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13 pages, 6150 KiB

Open AccessArticle

Naproxen-Derived New Compound Inhibits the NF-κB, MAPK and PI3K/Akt Signaling Pathways Synergistically with Resveratrol in RAW264.7 Cells

by Yi Ou, Zonglin You, Min Yao, Yingfan Cao, Xiu Xue, Min Chen, Rihui Wu, Lishe Gan, Dongli Li, Panpan Wu, Xuetao Xu, Wingleung Wong, Vincent Kam Wai Wong, Wenfeng Liu, Jiming Ye and Jingwei Jin

Molecules 2023, 28(8), 3395; https://doi.org/10.3390/molecules28083395 - 12 Apr 2023

Cited by 1 | Viewed by 1383

Abstract

Naproxen is widely used for anti-inflammatory treatment but it can lead to serious side effects. To improve the anti-inflammatory activity and safety, a novel naproxen derivative containing cinnamic acid (NDC) was synthesized and used in combination with resveratrol. The results showed that the [...] Read more.

Naproxen is widely used for anti-inflammatory treatment but it can lead to serious side effects. To improve the anti-inflammatory activity and safety, a novel naproxen derivative containing cinnamic acid (NDC) was synthesized and used in combination with resveratrol. The results showed that the combination of NDC and resveratrol at different ratios have a synergistic anti-inflammatory efficacy in RAW264.7 macrophage cells. It was indicated that the combination of NDC and resveratrol at a ratio of 2:1 significantly inhibited the expression of carbon monoxide (NO), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), induced nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2) and reactive oxygen species (ROS) without detectable side effects on cell viability. Further studies revealed that these anti-inflammatory effects were mediated by the activation of nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt) signaling pathways, respectively. Taken together, these results highlighted the synergistic NDC and resveratrol anti-inflammatory activity that could be further explored as a strategy for the treatment of inflammatory disease with an improved safety profile. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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17 pages, 2140 KiB

Open AccessArticle

The Potent G-Quadruplex-Binding Compound QN-302 Downregulates S100P Gene Expression in Cells and in an In Vivo Model of Pancreatic Cancer

by Ahmed A. Ahmed, William Greenhalf, Daniel H. Palmer, Nicole Williams, Jenny Worthington, Tariq Arshad, Shozeb Haider, Effrosyni Alexandrou, Dilek Guneri, Zoe A. E. Waller and Stephen Neidle

Molecules 2023, 28(6), 2452; https://doi.org/10.3390/molecules28062452 - 07 Mar 2023

Cited by 6 | Viewed by 3119

Abstract

The naphthalene diimide compound QN-302, designed to bind to G-quadruplex DNA sequences within the promoter regions of cancer-related genes, has high anti-proliferative activity in pancreatic cancer cell lines and anti-tumor activity in several experimental models for the disease. We show here that QN-302 [...] Read more.

The naphthalene diimide compound QN-302, designed to bind to G-quadruplex DNA sequences within the promoter regions of cancer-related genes, has high anti-proliferative activity in pancreatic cancer cell lines and anti-tumor activity in several experimental models for the disease. We show here that QN-302 also causes downregulation of the expression of the S100P gene and the S100P protein in cells and in vivo. This protein is well established as being involved in key proliferation and motility pathways in several human cancers and has been identified as a potential biomarker in pancreatic cancer. The S100P gene contains 60 putative quadruplex-forming sequences, one of which is in the promoter region, 48 nucleotides upstream from the transcription start site. We report biophysical and molecular modeling studies showing that this sequence forms a highly stable G-quadruplex in vitro, which is further stabilized by QN-302. We also report transcriptome analyses showing that S100P expression is highly upregulated in tissues from human pancreatic cancer tumors, compared to normal pancreas material. The extent of upregulation is dependent on the degree of differentiation of tumor cells, with the most poorly differentiated, from more advanced disease, having the highest level of S100P expression. The experimental drug QN-302 is currently in pre-IND development (as of Q1 2023), and its ability to downregulate S100P protein expression supports a role for this protein as a marker of therapeutic response in pancreatic cancer. These results are also consistent with the hypothesis that the S100P promoter G-quadruplex is a potential therapeutic target in pancreatic cancer at the transcriptional level for QN-302. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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24 pages, 4906 KiB

Open AccessArticle

Novel 2-Thiouracil-5-Sulfonamide Derivatives: Design, Synthesis, Molecular Docking, and Biological Evaluation as Antioxidants with 15-LOX Inhibition

by Naglaa M. Ahmed, Ahmed H. Lotfallah, Mohamed S. Gaballah, Samir M. Awad and Moustafa K. Soltan

Molecules 2023, 28(4), 1925; https://doi.org/10.3390/molecules28041925 - 17 Feb 2023

Cited by 3 | Viewed by 1503

Abstract

New antioxidant agents are urgently required to combat oxidative stress, which is linked to the emergence of serious diseases. In an effort to discover potent antioxidant agents, a novel series of 2-thiouracil-5-sulfonamides (4–9) were designed and synthesized. In line [...] Read more.

New antioxidant agents are urgently required to combat oxidative stress, which is linked to the emergence of serious diseases. In an effort to discover potent antioxidant agents, a novel series of 2-thiouracil-5-sulfonamides (4–9) were designed and synthesized. In line with this approach, our target new compounds were prepared from methyl ketone derivative 3, which was used as a blocking unit for further synthesis of a novel series of chalcone derivatives 4a–d, thiosemicarbazone derivatives 5a–d, pyridine derivatives 6a–d and 7a–d, bromo acetyl derivative 8, and thiazole derivatives 9a–d. All compounds were evaluated as antioxidants against 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydrogen peroxide (H₂O₂), lipid peroxidation, and 15-lipoxygenase (15-LOX) inhibition activity. Compounds 5c, 6d, 7d, 9b, 9c, and 9d demonstrated significant RSA in all three techniques in comparison with ascorbic acid and 15-LOX inhibitory effectiveness using quercetin as a standard. Molecular docking of compound 9b endorsed its proper binding at the active site pocket of the human 15-LOX which explains its potent antioxidant activity in comparison with standard ascorbic acid. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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16 pages, 1034 KiB

Open AccessArticle

Biological Activity of Amidino-Substituted Imidazo [4,5-b]pyridines

by Ida Boček Pavlinac, Katarina Zlatić, Leentje Persoons, Dirk Daelemans, Mihajlo Banjanac, Vedrana Radovanović, Kristina Butković, Marijeta Kralj and Marijana Hranjec

Molecules 2023, 28(1), 34; https://doi.org/10.3390/molecules28010034 - 21 Dec 2022

Cited by 4 | Viewed by 1631

Abstract

A series of cyano- and amidino-substituted imidazo[4,5-b]pyridines were synthesized using standard methods of organic synthesis, and their biological activity was evaluated. Biological evaluation included in vitro assessment of antiproliferative effects on a diverse selection of human cancer cell lines, antibacterial activity [...] Read more.

A series of cyano- and amidino-substituted imidazo[4,5-b]pyridines were synthesized using standard methods of organic synthesis, and their biological activity was evaluated. Biological evaluation included in vitro assessment of antiproliferative effects on a diverse selection of human cancer cell lines, antibacterial activity against chosen Gram-positive and Gram-negative bacterial strains, and antiviral activity on a broad panel of DNA and RNA viruses. The most pronounced antiproliferative activity was observed for compound 10, which contained an unsubstituted amidino group, and compound 14, which contained a 2-imidazolinyl amidino group; both displayed selective and strong activity in sub-micromolar inhibitory concentration range against colon carcinoma (IC₅₀ 0.4 and 0.7 μM, respectively). All tested compounds lacked antibacterial activity, with the exception of compound 14, which showed moderate activity against E. coli (MIC 32 μM). Bromo-substituted derivative 7, which contained an unsubstituted phenyl ring (EC₅₀ 21 μM), and para-cyano-substituted derivative 17 (EC₅₀ 58 μM) showed selective but moderate activity against respiratory syncytial virus (RSV). Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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19 pages, 3158 KiB

Open AccessArticle

Discovery of Novel and Selective G-Protein Coupled Receptor 120 (GPR120) Agonists for the Treatment of Type 2 Diabetes Mellitus

by Xuekun Wang, Xu Li, Shiting Wei, Min Wang, Yao Xu, Weidi Hu, Zhenzhen Gao, Renmin Liu, Shiben Wang and Guoxia Ji

Molecules 2022, 27(24), 9018; https://doi.org/10.3390/molecules27249018 - 17 Dec 2022

Cited by 4 | Viewed by 1674

Abstract

Diabetes mellitus (DM), a chronic metabolic disorder characterized by high blood glucose, not only poses a serious threat to human life and health, but also places an economic burden on society. Currently available antidiabetic pharmacological agents have some adverse effects, which have stimulated [...] Read more.

Diabetes mellitus (DM), a chronic metabolic disorder characterized by high blood glucose, not only poses a serious threat to human life and health, but also places an economic burden on society. Currently available antidiabetic pharmacological agents have some adverse effects, which have stimulated researchers to explore novel antidiabetic agents with different mechanisms of action. G-protein Coupled Receptor 120 (GPR120), also known as free fatty acid receptor 4 (FFAR4), which is activated by medium-chain and long-chain fatty acids, has emerged as an interesting potential target for the treatment of metabolic disorders. Herein, we designed and synthesized a series of novel GPR120 agonists based on the structure of TUG-891, which is susceptible to β-oxidation and loses its GPR120 agonistic activity in vivo. Among the designed compounds, 14d showed excellent agonistic activity and selectivity and could improve glucose tolerance in normal mice in a dose-dependent manner. In addition, the compound 14d displayed good antidiabetic effects in diet-induced obese (DIO) mice and elevated insulin levels. Molecular simulations illustrated that compound 14d could enter the active site of GPR120 and interact with ARG99, which plays an important role in GPR120 activation. Based on these observations, compound 14d may be a promising lead compound deserving of further biological evaluation and structural modifications. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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14 pages, 3425 KiB

Open AccessArticle

Natural Product 2-Oxokolavenol Is a Novel FXR Agonist

by Fusheng Guo, Yihui Gao, Xiaobao Li and Xiaoguang Lei

Molecules 2022, 27(24), 8968; https://doi.org/10.3390/molecules27248968 - 16 Dec 2022

Cited by 2 | Viewed by 1551

Abstract

Acetaminophen (APAP) toxicity is a common cause of hepatic failure, and the development of effective therapy is still urgently needed. Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has been identified as a master gene for regulating enterohepatic metabolic homeostasis [...] Read more.

Acetaminophen (APAP) toxicity is a common cause of hepatic failure, and the development of effective therapy is still urgently needed. Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has been identified as a master gene for regulating enterohepatic metabolic homeostasis and has proven to be a promising drug target for various liver diseases. Through high-throughput chemical screening, the natural product 2-oxokolavenol was identified as a novel and selective FXR agonist. Further investigations revealed that 2-oxokolavenol exerts therapeutic efficacy against APAP-induced hepatocyte damage in an FXR-dependent manner. Mechanistically, 2-oxokolavenol forms two hydrogen bonds with M265 and Y369 of human FXR to compatibly fit into the ligand binding pocket of FXR, which potently leads to the recruitment of multiple co-regulators and selectively induces the transcriptional activity of FXR. Our findings thus not only reveal the direct target of natural product 2-oxokolavenol, but also provide a promising hit compound for the design of new FXR modulators with potential clinical value. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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10 pages, 1407 KiB

Open AccessArticle

The Anti-Multidrug-Resistant Acinetobacter baumannii Study on 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline Compounds

by Han Wu, Hongtong Chen, Jungan Zhang, Xinxin Hu, Chunyang Xie, Weiting Cao, Ziqi Zhao, Zengshuo Xiao, Yixin Ren, Luyao Dong, Peiyi Sun, Xuefu You, Xinyi Yang, Wei Hong and Hao Wang

Molecules 2022, 27(23), 8609; https://doi.org/10.3390/molecules27238609 - 06 Dec 2022

Cited by 1 | Viewed by 1466

Abstract

As a major public health problem, the prevalence of Acinetobacter baumannii (A. baumannii) infections in hospitals due to the pathogen’s multiple-antibiotic resistance has attracted extensive attention. We previously reported a series of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline (PQZ) compounds, which were designed by targeting Escherichia [...] Read more.

As a major public health problem, the prevalence of Acinetobacter baumannii (A. baumannii) infections in hospitals due to the pathogen’s multiple-antibiotic resistance has attracted extensive attention. We previously reported a series of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline (PQZ) compounds, which were designed by targeting Escherichia coli dihydrofolate reductase (ecDHFR), and exhibited potent antibacterial activities. In the current study, based on our molecular-modeling study, it was proposed that PQZ compounds may function as potent A. baumannii DHFR (abDHFR)-inhibitors as well, which inspired us to consider their anti-A. baumannii abilities. We further found that three PQZ compounds, OYYF-171, -172, and -175, showed significant antibacterial activities against A. baumannii, including multidrug-resistant (MDR) strains, which are significantly stronger than the typical DHFR-inhibitor, trimethoprim (TMP), and superior to, or comparable to, the other tested antibacterial agents belonging to β-lactam, aminoglycoside, and quinolone. The significant synergistic effect between the representative compound OYYF-171 and the dihydropteroate synthase (DHPS)-inhibitor sulfamethoxazole (SMZ) was observed in both the microdilution-checkerboard assay and time-killing assay, which indicated that using SMZ in combination with PQZ compounds could help to reduce the required dosage and forestall resistance. Our study shows that PQZ is a promising scaffold for the further development of folate-metabolism inhibitors against MDR A. baumannii. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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14 pages, 3158 KiB

Open AccessArticle

Induction of Apoptosis via Inactivating PI3K/AKT Pathway in Colorectal Cancer Cells Using Aged Chinese Hakka Stir-Fried Green Tea Extract

by Xinyue Zhang, Haiying Huang, Shili Sun, Dongli Li, Lingli Sun, Qiuhua Li, Ruohong Chen, Xingfei Lai, Zhenbiao Zhang, Xi Zheng, Wing-Leung Wong and Shuai Wen

Molecules 2022, 27(23), 8272; https://doi.org/10.3390/molecules27238272 - 27 Nov 2022

Cited by 2 | Viewed by 1619

Abstract

Food extract supplements, with high functional activity and low side effects, play a recognized role in the adjunctive therapy of human colorectal cancer. The present study reported a new functional beverage, which is a type of Chinese Hakka stir-fried green tea (HSGT) aged [...] Read more.

Food extract supplements, with high functional activity and low side effects, play a recognized role in the adjunctive therapy of human colorectal cancer. The present study reported a new functional beverage, which is a type of Chinese Hakka stir-fried green tea (HSGT) aged for several years. The extracts of the lyophilized powder of five HSGT samples with different aging periods were analyzed with high-performance liquid chromatography. The major components of the extract were found to include polyphenols, catechins, amino acids, catechins, gallic acid and caffeine. The tea extracts were also investigated for their therapeutic activity against human colorectal cancer cells, HT-29, an epithelial cell isolated from the primary tumor. The effect of different aging time of the tea on the anticancer potency was compared. Our results showed that, at the cellular level, all the extracts of the aged teas significantly inhibited the proliferation of HT-29 in a concentration-dependent manner. In particular, two samples prepared in 2015 (15Y, aged for 6 years) and 2019 (19Y, aged for 2 years) exhibited the highest inhibition rate for 48 h treatment (cell viability was 50% at 0.2 mg/mL). Further, all the aged tea extracts examined were able to enhance the apoptosis of HT-29 cells (apoptosis rate > 25%) and block the transition of G1/S phase (cell-cycle distribution (CSD) from <20% to >30%) population to G2/M phase (CSD from nearly 30% to nearly 10%) at 0.2 mg/mL for 24 h or 48 h. Western blotting results also showed that the tea extracts inhibited cyclin-dependent kinases 2/4 (CDK2, CDK4) and CylinB1 protein expression, as well as increased poly ADP-ribose polymerase (PRAP) expression and Bcl2-associated X (Bax)/B-cell lymphoma-2 (Bcl2) ratio. In addition, an upstream signal of one of the above proteins, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling, was found to be involved in the regulation, as evidenced by the inhibition of phosphorylated PI3K and AKT by the extracts of the aged tea. Therefore, our study reveals that traditional Chinese aged tea (HSGT) may inhibit colon cancer cell proliferation, cell-cycle progression and promoted apoptosis of colon cancer cells by inactivating PI3K/AKT signalling. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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15 pages, 5319 KiB

Open AccessArticle

The New Strategy for Studying Drug-Delivery Systems with Prolonged Release: Seven-Day In Vitro Antibacterial Action

by Anna A. Skuredina, Tatiana Yu. Kopnova, Anastasia S. Tychinina, Sergey A. Golyshev, Irina M. Le-Deygen, Natalya G. Belogurova and Elena V. Kudryashova

Molecules 2022, 27(22), 8026; https://doi.org/10.3390/molecules27228026 - 18 Nov 2022

Cited by 8 | Viewed by 2001

Abstract

The new method of antibacterial-drug-activity investigation in vitro is proposed as a powerful strategy for understanding how carriers affect drug action during long periods (7 days). In this paper, we observed fluoroquinolone moxifloxacin (MF) antibacterial-efficiency in non-covalent complexes, with the sulfobutyl ether derivative [...] Read more.

The new method of antibacterial-drug-activity investigation in vitro is proposed as a powerful strategy for understanding how carriers affect drug action during long periods (7 days). In this paper, we observed fluoroquinolone moxifloxacin (MF) antibacterial-efficiency in non-covalent complexes, with the sulfobutyl ether derivative of β-cyclodextrin (SCD) and its polymer (SCDpol). We conducted in vitro studies on two Escherichia coli strains that differed in surface morphology. It was found that MF loses its antibacterial action after 3–4 days in liquid media, whereas the inclusion of the drug in SCD led to the increase of MF antibacterial activity by up to 1.4 times within 1–5 days of the experiment. In the case of MF-SCDpol, we observed a 12-fold increase in the MF action, and a tendency to prolonged antibacterial activity. We visualized this phenomenon (the state of bacteria, cell membrane, and surface morphology) during MF and MF-carrier exposure by TEM. SCD and SCDpol did not change the drug’s mechanism of action. Particle adsorption on cells was the crucial factor for determining the observed effects. The proteinaceous fimbriae on the bacteria surface gave a 2-fold increase of the drug carrier adsorption, hence the strains with fimbriae are more preferable for the proposed treatment. Furthermore, the approach to visualize the CD polymer adsorption on bacteria via TEM is suggested. We hope that the proposed comprehensive method will be useful for the studies of drug-delivery systems to uncover long-term antibacterial action. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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21 pages, 6125 KiB

Open AccessArticle

High-Resolution Mass Spectrometry Identification and Characterization of Flavonoids from Fridericia chica Leaves Extract with Anti-Arbovirus Activity

by Ana Flávia Gomes da Cruz, Adriana Cotta Cardoso Reis, Jordano Augusto Carvalho Sousa, Luana Beatriz Araújo Vaz, Breno de Mello Silva, Cíntia Lopes de Brito Magalhães, Markus Kohlhoff, Alaíde Braga de Oliveira and Geraldo Célio Brandão

Molecules 2022, 27(18), 6043; https://doi.org/10.3390/molecules27186043 - 16 Sep 2022

Cited by 5 | Viewed by 1773

Abstract

Plant extracts are complex mixtures that are difficult to characterize, and mass spectrometry is one of the main techniques currently used in dereplication processes. Fridericia chica is a species with medicinal uses in Latin American countries, used in the treatment of inflammatory and [...] Read more.

Plant extracts are complex mixtures that are difficult to characterize, and mass spectrometry is one of the main techniques currently used in dereplication processes. Fridericia chica is a species with medicinal uses in Latin American countries, used in the treatment of inflammatory and infectious diseases. Extracts of this plant species are characterized by the presence of anthocyanidins. In this study, using high-resolution mass spectrometry coupled with liquid chromatography, it was possible to determine the molecular formula of thirty-nine flavonoids. Fragmentation analysis, ultraviolet spectrum and nuclear magnetic resonance data allowed the partial characterization of the structures of these compounds. The spectral dataset allowed the identification of a series of flavones in addition to the desoxyanthocyanidins common in extracts of the species. The occurrence of some of the proposed structures is uncommon in extracts of species of the Bignoniaceae family, and they are reported for the first time in the extract of this species. Quantitative analyses of total flavonoids confirmed the high content of these constituents in the species, with 4.09 ± 0.34 mg/g of dry plant material. The extract under study showed low in vitro cytotoxicity with CC₅₀ ≥ 296.7 ± 1.4 µg/mL for Vero, LLC-MK2 and MRC-5 cell lines. In antiviral activity assays, inhibition of the cytopathic effects of Dengue, Zika and Mayaro viruses was observed, with EC₅₀ values ranging between 30.1 and 40.9 µg/mL. The best result was observed against the Mayaro virus, with an EC₅₀ of 30.1 µg/mL. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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11 pages, 1747 KiB

Open AccessArticle

In Vitro and In Vivo Antibacterial Activity, Toxicity and Resistance Analysis of Pleuromutilin Derivative Z33 against Methicillin-Resistant Staphylococcus aureus

by Yuhan Hu, Fang Chen, Kexin Zhou, Zhe Zhang, Fei Li, Jianfeng Zhang, Youzhi Tang and Zhen Jin

Molecules 2022, 27(15), 4939; https://doi.org/10.3390/molecules27154939 - 03 Aug 2022

Cited by 4 | Viewed by 1537

Abstract

The novel pleuromutilin derivative, which showed excellent in vitro antibacterial activity against MRSA, 22-(2-(2-(4-((4-(4-nitrophenyl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)acetamido)phenyl)thioacety-l-yl-22-deoxypleuromutilin (Z33), was synthesized and characterized in our previous work. In this study, the preliminary pharmacodynamics and safety of Z33 were further evaluated. In in vitro antibacterial activity [...] Read more.

The novel pleuromutilin derivative, which showed excellent in vitro antibacterial activity against MRSA, 22-(2-(2-(4-((4-(4-nitrophenyl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)acetamido)phenyl)thioacety-l-yl-22-deoxypleuromutilin (Z33), was synthesized and characterized in our previous work. In this study, the preliminary pharmacodynamics and safety of Z33 were further evaluated. In in vitro antibacterial activity assays, Z33 was found to be a potent bactericidal antibiotic against MRSA that induced dose-dependent growth inhibition and long-term post-antibiotic effect (PAE). The drug-resistance test demonstrated that Z33 possessed a narrow mutant selection window and lower propensities to select resistance than that of tiamulin. Cytochrome P450 (CYP450) inhibition assay determined that the inhibitory effect of Z33 was similar to that of tiamulin against the activity of CYP3A4, and was lower than that of tiamulin on the activity of CYP2E1. Toxicity determination showed that both Z33 and tiamulin displayed low cytotoxicity of RAW264.7 cells. Furthermore, Z33 was found to be a high-security compound with a 50% lethal dose (LD₅₀) above 5000 mg/kg in the acute oral toxicity test in mice. In an in vivo antibacterial activity test, Z33 displayed better therapeutic effectiveness than tiamulin in the neutropenic mouse thigh infection model. In summary, Z33 was worthy of further development as a highly effective and safe antibiotic agent against MRSA infection. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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12 pages, 1278 KiB

Open AccessArticle

Coumarin Derivatives Inhibit ADP-Induced Platelet Activation and Aggregation

by Ping-Hsun Lu, Tzu-Hsien Liao, Yau-Hung Chen, Yeng-Ling Hsu, Chan-Yen Kuo, Chuan-Chi Chan, Lu-Kai Wang, Ching-Yuh Chern and Fu-Ming Tsai

Molecules 2022, 27(13), 4054; https://doi.org/10.3390/molecules27134054 - 23 Jun 2022

Cited by 8 | Viewed by 1953

Abstract

Coumarin was first discovered in Tonka bean and then widely in other plants. Coumarin has an anticoagulant effect, and its derivative, warfarin, is a vitamin K analogue that inhibits the synthesis of clotting factors and is more widely used in the clinical treatment [...] Read more.

Coumarin was first discovered in Tonka bean and then widely in other plants. Coumarin has an anticoagulant effect, and its derivative, warfarin, is a vitamin K analogue that inhibits the synthesis of clotting factors and is more widely used in the clinical treatment of endovascular embolism. At present, many artificial chemical synthesis methods can be used to modify the structure of coumarin to develop many effective drugs with low toxicity. In this study, we investigated the effects of six coumarin derivatives on the platelet aggregation induced by adenosine diphosphate (ADP). We found that the six coumarin derivatives inhibited the active form of GPIIb/IIIa on platelets and hence inhibit platelet aggregation. We found that 7-hydroxy-3-phenyl 4H-chromen-4-one (7-hydroxyflavone) had the most severe effect. In addition, we further analyzed the downstream signal transduction of the ADP receptor, including the release of calcium ions and the regulation of cAMP, which were inhibited by the six coumarin derivatives selected in this study. These results suggest that coumarin derivatives inhibit coagulation by inhibiting the synthesis of coagulation factors and they may also inhibit platelet aggregation. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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Review

Jump to: Research

29 pages, 8729 KiB

Open AccessReview

Aurora B Inhibitors as Cancer Therapeutics

by Antal H. Kovacs, Dong Zhao and Jinqiang Hou

Molecules 2023, 28(8), 3385; https://doi.org/10.3390/molecules28083385 - 11 Apr 2023

Cited by 10 | Viewed by 3688

Abstract

The Aurora kinases (A, B, and C) are a family of three isoform serine/threonine kinases that regulate mitosis and meiosis. The Chromosomal Passenger Complex (CPC), which contains Aurora B as an enzymatic component, plays a critical role in cell division. Aurora B in [...] Read more.

The Aurora kinases (A, B, and C) are a family of three isoform serine/threonine kinases that regulate mitosis and meiosis. The Chromosomal Passenger Complex (CPC), which contains Aurora B as an enzymatic component, plays a critical role in cell division. Aurora B in the CPC ensures faithful chromosome segregation and promotes the correct biorientation of chromosomes on the mitotic spindle. Aurora B overexpression has been observed in several human cancers and has been associated with a poor prognosis for cancer patients. Targeting Aurora B with inhibitors is a promising therapeutic strategy for cancer treatment. In the past decade, Aurora B inhibitors have been extensively pursued in both academia and industry. This paper presents a comprehensive review of the preclinical and clinical candidates of Aurora B inhibitors as potential anticancer drugs. The recent advances in the field of Aurora B inhibitor development will be highlighted, and the binding interactions between Aurora B and inhibitors based on crystal structures will be presented and discussed to provide insights for the future design of more selective Aurora B inhibitors. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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26 pages, 6377 KiB

Open AccessReview

Targeting Epigenetic Changes Mediated by Members of the SMYD Family of Lysine Methyltransferases

by Alyssa Padilla, John F. Manganaro, Lydia Huesgen, Deborah A. Roess, Mark A. Brown and Debbie C. Crans

Molecules 2023, 28(4), 2000; https://doi.org/10.3390/molecules28042000 - 20 Feb 2023

Cited by 3 | Viewed by 3230

Abstract

A comprehensive understanding of the mechanisms involved in epigenetic changes in gene expression is essential to the clinical management of diseases linked to the SMYD family of lysine methyltransferases. The five known SMYD enzymes catalyze the transfer of donor methyl groups from S-adenosylmethionine [...] Read more.

A comprehensive understanding of the mechanisms involved in epigenetic changes in gene expression is essential to the clinical management of diseases linked to the SMYD family of lysine methyltransferases. The five known SMYD enzymes catalyze the transfer of donor methyl groups from S-adenosylmethionine (SAM) to specific lysines on histones and non-histone substrates. SMYDs family members have distinct tissue distributions and tissue-specific functions, including regulation of development, cell differentiation, and embryogenesis. Diseases associated with SMYDs include the repressed transcription of SMYD1 genes needed for the formation of ion channels in the heart leading to heart failure, SMYD2 overexpression in esophageal squamous cell carcinoma (ESCC) or p53-related cancers, and poor prognosis associated with SMYD3 overexpression in more than 14 types of cancer including breast cancer, colon cancer, prostate cancer, lung cancer, and pancreatic cancer. Given the importance of epigenetics in various pathologies, the development of epigenetic inhibitors has attracted considerable attention from the pharmaceutical industry. The pharmacologic development of the inhibitors involves the identification of molecules regulating both functional SMYD SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domains, a process facilitated by available X-ray structures for SMYD1, SMYD2, and SMYD3. Important leads for potential pharmaceutical agents have been reported for SMYD2 and SMYD3 enzymes, and six epigenetic inhibitors have been developed for drugs used to treat myelodysplastic syndrome (Vidaza, Dacogen), cutaneous T-cell lymphoma (Zoinza, Isrodax), and peripheral T-cell lymphoma (Beleodag, Epidaza). The recently demonstrated reversal of SMYD histone methylation suggests that reversing the epigenetic effects of SMYDs in cancerous tissues may be a desirable target for pharmacological development. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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20 pages, 5188 KiB

Open AccessReview

Anti-Melanogenic Potential of Natural and Synthetic Substances: Application in Zebrafish Model

by Adriana M. Ferreira, Agerdânio A. de Souza, Rosemary de Carvalho R. Koga, Iracirema da S. Sena, Mateus de Jesus S. Matos, Rosana Tomazi, Irlon M. Ferreira and José Carlos T. Carvalho

Molecules 2023, 28(3), 1053; https://doi.org/10.3390/molecules28031053 - 20 Jan 2023

Cited by 9 | Viewed by 2722

Abstract

Melanogenesis is a biosynthetic pathway for the formation of the pigment melanin in human skin. A key enzyme in the process of pigmentation through melanin is tyrosinase, which catalyzes the first and only limiting step in melanogenesis. Since the discovery of its methanogenic [...] Read more.

Melanogenesis is a biosynthetic pathway for the formation of the pigment melanin in human skin. A key enzyme in the process of pigmentation through melanin is tyrosinase, which catalyzes the first and only limiting step in melanogenesis. Since the discovery of its methanogenic properties, tyrosinase has been the focus of research related to the anti-melanogenesis. In addition to developing more effective and commercially safe inhibitors, more studies are required to better understand the mechanisms involved in the skin depigmentation process. However, in vivo assays are necessary to develop and validate new drugs or molecules for this purpose, and to accomplish this, zebrafish has been identified as a model organism for in vivo application. In addition, such model would allow tracking and studying the depigmenting activity of many bioactive compounds, important to genetics, medicinal chemistry and even the cosmetic industry. Studies have shown the similarity between human and zebrafish genomes, encouraging their use as a model to understand the mechanism of action of a tested compound. Interestingly, zebrafish skin shares many similarities with human skin, suggesting that this model organism is suitable for studying melanogenesis inhibitors. Accordingly, several bioactive compounds reported herein for this model are compared in terms of their molecular structure and possible mode of action in zebrafish embryos. In particular, this article described the main metabolites of Trichoderma fungi, in addition to substances from natural and synthetic sources. Full article

(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery)

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