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1.
BMC Chem ; 17(1): 184, 2023 Dec 20.
Article in English | MEDLINE | ID: mdl-38124159

ABSTRACT

The discovery of new lead skeleton against melanoma are urgently needed due to its highly malignant and mortality. Herein, a new molecular entity (EU-5) derived from eudistomin U was synthesized with total yield of 46%, which displayed potent activity against malignant melanoma A375 cells (IC50 = 4.4 µM), no hemolytic toxicity and good physicochemical properties in silico. Colony formation and cell cycle arrest assays revealed that EU-5 suppressed cell proliferation by causing cell cycle arrest at G0/G1 phase. Wound healing and transwell assays suggested that EU-5 could effectively inhibit migration of A375 cells in a dose-dependent manner. Calcein-AM/PI staining, Annexin V-FITC/PI apoptosis detection, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), transcriptomics, quantitative real­time polymerase chain reaction (qRT­PCR), spectrometric titration and molecular docking assays indicated that EU-5 could activate p53 signaling pathway and trigger mitochondria-mediated cell apoptosis. Taken together, this study provided a promising lead structure for the design of a new generation of anti-melanoma drugs.

2.
J Adv Res ; 2023 Nov 04.
Article in English | MEDLINE | ID: mdl-37931657

ABSTRACT

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA)-caused infections greatly threaten public health. The discovery of natural-product-based anti-MRSA agents for treating infectious diseases has become one of the current research focuses. OBJECTIVES: This study aims to identify promising anti-MRSA agents with a clear mechanism based on natural norharmane modified by quaternization or dimerization. METHODS: A total of 32 norharmane analogues were prepared and characterized. Their antibacterial activities and resistance development propensity were tested by the broth double-dilution method. Cell counting kit-8 and hemolysis experiments were used to assess their biosafety. The plasma stability, bactericidal mode, and biofilm disruption effects were examined by colony counting and crystal violet staining assays. Fluorescence microscopy, metabolomic analysis, docking simulation and spectra titration revealed its anti-MRSA mechanisms. The mouse skin infection model was used to investigate the in vivo efficacy. RESULTS: Compound 5a was selected as a potential anti-MRSA agent, which exhibited potent anti-MRSA activity in vitro and in vivo, low cytotoxicity and hemolysis under an effective dose. Moreover, compound 5a showed good stability in 50% plasma, a low tendency of resistance development and capabilities to disrupt bacterial biofilms. The mechanism studies revealed that compound 5a could inhibit the biosynthesis of bacteria cell walls, damage the membrane, disturb energy metabolism and amino acid metabolism pathways, and interfere with protein synthesis and nucleic acid function. CONCLUSIONS: These results suggested that compound 5a is a promising candidate for combating MRSA infections, providing valuable information for further exploiting a new generation of therapeutic antibiotics.

3.
Molecules ; 28(15)2023 Jul 27.
Article in English | MEDLINE | ID: mdl-37570664

ABSTRACT

The natural alkaloid gramine has attracted significant attention in both academic and industrial circles because of its potential and diverse biological activities, including antiviral, antibacterial, antifungal, anti-inflammatory and antitumor activities; application in therapy for Alzheimer's disease; serotonin-receptor-related activity; insecticidal activity; and application as an algicide. In this review, we focus on the research advances that have been made for gramine-based molecules since their discovery, providing key information on their extraction and separation, chemical synthesis and diverse biological activities. Data regarding their mechanisms of action are also presented. This comprehensive and critical review will serve as a guide for developing more drug candidates based on gramine skeletons.


Subject(s)
Alkaloids , Indole Alkaloids , Indole Alkaloids/pharmacology , Alkaloids/pharmacology , Alkaloids/chemistry
4.
Bioorg Chem ; 133: 106378, 2023 04.
Article in English | MEDLINE | ID: mdl-36736035

ABSTRACT

A series of new α-carboline analogues modified at N1 or N9 positions by alkyl, benzyl and phenyl were synthesized and characterized as potential ligands for AD therapy. These compounds exhibited multifunctional neurobiological activities including anti-neuroinflammatory, neuroprotective and cholinesterase inhibition. Among them, compound 5d with good drug-like properties and no cytotoxicity, showed potent inhibitory activity against NO production (IC50 = 1.45 µM), which could suppress the expression levels of iNOS and COX-2 in a dose-dependent manner. Further mechanism exploration indicated that compound 5d could regulate the NF-κB signaling pathway by decreasing the phosphorylation of IκB-α and p65. Notably, compound 5d could effectively decrease the LPS-induced aberrations in zebrafish. Compounds 3b, 4f, 5c, 5g, 5m and 6i exhibited potential neuroprotective activity (cell viability > 70 %) in the H2O2-induced PC-12 neuronal death model and rescued the SOD activity. In particular, compounds 3b, 4f, and 5g activated the Nrf2 signaling pathway, and improved the expressions of antioxidant proteins NQO-1 and HO-1, which alleviated the head cell apoptosis in zebrafish. Additionally, compound 6i exhibited potential inhibitory activity against BuChE with IC50 of 0.77 µM. Overall, this work provided some lead compounds based on α-carboline used for AD therapy.


Subject(s)
Alzheimer Disease , Neuroprotective Agents , Animals , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Zebrafish/metabolism , Hydrogen Peroxide , Carbolines/pharmacology , Carbolines/therapeutic use , Cholinesterase Inhibitors , Acetylcholinesterase/metabolism
5.
Eur J Med Chem ; 243: 114765, 2022 Dec 05.
Article in English | MEDLINE | ID: mdl-36116235

ABSTRACT

Bacterial infections have seriously threatened public health especially with the increasing resistance and the cliff-like decline of the number of newly approved antibacterial agents. Quaternary ammonium compounds (QACs) possess potent medicinal properties with 95 successfully marketed drugs, which also have a long history as antibacterial agents. In this review, we summarize the chemical diversity of antibacterial QACs, divided into chain-like and aromatic ring, reported over the past decade (2012 to mid-2022). Additionally, the structure-activity relationships, mainly covering hydrophobicity, charges and skeleton features, are discussed. In the cases where sufficient information is available, antibacterial mechanisms including biofilm, cell membrane, and intracellular targets are presented. It is hoped that this review will provide sufficient information for medicinal chemists to discover the new generation of antibacterial agents based on QACs.


Subject(s)
Ammonium Compounds , Anti-Bacterial Agents , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Microbial Sensitivity Tests , Quaternary Ammonium Compounds/pharmacology , Quaternary Ammonium Compounds/chemistry , Biofilms
6.
Curr Comput Aided Drug Des ; 18(1): 73-80, 2022.
Article in English | MEDLINE | ID: mdl-34080967

ABSTRACT

BACKGROUND: The discovery of therapeutic anticancer agents based on natural products is one of the current research focuses. Network pharmacology will broaden our understanding of drug actions by bioinformatics analysis. OBJECTIVE: To explore the potential and provide scientific evidence for methylaervine as a lead compound against cervical carcinoma. METHODS: Methylaervine was synthesized, and its activity against four cancer cell lines was evaluated by MTT assay. Pharmacokinetic properties were obtained by in silico approaches, and the pharmacologic mechanism was predicted by network pharmacology. Then we validated and investigated our predictions of candidate targets using a molecular docking study. RESULTS: Methylaervine was synthesized with a total yield of 54.9%, which displayed activity against HeLa (IC50 = 14.8 µM) with good predicted pharmacokinetic properties, thus it was considered a potential lead compound. The network pharmacology study indicated that methylaervine could act against cervical carcinoma by regulating the function of multiple pivotal targets, such as CTNNB1, PTPRJ, RPA1, and TJP1, mainly covering cell growth, cell motility, and cell proliferation. Moreover, docking analysis showed that hydrogen bonds and hydrophobic interactions were the main forms of interactions. CONCLUSION: This work would provide new insight into the design of anti-cervical carcinoma drugs based on methylaervine.


Subject(s)
Antineoplastic Agents , Carcinoma , Uterine Cervical Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Carcinoma/drug therapy , Cell Line, Tumor , Cell Proliferation , Drug Screening Assays, Antitumor , Female , Humans , Molecular Docking Simulation , Molecular Structure , Network Pharmacology , Structure-Activity Relationship
7.
Eur J Med Chem ; 229: 114057, 2022 Feb 05.
Article in English | MEDLINE | ID: mdl-34954591

ABSTRACT

The discovery of antifungal agents with novel structure, broad-spectrum, low toxicity, and high efficiency has been the focus of medicinal chemists. Over the past decades, ß-carboline scaffold has attracted extensive attention in the scientific community due to its potent and diverse biological activities with nine successfully marketed ß-carboline-based drugs. In this review, we summarized the current states and advances in the antifungal activity of natural and synthetic ß-carbolines. Additionally, the structure-activity relationships and their antifungal mechanisms targeting biofilm, cell wall, cell membrane, and fungal intracellular targets were also systematically discussed. In summary, ß-carbolines have the great potential to develop new efficient scaffolds to combat fungal infections.


Subject(s)
Antifungal Agents/chemistry , Biological Products/chemistry , Carbolines/chemical synthesis , Mycoses/drug therapy , Animals , Antifungal Agents/pharmacology , Biological Products/pharmacology , Carbolines/pharmacology , Drug Discovery , Female , Humans , Male , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Protein Binding , Signal Transduction , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 43: 128068, 2021 07 01.
Article in English | MEDLINE | ID: mdl-33915256

ABSTRACT

Botanical fungicides are promising replacements for pure chemical synthetic pesticides in agriculture and organic food production. Methylaervine with good physicochemical properties exhibited effective activity against F. solani (EC50 = 10.56 µM) better than the positive control thiophanate-methyl (EC50 = 27.94 µM). The activity changes of malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD) showed that methylaervine could significantly induce lipid peroxidation and activate the antioxidant enzymes. According to the metabolomics analysis, fifty-one differential metabolites and two major antifungal-related pathways covering tricarboxylic acid (TCA) cycle and steroid biosynthesis were identified. Moreover, the disturbance for TCA cycle was validated by the activity changes of dehydrogenase (MDH) and succinate dehydrogenase (SDH) as well as docking simulation. Homology modeling and docking study revealed that hydrogen bonds and hydrophobic interactions played a vital role in methylaervine-protein stability. This study provided new insight into the antifungal activity of methylaervine, which is important for the development of novel botanical fungicides based on methylaervine.


Subject(s)
Antifungal Agents/pharmacology , Fusarium/drug effects , Metabolomics , Antifungal Agents/chemistry , Antifungal Agents/metabolism , Dose-Response Relationship, Drug , Fusarium/metabolism , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship
9.
Bioorg Chem ; 101: 103922, 2020 08.
Article in English | MEDLINE | ID: mdl-32559577

ABSTRACT

The discovery of novel antibacterial molecules plays a key role in solving the current antibiotic crisis issue. Natural products have long been an important source of drug discovery. Herein, we reviewed 256 natural products from 11 structural classes in the period of 2016-01/2020, which were selected by SciFinder with new compounds or new structures and MICs lower than 10 µg/mL or 10 µM as criterions. This review will provide some effective antibacterial lead compounds for medicinal chemists, which will promote the antibiotics research based on natural products to the next level.


Subject(s)
Anti-Bacterial Agents/pharmacology , Biological Products/pharmacology , Drug Discovery , Microbial Sensitivity Tests
10.
Eur J Med Chem ; 187: 111950, 2020 Feb 01.
Article in English | MEDLINE | ID: mdl-31865013

ABSTRACT

Histone deacetylase 6 (HDAC6) has gained popular attention for its wide participation in various pathological process recently. In this paper, a series of novel derivatives containing 2, 5-diketopiperazine (DKP) skeleton were developed as potent selective HDAC6 inhibitors (sHDAC6is). Most of these compounds exhibited low nanomolar IC50 values toward HDAC6, and the best compound was 21b (IC50 = 0.73 nM) which had 144-10941-fold selectivity over other HDAC isoforms. Western blot assay further validated these compounds to be sHDAC6is. Molecular simulation of 21b was conducted to rationalize the high binding affinity for HDAC6. In the cytotoxicity experiment, 18a, 18b and 18d gave superior or comparable influence on the growth of two multiple myeloma cells U266 and RPMI-8226 compared to ACY-1215. Moreover, the combination of 18a and adriamycin showed synergistic effect against non-small cell lung cancer cell A549. 18a and 18b also demonstrated appropriate drug metabolism in human liver microsome (HLM).


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Histone Deacetylase 6/metabolism , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Tumor Cells, Cultured
11.
Eur J Med Chem ; 187: 111980, 2020 Feb 01.
Article in English | MEDLINE | ID: mdl-31877539

ABSTRACT

Chalcones, containing an α,ß-unsaturated ketone fragment, are an important pharmacologically active agents because of their diverse mechanisms. This review provides an update on the recent developments (2009-2019.3) in the antibacterial activity of natural and synthetic chalcones. Moreover, the structure-activity relationships and mechanisms are also carefully summarized which will provide some important guidance for design and synthesis in future. This comprehensive and critical review will be helpful for medicinal chemists to develop more candidate antibacterial agents.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Chalcones/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Chalcones/chemical synthesis , Chalcones/chemistry , Chemistry, Pharmaceutical , Humans , Microbial Sensitivity Tests
12.
J Nat Prod ; 82(11): 2963-2971, 2019 11 22.
Article in English | MEDLINE | ID: mdl-31710213

ABSTRACT

A new tetranorditerpenoid (1), two new labdane diterpenoids (2, 3), and nine known analogues (4-12) were isolated from the rhizomes of Amomum villosum var. xanthioides. Compound 1 is an unprecedented rearranged tetranorlabdane diterpenoid, featuring a 6/6/5 fused tricarbocyclic skeleton with an α,ß-unsaturated cyclopentenone unit, while 2 is a structurally rare labdane diterpenoid carrying a five-membered cyclic anhydride moiety. Their structures and absolute configurations were established on the basis of spectroscopic data and the experimental and calculated ECD data. Compound 4 showed inhibitory activity against nitric oxide production, with an IC50 value of 2.4 µM, and also inhibited α-glucosidase activity (IC50 = 10.0 µM).


Subject(s)
Amomum/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Diterpenes/chemistry , Diterpenes/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/pharmacology , Rhizome/chemistry , Humans , Macrophages/drug effects , Macrophages/metabolism , Molecular Docking Simulation , Molecular Structure , Nitric Oxide/biosynthesis , Polycyclic Compounds/chemistry , Polycyclic Compounds/pharmacology
13.
Pestic Biochem Physiol ; 159: 41-50, 2019 Sep.
Article in English | MEDLINE | ID: mdl-31400783

ABSTRACT

Emerging fungal phytodiseases are a food security threat and novel fungicides are in an urgent need. Herein, a series of isobutyrophenone derivatives were designed and synthesized. The derivatives exhibited excellent fungicidal activities against seven fungi. The structure-activity relationship (SAR) study indicated that the introduction of a bromo group at the position 3 or 5 of the phenyl ring, as well as esterification of the 4-hydroxy with a chloroacetyl group, could substantially increase the antifungal activity and spectrum of the compounds. Among all 23 compounds, 2-bromo-3-hydroxy-4-isobutyryl-6-methylphenyl 2-chloroacetate (12b) showed the highest fungicidal activity against all seven tested fungal pathogens with EC50 values ranging from 1.22 to 39.94 µg/mL and exhibited the most potent inhibition against class II fructose-1,6-bisphosphate aldolase with an IC50 of 3.63 µM. The lead compounds were proven to be safe to NIH3T3/293 T cells and silkworm larvae, and relatively stable under different harsh conditions. Detached fruit tests showed the practical potential of lead compounds for fruit (or plant) protection. Taken together, our results indicated that the isobutyrophenone derivatives could be further optimized and developed as advanced leads for new fungicides.


Subject(s)
Antifungal Agents/chemistry , Antifungal Agents/metabolism , Fructose-Bisphosphate Aldolase/metabolism , Animals , Bombyx/metabolism , Cell Line , Fructose-Bisphosphate Aldolase/genetics , Humans , Larva/metabolism , Mice , Microbial Sensitivity Tests , Molecular Structure , NIH 3T3 Cells , Structure-Activity Relationship
14.
J Enzyme Inhib Med Chem ; 34(1): 937-945, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31072245

ABSTRACT

In this article, 23 compounds (6 and 7a-7v) were prepared and evaluated for their in vitro α-glucosidase inhibitory activity. The compounds 7d, 7f, 7i, 7n, 7o, 7r, 7s, 7u, and 7v displayed the α-glucosidase inhibition activity with IC50 values ranging from 1.68 to 7.88 µM. Among all tested compounds, 7u was found to be the most efficient, being 32-fold more active than the standard drug acarbose, which significantly attenuated postprandial blood glucose in mice. In addition, the compound 7u also induced the fluorescence quenching and conformational changes of enzyme, by forming α-glucosidase-7u complex in a mixed inhibition type. The thermodynamic constants recognised the interaction between 7u and α-glucosidase and was an enthalpy-driven spontaneous exothermic reaction. The synchronous fluorescence and CD spectra also indicate that the compound 7u changed the enzyme conformation. The findings identify the binding interactions between new ligands and α-glucosidase and reveal the compound 7u as a potent α-glucosidase inhibitor.


Subject(s)
Acetophenones/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , alpha-Glucosidases/metabolism , Acetophenones/chemical synthesis , Acetophenones/chemistry , Dose-Response Relationship, Drug , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Humans , Molecular Structure , Structure-Activity Relationship , Thermodynamics
15.
Eur J Med Chem ; 160: 23-36, 2018 Dec 05.
Article in English | MEDLINE | ID: mdl-30317023

ABSTRACT

Thirty-three new quaternization harman analogues were synthesized and their antibacterial activity against four Gram-positive and two Gram-negative bacteria were evaluated. The structure-activity relationships were summarized and compounds 4f, 4i, 4l, 4u, 4w, 4x and 5c showed excellent antibacterial activity, low cytotoxicity, good thermal stability and "drug-like" properties. In particular, compound 4x exhibited better bactericidal effect (4-fold superiority against methicillin-resistant Staphylococcus aureus) than standard drugs fosfomycin sodium and ampicillin sodium (minimum inhibitory concentration = 50 nmol/mL). Scanning electron microscopy revealed morphological changes of the bacterial cell surface and the docking evaluation provided a good total score (6.4952) for 4x which is close to the score of ciprofloxacin (6.9723). The results indicated that the quaternization harman analogues might exert their bactericidal effect by damaging bacterial cell membrane and wall, and disrupting the function of type II topoisomerase. In addition, the in vivo antibacterial assay with a protective efficacy of 81.3% further demonstrated the potential of these derivatives as new bactericides and antibiotics.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Design , Harmine/analogs & derivatives , Methicillin-Resistant Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cell Membrane/drug effects , Cell Wall/drug effects , Dose-Response Relationship, Drug , Harmine/chemical synthesis , Harmine/chemistry , Harmine/pharmacology , Methicillin-Resistant Staphylococcus aureus/cytology , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship
16.
Eur J Med Chem ; 157: 622-656, 2018 Sep 05.
Article in English | MEDLINE | ID: mdl-30125723

ABSTRACT

ß-Carboline alkaloids are a family of natural and synthetic products with great structural diversity and outstanding biological activities. This review covers critically important developments in the field of ß-carbolines, predominantly over the past decade (2006-2017.7). It is focused on both natural and synthetic monomers as well as dimers, and includes key information on occurrence, structural diversity, and biological activities. In the cases where sufficient information is available, structure-activity relationship (SAR) and mechanism of their biological activities were presented. In addition, innovative syntheses of the ß-carboline core and potential future directions have been discussed.


Subject(s)
Anti-Infective Agents/pharmacology , Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Antiparasitic Agents/pharmacology , Carbolines/pharmacology , Hypoglycemic Agents/pharmacology , Animals , Anti-Infective Agents/chemistry , Antineoplastic Agents/chemistry , Antioxidants/chemistry , Antiparasitic Agents/chemistry , Carbolines/chemistry , Dimerization , Humans , Hypoglycemic Agents/chemistry , Molecular Structure
17.
Bioorg Med Chem Lett ; 28(18): 3123-3128, 2018 10 01.
Article in English | MEDLINE | ID: mdl-30097370

ABSTRACT

A series of canthin-6-one analogues were designed and synthesized in order to study their antibacterial activity and structure-activity relationships. Compound 22 showed a broad spectrum of antibacterial activity and exhibited better bactericidal effect (8-fold superiority against Staphylococcus aureus and 2-fold superiority against Ralstonia solanacearum) than fosfomycin sodium and propineb with a minimum inhibitory concentration value of 2 µg/mL. Moreover, it showed low cytotoxicity, stimulation on germination rates and good "drug-like" properties. Membrane-active mechanism was further studied by fluorescent microscopy, scanning electron microscopy, cytoplasmic ß-galactosidase leakage assay and evaluation of the molecular docking. The results showed that 22 may exert its bactericidal effect by damaging bacterial cell membranes and influencing the membrane formation, both of which could lead to cell death. The in vivo antibacterial assay with a protective efficacy of 68% demonstrated the potential of C ring-truncated canthin-6-one 22 as a new bactericide.


Subject(s)
Anti-Bacterial Agents/pharmacology , Carbolines/pharmacology , Drug Design , Indole Alkaloids/pharmacology , Ralstonia solanacearum/drug effects , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Carbolines/chemical synthesis , Carbolines/chemistry , Cell Death/drug effects , Cell Membrane/drug effects , Dose-Response Relationship, Drug , Indole Alkaloids/chemical synthesis , Indole Alkaloids/chemistry , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Ralstonia solanacearum/cytology , Staphylococcus aureus/cytology , Structure-Activity Relationship
18.
Eur J Med Chem ; 157: 447-461, 2018 Sep 05.
Article in English | MEDLINE | ID: mdl-30103193

ABSTRACT

γ-Carboline alkaloids are a family of natural and synthetic agents that have diverse bioactivities including antiviral, antibacterial, antifungal, antiparasitic, antitumor, anti-inflammatory, neuropharmacological activities and so on. They constitute an important class of pharmacologically active scaffolds that exhibit biological activity via diverse mechanisms. This review provides an update on the recent developments (2010-2017) in the synthesis and biological activities of these compounds. In cases where sufficient information is available, the mechanism and the structure-activity relationship (SAR) of biological activity are presented, and based on our expertise in the field and careful analysis of the recent literature, for the potential of γ-carboline alkaloids as medicinal drugs is proposed.


Subject(s)
Anti-Infective Agents/pharmacology , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Carbolines/pharmacology , Neoplasms/drug therapy , Animals , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Carbolines/chemical synthesis , Carbolines/chemistry , Humans , Neuralgia/drug therapy , Neurodegenerative Diseases/drug therapy , Psychophysiologic Disorders/drug therapy
19.
Eur J Med Chem ; 157: 333-338, 2018 Sep 05.
Article in English | MEDLINE | ID: mdl-30099255

ABSTRACT

Thirty-two new 3,9-disubstituted eudistomin U derivatives were designed and synthesized based on computer-aided drug discovery (CADD). Sixteen 3,9-disubstituted eudistomin U derivatives (6a-6p) have exhibited potent antibacterial activity. Specially, the most active compound 6p displayed better activity than commercial drugs fosfomycin sodium, ciprofloxacin and propineb, with a peak minimum inhibitory concentration (MIC) of 1.5625 µmol/L. The antibacterial mechanism indicated that these compounds could exert bactericidal effect by damaging bacterial cell membrane and disrupting the function of DNA gyrase.


Subject(s)
Anti-Bacterial Agents/pharmacology , Carbolines/pharmacology , Computer-Aided Design , Drug Discovery , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Carbolines/chemical synthesis , Carbolines/chemistry , Cell Membrane/drug effects , DNA Gyrase/metabolism , Dose-Response Relationship, Drug , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/enzymology , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/enzymology , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship
20.
Bioorg Med Chem Lett ; 28(17): 2861-2864, 2018 09 15.
Article in English | MEDLINE | ID: mdl-30037493

ABSTRACT

A series of acetophenone derivatives (10a-10i, 11, 12a-12g, 13a-13g, 14a-14d and 15a-15l) were designed, synthesized and evaluated for antifungal activities in vitro and in vivo. The antifungal activities of 53 compounds were tested against several plant pathogens, and their structure-activity relationship was summarized. Compounds 10a-10f displayed better antifungal effects than two reference fungicides. Interestingly, the most potent compound 10d exhibited antifungal properties against Cytospora sp., Botrytis cinerea, Magnaporthe grisea, with IC50 values of 6.0-22.6 µg/mL, especially Cytospora sp. (IC50 = 6.0 µg/mL). In the in vivo antifungal assays, 10d displayed the significant protective efficacy of 55.3% to Botrytis cinerea and 73.1% to Cytospora sp. The findings indicated that 10d may act as a potential pesticide lead compound that merits further investigation.


Subject(s)
Acetophenones/pharmacology , Ascomycota/drug effects , Biological Products/pharmacology , Botrytis/drug effects , Fungicides, Industrial/pharmacology , Magnaporthe/drug effects , Acetophenones/chemical synthesis , Acetophenones/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Dose-Response Relationship, Drug , Drug Design , Fungicides, Industrial/chemical synthesis , Fungicides, Industrial/chemistry , Inhibitory Concentration 50 , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship
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