


Assuntos
Ascomicetos , Botrytis , Fungicidas Industriais , Floroglucinol , Doenças das Plantas , Botrytis/efeitos dos fármacos , Botrytis/crescimento & desenvolvimento , Floroglucinol/farmacologia , Floroglucinol/química , Fungicidas Industriais/farmacologia , Fungicidas Industriais/química , Ascomicetos/efeitos dos fármacos , Doenças das Plantas/microbiologia , Testes de Sensibilidade Microbiana
2.
J Agric Food Chem ; 72(38): 20831-20841, 2024 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-39284582

RESUMO

This research adopted the Fischer indole synthesis method to continue constructing a novel drug-like chemical entity based on the guidance of isocryptolepine and obtained four series of derivatives: Y, Da, Db, and Dc. The antimicrobial activity of these derivatives against plant pathogens was further evaluated. The results showed that Dc-2 had the best antifungal effect against Botrytis cinerea, and its EC50 value was up to 1.29 µg/mL. In addition, an in vivo activity test showed that the protective effect of Dc-2 on apples was 82.2% at 200 µg/mL, which was better than that of Pyrimethanil (45.4%). Meanwhile, it was found by scanning electron microscopy and transmission electron microscopy that the compound Dc-2 affected the morphology of mycelia. The compound Dc-2 was found to damage the cell membrane by PI and ROS staining. Through experiments such as leakage of cell contents, it was found that the compound Dc-2 changed the permeability of the cell membrane and caused the leakage of substances in the cell. According to the above studies, compound Dc-2 can be used as a candidate lead compound for further structural optimization and development.


Assuntos
Botrytis , Desenho de Fármacos , Fungicidas Industriais , Doenças das Plantas , Botrytis/efeitos dos fármacos , Botrytis/crescimento & desenvolvimento , Doenças das Plantas/microbiologia , Fungicidas Industriais/farmacologia , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Relação Estrutura-Atividade , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Testes de Sensibilidade Microbiana , Malus/química , Malus/microbiologia , Bactérias/efeitos dos fármacos , Estrutura Molecular
3.
Bioorg Med Chem ; 112: 117880, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39216382

RESUMO

Berberine is a quaternary ammonium isoquinoline alkaloid derived from traditional Chinese medicines Coptis chinensis and Phellodendron chinense. It has many pharmacological activities such as hypoglycemic, hypolipidemic, anti-tumor, antimicrobial and anti-inflammatory. Through structural modifications at various sites of berberine, the introduction of different groups can change berberine's physical and chemical properties, thereby improving the biological activity and clinical efficacy, and expanding the scope of application. This paper reviews the research progress and structure-activity relationships of berberine in recent years, aiming to provide valuable insights for the exploration of novel berberine derivatives.


Assuntos
Berberina , Berberina/química , Berberina/farmacologia , Berberina/análogos & derivados , Relação Estrutura-Atividade , Humanos , Estrutura Molecular , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/síntese química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química
4.
Nat Prod Res ; : 1-10, 2024 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-39155512

RESUMO

With the intention of advancing our research on diverse C-20 derivatives of camptothecin (CPT), 38 CPT derivatives bearing sulphonamide and sulfonylurea chemical scaffolds and different substituent groups have been designed, synthesised and evaluated in vitro for cytotoxicity against four tumour cell lines, A-549 (lung carcinoma), KB (nasopharyngeal carcinoma), MDA-MB-231 (triple-negative breast cancer) and KBvin (an MDR KB subiline). As a result, all the synthesised compounds showed promising in vitro cytotoxic activity against the four cancer cell lines tested, and were more potent than irinotecan. Importantly, compounds 12b, 12f, 12j and 13 l possessed better antiproliferative activity against all tested tumour cell lines with IC50 values of 0.0118 - 0.5478 µM, and resulted approximately 3 to 4 times more cytotoxic than topotecan against multidrug-resistant KBvin subline. Convincing evidences are achieved that incorporation of sulphonamide and sulfonylurea motifs into position-20 of camptothecin confers markedly enhanced cytotoxic activity against cancer cell lines.

5.
Pest Manag Sci ; 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39136433

RESUMO

BACKGROUND: The threats to the safety of humans and the environment and the resistance of agricultural chemicals to plant pathogenic fungi and bacteria highlight an urgent need to find safe and efficient alternatives to chemical fungicides and bactericides. In this study, a series of Berberine (BBR) derivatives were designed, synthesized and evaluated for in vitro and in vivo antimicrobial activity against plant pathogenic fungi and bacteria. RESULTS: Bioassay results indicated that compounds A11, A14, A20, A21, A22, A25, A26, E1, E2, E3, Z1 and Z2 showed high inhibitory activity against Sclerotinia sclerotiorum and Botrytis cinerea. Especially, A25 showed a broad spectrum and the highest antifungal activity among these compounds. Its EC50 value against Botrytis cinerea was 1.34 µg mL-1. Compound E6 possessed high inhibitory activity against Xanthomonas oryzae and Xanthomonas Campestris, with MIC90 values of 3.12 µg mL-1 and 1.56 µg mL-1. A Topomer CoMFA model was generated for 3D-QSAR studies based on anti-B. cinerea effects, with high predictive accuracy, showed that the addition of an appropriate substituent group at the para-position of benzyl of BBR derivatives could effectively improve the anti-B. cinerea activity. In addition, compound A25 could significantly inhibit the spore germination of Botrytis cinerea at low concentration, and compound F4 exhibited remarkable curative and protective efficiencies on rice bacterial leaf blight. CONCLUSION: This study indicates that the BBR derivatives are hopeful for further exploration as the lead compound with novel antimicrobial agents. © 2024 Society of Chemical Industry.

6.
J Agric Food Chem ; 72(36): 19618-19628, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39193844

RESUMO

Sophora flavescens, a traditional Chinese herb, produces a wide range of secondary metabolites with a broad spectrum of biological activities. In this study, we isolated six isopentenyl flavonoids (1-6) from the roots of S. flavescens and evaluated their activities against phytopathogenic fungi. In vitro activities showed that kurarinone and sophoraflavanone G displayed broad spectrum and superior activities, among which sophoraflavanone G displayed excellent activity against tested fungi, with EC50 values ranging from 4.76 to 13.94 µg/mL. Notably, kurarinone was easily purified and showed potential activity against Rhizoctonia solani, Botrytis cinerea, and Fusarium graminearum with EC50 values of 16.12, 16.55, and 16.99 µg/mL, respectively. Consequently, we initially investigated the mechanism of kurarinone against B. cinerea. It was found that kurarinone disrupted cell wall components, impaired cell membrane integrity, increased cell membrane permeability, and affected cellular energy metabolism, thereby exerting its effect against B. cinerea. Therefore, kurarinone is expected to be a potential candidate for the development of plant fungicides.


Assuntos
Botrytis , Flavonoides , Fungicidas Industriais , Fusarium , Doenças das Plantas , Raízes de Plantas , Rhizoctonia , Sophora , Botrytis/efeitos dos fármacos , Botrytis/crescimento & desenvolvimento , Sophora/química , Flavonoides/farmacologia , Flavonoides/química , Flavonoides/isolamento & purificação , Fusarium/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Fungicidas Industriais/química , Raízes de Plantas/química , Doenças das Plantas/microbiologia , Rhizoctonia/efeitos dos fármacos , Rhizoctonia/crescimento & desenvolvimento , Prenilação , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Sophora flavescens
7.
J Agric Food Chem ; 72(13): 6988-6997, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38506764

RESUMO

Bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv oryzae (Xoo) is extremely harmful to rice production. The traditional control approach is to use bactericides that target key bacterial growth factors, but the selection pressure on the pathogen makes resistant strains the dominant bacterial strains, leading to a decline in bactericidal efficacy. Type III secretion system (T3SS) is a conserved and critical virulence factor in most Gram-negative bacteria, and its expression or absence does not affect bacterial growth, rendering it an ideal target for creating drugs against Gram-negative pathogens. In this work, we synthesized a range of derivatives from cryptolepine and neocryptolepine. We found that compound Z-8 could inhibit the expression of Xoo T3SS-related genes without affecting the growth of bacteria. an in vivo bioassay showed that compound Z-8 could effectively reduce the hypersensitive response (HR) induced by Xoo in tobacco and reduce the pathogenicity of Xoo in rice. Furthermore, it exhibited synergy in control of bacterial leaf blight when combined with the quorum quenching bacterial F20.


Assuntos
Alcaloides , Alcaloides Indólicos , Oryza , Quinolinas , Xanthomonas , Oryza/genética , Sistemas de Secreção Tipo III/genética , Bactérias/metabolismo , Xanthomonas/genética , Doenças das Plantas/prevenção & controle , Doenças das Plantas/microbiologia
8.
J Agric Food Chem ; 72(14): 7716-7726, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38536397

RESUMO

The emergence of resistant pathogens has increased the demand for alternative fungicides. The use of natural products as chemical scaffolds is a potential method for developing fungicides. HWY-289, a semisynthetic protoberberine derivative, demonstrated broad-spectrum and potent activities against phytopathogenic fungi, particularly Botrytis cinerea (with EC50 values of 1.34 µg/mL). SEM and TEM imaging indicated that HWY-289 altered the morphology of the mycelium and the internal structure of cells. Transcriptomics revealed that it could break down cellular walls through amino acid sugar and nucleotide sugar metabolism. In addition, it substantially decreased chitinase activity and chitin synthase gene (BcCHSV) expression by 53.03 and 82.18% at 1.5 µg/mL, respectively. Moreover, this impacted the permeability and integrity of cell membranes. Finally, HWY-289 also hindered energy metabolism, resulting in a significant reduction of ATP content, ATPase activities, and key enzyme activities in the TCA cycle. Therefore, HWY-289 may be a potential candidate for the development of plant fungicides.


Assuntos
Antifúngicos , Alcaloides de Berberina , Berberina/análogos & derivados , Fungicidas Industriais , Antifúngicos/farmacologia , Antifúngicos/química , Fungicidas Industriais/farmacologia , Fungicidas Industriais/química , Botrytis , Açúcares , Doenças das Plantas/microbiologia
9.
Chem Biodivers ; 20(11): e202300998, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37755070

RESUMO

Based on the research strategy of "drug repurposing", a series of derivatives and marketed drugs that containing salicylic acid skeleton were tested for their antibacterial activities against phytopathogens. Salicylic acid can not only regulate some important growth metabolism of plants, but also induce plant disease resistance. The bioassay results showed that the salicylamides exhibited excellent antibacterial activity. Especially, oxyclozanide showed the best antibacterial effect against Xanthomonas oryzae, Xanthomonas axonopodis pv. citri and Pectobacterium atroseptica with MICs of 0.78, 3.12 and 12.5 µg.mL-1, respectively. In vivo experiments with rice bacterial leaf blight had further demonstrated that oxyclozanide exhibited stronger antibacterial activity than the commercial bactericide, thiodiazole copper. Oxyclozanide could induce plant defense responses through the determination of salicylic acid content and the activities of defense-related enzymes including CAT, POD, and SOD in rice. The preliminarily antibacterial mechanism study indicated that oxyclozanide exhibited the antibacterial activity by disrupting cell integrity and reducing bacterial pathogenicity. Additionally, oxyclozanide could induce plant defense responses through the determination of salicylic acid content.


Assuntos
Oryza , Xanthomonas , Salicilamidas/farmacologia , Reposicionamento de Medicamentos , Oxiclozanida/farmacologia , Antibacterianos/farmacologia , Oryza/microbiologia , Testes de Sensibilidade Microbiana , Ácido Salicílico/farmacologia , Doenças das Plantas/prevenção & controle , Doenças das Plantas/microbiologia , Oxidiazóis/farmacologia
10.
Pest Manag Sci ; 79(12): 5321-5332, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37615260

RESUMO

BACKGROUND: Chemical fungicides are the mainstay of plant disease control in agricultural production, but there are a very limited number of drugs that can effectively control plant diseases. Two series of secondary amine derivatives were synthesized using the diamine skeleton combined with saturated aromatic and aliphatic aldehydes, and their antibacterial and antifungal activities against plant pathogens were determined. In addition, the antimicrobial mechanism of the highly active compound A26 was preliminarily examined against Xanthomonas oryzae (Xoo). RESULTS: Compound A26 exhibited the highest antibacterial potency among all the target compounds, with MIC values of 3.12, 3.12 and 12.5 µg mL-1 against Xoo, Xanthomonas axonopodis pv. Citri and Pseudomonas sollamacearum, respectively. In addition, compound A26 had powerful curative and protective effects against Xoo at 200 µg mL-1 , and was better than the control agent Xinjunan. Preliminary mechanistic studies showed that compound A26 reduced the bacterial pathogenicity by targeting cell membranes and inhibiting the secretion of extracellular polysaccharides. Meanwhile, the toxicity of compound A26 to Human Embryonic Kidney 293 cells and Human Liver-7702 was similar to that of Xinjunan, and it had moderate toxicity according to the World Health Organization classification standard of oral exogenous toxicity, with an LD50 of 245.47 mg kg-1 . CONCLUSION: Secondary amines have efficient and broad-spectrum antibacterial activity against plant pathogenic bacteria and are expected to be a new class of candidate compounds for antibacterial drugs. © 2023 Society of Chemical Industry.


Assuntos
Oryza , Xanthomonas , Humanos , Testes de Sensibilidade Microbiana , Oxidiazóis/química , Antibacterianos/farmacologia , Antibacterianos/química , Poliaminas/farmacologia , Doenças das Plantas
11.
Int J Food Microbiol ; 404: 110318, 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37454507

RESUMO

Aspergillus flavus, a widespread saprotrophic filamentous fungus, could colonize agricultural crops with aflatoxin contamination, which endangers food security and the agricultural economy. A safe, effective and environmentally friendly fungicide is urgently needed. Pterostilbene, a natural phytoalexin originated from Pterocarpus indicus Willd., Vaccinium spp. and Vitis vinifera L., has been reported to possess excellent antimicrobial activity. More importantly, it is quite safe and healthy. In our screening tests of plant polyphenols for the inhibition of A. flavus, we found that pterostilbene evidently inhibited mycelial growth of Aspergillus flavus (EC50 = 15.94 µg/mL) and the inhibitory effect was better than that of natamycin (EC50 = 22.01 µg/mL), which is a natural product widely used in food preservation. Therefore, we provided insights into the efficacy of pterostilbene suppression on A. flavus growth, aflatoxin B1 biosynthesis and its potential mechanisms against A. flavus in the present study. Here, pterostilbene at concentrations of 250 and 500 µg/mL could effectively inhibit the infection of A. flavus on peanuts. And the biosynthesis of the secondary metabolite aflatoxin B1 was also inhibited. The antifungal effects of pterostilbene are exerted by inducing a large amount of intracellular reactive oxygen species production to bring the cells into a state of oxidative stress, damaging cellular biomolecules such as DNA, proteins and lipids and destroying the integrity of the cell membrane. Taken together, our study strongly supported the fact that pterostilbene could be considered a safe and effective antifungal agent against A. flavus infection.


Assuntos
Aflatoxinas , Aspergillus flavus , Aspergillus flavus/metabolismo , Aflatoxina B1 , Antifúngicos/farmacologia , Antifúngicos/metabolismo
12.
Eur J Med Chem ; 259: 115627, 2023 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-37467619

RESUMO

Since the first natural carbazole alkaloid, murrayanine, was isolated from Mwraya Spreng, carbazole alkaloid derivatives have been widely concerned for their anti-tumor, anti-viral and anti-bacterial activities. In recent decades, a growing body of data suggest that carbazole alkaloids and their derivatives have different biological activities. This is the first comprehensive description of the antifungal and antibacterial activities of carbazole alkaloids in the past decade (2012-2022), including natural and partially synthesized carbazole alkaloids in the past decade. Finally, the challenges and problems faced by this kind of alkaloids are summarized. This paper will be helpful for further exploration of this kind of alkaloids.


Assuntos
Alcaloides , Antineoplásicos , Alcaloides/farmacologia , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Carbazóis/farmacologia , Estrutura Molecular
13.
Bioorg Chem ; 139: 106652, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37390632

RESUMO

Primary liver cancer is one of the most common malignant cancers of the digestive system that lacks effective chemotherapeutic drugs in clinical settings. Camptothecin (CPT) and its derivatives have been approved for cancer treatment; however, their application is limited by their systemic toxicity. For lead optimization in new drug discovery stages, fluorination is an effective and robust approach to increase the bioavailability and optimize the pharmacokinetics of candidate compounds, thereby improving their efficacy. To obtain new and highly active CPT derivatives, we designed, synthesized, and evaluated two new fluorinated CPT derivatives, 9-fluorocamptothecin (A1) and 7-ethyl-9-fluorocamptothecin (A2), in this study. In vitro, A1 and A2 exhibited more robust anti-tumor activity than topotecan (TPT) in various cancer cells, particularly hepatocellular carcinoma (HCC) cells. In vivo, A1 and A2 exhibited greater anti-tumor activity than TPT in both AKT/Met induced primary HCC mouse models and implanted HepG2 cell xenografts. Acute toxicity tests revealed that A1 and A2 were not lethal and did not cause significant body weight loss at high doses. Moreover, A1 and A2 exhibited no significant toxicity in the mouse liver, heart, lung, spleen, kidney, and hematopoietic systems at therapeutic doses. Mechanistically, A1 and A2 blocked HCC cell proliferation by inhibiting the enzymatic activity of Topo I, subsequently inducing DNA damage, cell cycle arrest, and apoptosis. In summary, our results indicate that fluorination improves the anti-tumor activity of CPT while decreasing its toxicity and highlight the application potential of fluorination products A1 and A2 in clinical settings.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , DNA Topoisomerases Tipo I/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Topotecan/farmacologia , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
14.
Pest Manag Sci ; 79(8): 2748-2761, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36914877

RESUMO

BACKGROUND: The unreasonable use of chemical fungicides causes common adverse consequences that not only affect the environment, but also cause resistance and resurgence problems of plant pathogens, which are extremely harmful to human health, the economy, and the environment. Based on the rich biological activities of boron-based compounds, 82 phenylboronic acid derivatives were selected and their antifungal activities against six agricultural plant pathogens were determined. Combined with transcriptomics tools, the mechanism of action of compound A49 (2-chloro-5-trifluoromethoxybenzeneboronic acid) against Botrytis cinerea Pers (B. cinerea) was studied. RESULTS: The EC50 values of compounds A24, A25, A30, A31, A36, A41, A49 and B23 against all six fungi were under 10 µg/mL. Compound A49 displayed significant activity against B. cinerea (EC50 = 0.39 µg/mL), which was better than that of commercial fungicide boscalid (EC50 = 0.55 µg/mL). A49 not only inhibited the germination of B. cinerea spores, but also caused abnormal cell morphology, loss of cell membrane integrity, enhanced cell membrane permeability, and accumulation of intracellular reactive oxygen species. Further findings showed that A49 reduced cellular antioxidant activity, and peroxidase and catalase activities. Transcriptomic results indicated that A49 could degrade intracellular redox processes and alter the metabolism of some amino acids. Meanwhile, A49 showed obvious activity in vivo and low cytotoxicity to mammal cells. CONCLUSION: The boron-containing small molecule compounds had high efficiency and broad-spectrum antifungal activities against six plant pathogens, and are expected to be candidate compounds for a new class of antifungal drugs. © 2023 Society of Chemical Industry.


Assuntos
Antifúngicos , Fungicidas Industriais , Humanos , Antifúngicos/farmacologia , Antifúngicos/química , Boro , Fungicidas Industriais/farmacologia , Fungicidas Industriais/química , Botrytis , Relação Estrutura-Atividade
15.
Pest Manag Sci ; 79(6): 2135-2146, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36721354

RESUMO

BACKGROUND: The resistance of traditional chemical fungicides to plant pathogenic fungi and the threats to the safety of humans and the environment highlight an urgent need to find safe and efficient alternatives to chemical fungicides. Owing to the wide spectrum of antifungal activities, low persistence and nontoxicity to mammals and aquatic life, essential oils have considerable potential as low-risk pesticides. In this study, the essential oil and the main components of Angelica sinensis (Oliv.) Diels (Danggui) were extracted, analyzed by GC-MS, and evaluated for their antifungal activities against six plant pathogenic fungi. RESULTS: 3-butylidenephthalide (3-BPH) showed the best antifungal activity against Fusarium graminearum with an EC50 value of 14.35 µg mL-1 . The antifungal mechanistic studies revealed that 3-BPH induced the generation of endogenous ROS to cause lipid peroxidation of the cell membrane and inhibited the biosynthesis of ergosterol, thereby causing the cell membrane damaged to exert its fungicidal activity. Significantly, 3-BPH could reduce deoxynivalenol production compared to the control. CONCLUSION: This study demonstrated the potent fungicidal activity of natural phthalide compound 3-BPH and highlighted its potential as an alternative agent to control F. graminearum. © 2023 Society of Chemical Industry.


Assuntos
Angelica sinensis , Fungicidas Industriais , Fusarium , Óleos Voláteis , Animais , Angelica sinensis/química , Antifúngicos/farmacologia , Antifúngicos/química , Fungos , Fungicidas Industriais/farmacologia , Mamíferos , Plantas
16.
Alkaloids Chem Biol ; 89: 1-37, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36731966

RESUMO

Quinolizidine alkaloids isolated from various marine and terrestrial animals and plants are primarily composed of lupinine-, matrine-, and sparteine-type alkaloids. Matrine, phenanthroquinolizidines, bis-quinolizidines, and small molecules from amphibian skins are representative compounds of such alkaloids. Quinolizidine alkaloids harbor anticancer, antibacterial, antiinflammatory, antifibrosis, antiviral, and anti-arrhythmia. In this chapter, we comprehensively outline the biological activity and pharmacological action of quinolizidine alkaloids and discuss new avenues toward the discovery of novel and more efficient drugs based on these naturally occurring compounds. It is urgent for basic research and clinical practice to conduct more targeted comprehensive research based on the lead drugs of quinolizidine alkaloids with significant pharmacological activity.


Assuntos
Alcaloides , Quinolizidinas , Esparteína , Animais , Alcaloides Quinolizidínicos , Alcaloides/farmacologia , Quinolizidinas/farmacologia , Anti-Inflamatórios , Matrinas
17.
J Agric Food Chem ; 71(5): 2301-2312, 2023 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-36706432

RESUMO

A series of quinoline derivatives were designed and synthesized by the structural simplification of cryptolepine and evaluated for their fungicidal activity against six phytopathogenic fungi. Most of these compounds exhibited remarkable activities against Botrytis cinereain vitro. Among them, compounds A18 and L01 showed superior antifungal activity. Significantly, compared to cryptolepine, compound A18 exhibited broad-spectrum inhibitory activities against B. cinerea, Sclerotinia sclerotiorum, Rhizoctonia solani, Phytophthora capsica, Magnaporthe oryzae, and Fusarium graminearum with the respective EC50 values of 0.249, 1.569, 3.915, 0.505, 0.246, and 4.999 µg/mL. Compound L01 displayed the best antifungal activity against B. cinerea with an EC50 value of 0.156 µg/mL. Preliminary mechanistic studies showed that compound A18 could inhibit spore germination, affect the permeability of the cell membrane, increase the content of reactive oxygen species, and affect the morphology of hyphae and cells. Moreover, compound A18 showed excellent in vivo protective effect against B. cinerea, which was more potent than pyrimethanil and equitant to cryptolepine. These results evidenced that compound A18 displayed superior fungicidal activities and could be a potential fungicidal candidate against plant fungal diseases.


Assuntos
Fungicidas Industriais , Quinolinas , Antifúngicos/farmacologia , Fungicidas Industriais/química , Quinolinas/farmacologia , Alcaloides Indólicos/farmacologia , Botrytis , Relação Estrutura-Atividade , Fungos
18.
J Antibiot (Tokyo) ; 76(3): 131-182, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36707717

RESUMO

Epidemic diseases of crops caused by fungi deeply affected the course of human history and processed a major restriction on social and economic development. However, with the enormous misuse of existing antimicrobial drugs, an increasing number of fungi have developed serious resistance to them, making the diseases caused by pathogenic fungi even more challenging to control. Drug repurposing is an attractive alternative, it requires less time and investment in the drug development process than traditional R&D strategies. In this work, we screened 600 existing commercially available drugs, some of which had previously unknown activity against pathogenic fungi. From the primary screen at a fixed concentration of 100 µg/mL, 120, 162, 167, 85, 102, and 82 drugs were found to be effective against Rhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, Phytophthora capsici, Fusarium graminearum and Fusarium oxysporum, respectively. They were divided into nine groups lead compounds, including quinoline alkaloids, benzimidazoles/carbamate esters, azoles, isothiazoles, pyrimidines, pyridines, piperidines/piperazines, ionic liquids and miscellaneous group, and simple structure-activity relationship analysis was carried out. Comparison with fungicides to identify the most promising drugs or lead structures for the development of new antifungal agents in agriculture.


Assuntos
Anti-Infecciosos , Fungicidas Industriais , Fusarium , Humanos , Fungicidas Industriais/química , Reposicionamento de Medicamentos , Antifúngicos/farmacologia , Relação Estrutura-Atividade , Anti-Infecciosos/farmacologia
19.
J Antibiot (Tokyo) ; 76(1): 27-51, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36241714

RESUMO

Phytopathogenic bacteria are a major cause of crop mortality and yield reduction, especially in field cultivation. The lack of effective chemistry agri-bactericides is responsible for challenging field prevention and treatment, prompting the development of long-lasting solutions to prevent, reduce, or manage some of the most devastating plant diseases facing modern agriculture today and in the future. Therefore, there is an urgent need to find lead drugs preventing and treating phytopathogenic bacterial infection. Drug repurposing, a strategy used to identify novel uses for existing approved drugs outside of their original indication, takes less time and investment than Traditional R&D Strategies in the process of drug development. Based on this method, we conduct a screen of 700 chemically diverse and potentially safe drugs against Xanthomonas oryzae PV. oryzae ACCC 11602 (Xoo), Xanthomonas axonopodis PV. citri (Xac), and Pectobacterium atrosepticum ACCC 19901 (Pa). Furthermore, the structure-activity relationship and structural similarity analysis of active drugs classify potent agri-bactericides into 8 lead series: salicylanilides, cationic nitrogen-containing drugs, azole antifungals, N-containing group, hydroxyquinolines, piperazine, kinase inhibitor and miscellaneous groups. MIC values were evaluated as antibacterial activities in this study. Identifying highly active lead compounds from the screening of approved drugs and comparison with the currently applied plant pathogenic bactericide to validate the bactericidal activity of the best candidates and assess if selected molecules or scaffolds lead to develop new antibacterial agents in the future. In conclusion, this study provides a possibility for the development of potent and highly selective agri-bactericides leads.


Assuntos
Infecções Bacterianas , Oryza , Xanthomonas , Testes de Sensibilidade Microbiana , Reposicionamento de Medicamentos , Antibacterianos/farmacologia , Antibacterianos/química , Doenças das Plantas/microbiologia , Oryza/microbiologia
20.
Life Sci ; 311(Pt A): 121105, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36272467

RESUMO

AIMS: In this study, we synthesized a 10-fluorine-substitution derivative of CPT (Camptothecin) YCJ100 and evaluated its antitumor activity and systemic toxicity. MATERIALS AND METHODS: Determination of in vitro antitumor activity and mechanism of YCJ100 by the MTT assay, Molecular docking, EdU staining, Cell cycle and apoptosis determination, Western blot analysis and Topoisomerase I activity assay. The antitumor effects of YCJ100 were evaluated in primary HCC (hepatocellular carcinoma), ICC (intrahepatic cholangiocarcinoma) mouse models, and pancreatic cancer xenograft models. KEY FINDINGS: YCJ100 showed superior cytotoxic activity compared to Topotecan in SW480, SW1990, Hep3B, HepG2, A549, A2780, HeLa, and QBC cells. YCJ100 blocked the cell cycle in the G2/M phase, inhibited cell proliferation and induced apoptosis in HepG2 and SW1990 cells. Mechanistically, YCJ100 inhibited topoisomerase I activity in both a cell-free system and a cellular system, similar to the mechanism of Topotecan. YCJ100 showed significant antitumor activity and was more potent than Topotecan in primary HCC and ICC mouse models, as well as a xenograft mouse model. Additionally, YCJ100 showed only minor toxicity to the mouse hematopoietic system, liver, and kidney. These findings indicate that YCJ100 has high antitumor activity and low systemic toxicity. SIGNIFICANCE: Our findings demonstrate that YCJ100, as a Topoisomerase I inhibitor, has in vitro and in vitro antitumor activity. This study provides a new lead compound worthy of further preclinical evaluation and potential clinical development.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Pancreáticas , Inibidores da Topoisomerase I , Topotecan , Animais , Feminino , Humanos , Camundongos , Antineoplásicos/farmacologia , Camptotecina , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , DNA Topoisomerases Tipo I/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Simulação de Acoplamento Molecular , Topotecan/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores da Topoisomerase I/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico
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