Chemical Biology & Drug Design最新文献_第10页

The protective effect of karanjin against sepsis-induced acute lung injury in mice is involved in the suppression of the TLR4 pathway 卡朗津对败血症诱发的小鼠急性肺损伤的保护作用与抑制 TLR4 途径有关。

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2024-07-16 DOI: 10.1111/cbdd.14579

Chujie Zhang, Juncong Ma, Chang Liu, Xianliang Yan

{"title":"The protective effect of karanjin against sepsis-induced acute lung injury in mice is involved in the suppression of the TLR4 pathway","authors":"Chujie Zhang, Juncong Ma, Chang Liu, Xianliang Yan","doi":"10.1111/cbdd.14579","DOIUrl":"10.1111/cbdd.14579","url":null,"abstract":"Sepsis-induced acute lung injury (ALI) is a severe complication of sepsis. Karanjin, a natural flavonoid compound, has been proved to have anti-inflammatory function, but its role in sepsis-stimulated ALI is uncertain. Herein, the effect of karanjin on sepsis-stimulated ALI was investigated. We built a mouse model of lipopolysaccharide (LPS)-stimulated ALI. The histopathological morphology of lung tissues was scrutinized by hematoxylin–eosin (H&E) staining. The lung injury score and lung wet/dry weight ratio were detected. The myeloperoxidase (MPO) activity and malondialdehyde (MDA) content were scrutinized by commercial kits. Murine alveolar lung epithelial (MLE-12) cells were treated with LPS to mimic a cellular model of ALI. The cell viability was scrutinized by the CCK-8 assay. The contents of proinflammatory cytokines were scrutinized by qRT-PCR and ELISA. The TLR4 and MyD88 contents were scrutinized by qRT-PCR and western blotting. Results showed that karanjin alleviated LPS-stimulated ALI in mice by inhibiting lung tissue lesions, edema, and oxidative stress. Moreover, karanjin inhibited LPS-stimulated inflammation and TLR4 pathway activation in mice. However, treatment with GSK1795091, an agonist of TLR4, attenuated the effects of karanjin on LPS-induced ALI. Furthermore, karanjin repressed LPS-stimulated inflammatory response and TLR4 pathway activation in MLE-12 cells. Overexpression of TLR4 attenuated karanjin effects on LPS-stimulated inflammatory responses in MLE-12 cells. In conclusion, karanjin repressed sepsis-stimulated ALI in mice by suppressing the TLR4 pathway.","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141629579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis, biological evaluation and mechanism of action of benzothiazole derivatives with aromatic hydrazone moiety, a new class of antileishmanial compounds 具有芳香族腙分子的苯并噻唑衍生物--一类新的抗利什曼病化合物--的合成、生物学评价和作用机理。

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2024-07-16 DOI: 10.1111/cbdd.14585

Elaine Soares Coimbra, Luciana M. R. Antinarelli, Ari Sérgio de Oliveira Lemos, Adolfo Firmino da Silva Neto, Alessandra Campbell Pinheiro, Marcus Vinícius Nora de Souza

{"title":"Synthesis, biological evaluation and mechanism of action of benzothiazole derivatives with aromatic hydrazone moiety, a new class of antileishmanial compounds","authors":"Elaine Soares Coimbra, Luciana M. R. Antinarelli, Ari Sérgio de Oliveira Lemos, Adolfo Firmino da Silva Neto, Alessandra Campbell Pinheiro, Marcus Vinícius Nora de Souza","doi":"10.1111/cbdd.14585","DOIUrl":"10.1111/cbdd.14585","url":null,"abstract":"Leishmaniasis is a disease caused by protozoa Leishmania spp., considered as a significant and urgent public health problem mainly in developing countries. In the absence of an effective vaccine, the treatment of infected people is one of the most commonly prophylactic measures used to control this disease. However, the therapeutic arsenal is reduced to a few drugs, with serious side effects and variability in efficacy. Attempting to this problem, in this work, a series of benzothiazole derivatives was synthetized and assayed against promastigotes and intracellular amastigotes of L. amazonensis, as well as the toxicity on macrophages. In addition, studies about the mechanism of action were also performed. Among the synthesized molecules, the substitution at position 4 of the aromatic ring appears to be critical for activity. The best compound exhibited IC50 values of 28.86 and 7.70 μM, against promastigotes and amastigotes of L. amazonensis, respectively, being more active than miltefosine, used as reference drug. The in silico analysis of physicochemical and pharmacokinetic (ADMET) properties of this compound suggested a good profile of oral bioavailability and safety. In conclusion, the strategy of using benzothiazole nucleous in the search for new antileishmanial agents was advantageous and preliminar data provide information about the mechanism of action as well as in silico parameters suggest a good profile for preclinical studies.","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141629578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MK2 inhibitor PF-3644022 shows protective effect in mouse microglial N9 cell line induced with cigarette smoke extract MK2 抑制剂 PF-3644022 对用香烟烟雾提取物诱导的小鼠小胶质细胞 N9 细胞系具有保护作用。

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2024-07-16 DOI: 10.1111/cbdd.14592

Shikha Asthana, Shivam Kumar Pandey, Avtar Singh Gautam, Rakesh Kumar Singh

{"title":"MK2 inhibitor PF-3644022 shows protective effect in mouse microglial N9 cell line induced with cigarette smoke extract","authors":"Shikha Asthana, Shivam Kumar Pandey, Avtar Singh Gautam, Rakesh Kumar Singh","doi":"10.1111/cbdd.14592","DOIUrl":"10.1111/cbdd.14592","url":null,"abstract":"Neuroinflammation is suggested as one of the potential links between CS-induced neuronal dysfunction. Cigarette smoke (CS) is one of the significant contributors of neuroinflammation, consequently leading to cognitive impairment and neurodegeneration. Microglia are the key resident macrophage cells in the brain with cell surface TLR4 receptor for responding to various stress signals. The CS constituents promote inflammation and oxidative stress in microglia leading to cytotoxicity through the TLR4-MK2 axis. However, the role of MK2 kinase in CS-induced microglial inflammation is not yet clearly understood. Therefore, we have used an MK2 inhibitor, PF-3644022 to study modulation of CS-extract induced oxidative and inflammatory signaling in a mouse microglial cell line, Furthermore, we also evaluated the enzymatic activity of acetylcholinesterase (AChE) on a direct exposure of enzyme with CS. CS exposure led to microglial cytotoxicity and enhanced the level of oxidative stress and proinflammatory cytokine release by microglial cells. The microglial cells pretreated with MK2 inhibitor, PF-3644022 significantly reduced the levels of oxidative stress markers, proinflammatory markers, and improved the level of antioxidant proteins in these cells. In addition, direct exposure of CS showed reduction in the enzymatic activity of AChE.","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141629577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Leveraging binding pose metadynamics to optimise target fishing predictions for three diverse ligands and their true targets 利用结合姿态元动力学优化对三种不同配体及其真正靶标的钓靶预测。

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2024-07-15 DOI: 10.1111/cbdd.14591

Mei Qian Yau, Angeline J. Wan, Aaron S. H. Tiong, Yong Sheng Yiap, Jason S. E. Loo

{"title":"Leveraging binding pose metadynamics to optimise target fishing predictions for three diverse ligands and their true targets","authors":"Mei Qian Yau, Angeline J. Wan, Aaron S. H. Tiong, Yong Sheng Yiap, Jason S. E. Loo","doi":"10.1111/cbdd.14591","DOIUrl":"10.1111/cbdd.14591","url":null,"abstract":"Computational target fishing plays an important role in target identification, particularly in drug discovery campaigns utilizing phenotypic screening. Numerous approaches exist to predict potential targets for a given ligand, but true targets may be inconsistently ranked. More advanced simulation methods may provide benefit in such cases by reranking these initial predictions. We evaluated the ability of binding pose metadynamics to improve the predicted rankings for three diverse ligands and their six true targets. Initial predictions using pharmacophore mapping showed no true targets ranked in the top 50 and two targets each ranked within the 50–100, 100–150, and 250–300 ranges respectively. Following binding pose metadynamics, ranking of true targets improved for four out of the six targets and included the highest ranked predictions overall, while rankings deteriorated for two targets. The revised rankings predicted two true targets ranked within the top 50, and one target each within the 50–100, 100–150, 150–200, and 200–250 ranges respectively. The findings of this study demonstrate that binding pose metadynamics may be of benefit in refining initial predictions from structure-based target fishing algorithms, thereby improving the efficiency of the target identification process in drug discovery efforts.","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel phenylpiperazine derivatives as potent transient receptor potential vanilloid 1 antagonists 新型苯基哌嗪衍生物作为有效的瞬态受体潜在香草素 1 拮抗剂。

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2024-07-12 DOI: 10.1111/cbdd.14584

Lina Jing, Chunxia Liu

引用次数: 0

Synthesis and cytotoxic evaluation of heterocyclic compounds by vinylic substitution of ketene dithioacetals 通过乙烯基取代烯酮二硫代乙酸酯合成杂环化合物并进行细胞毒性评估。

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2024-07-12 DOI: 10.1111/cbdd.14581

Larissa R. S. P. Baliza, Túlio R. Freitas, Edward K. S. Gonçalves, Gabriel R. Antunes, Ana J. F. Souza, Julliane Yoneda, Caique Lopes Duarte, Silmara N. Andrade, Adriano de Paula Sabino, Fernando P. Varotti, Diego P. Sangi

{"title":"Synthesis and cytotoxic evaluation of heterocyclic compounds by vinylic substitution of ketene dithioacetals","authors":"Larissa R. S. P. Baliza, Túlio R. Freitas, Edward K. S. Gonçalves, Gabriel R. Antunes, Ana J. F. Souza, Julliane Yoneda, Caique Lopes Duarte, Silmara N. Andrade, Adriano de Paula Sabino, Fernando P. Varotti, Diego P. Sangi","doi":"10.1111/cbdd.14581","DOIUrl":"10.1111/cbdd.14581","url":null,"abstract":"N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis of curcumin derivatives targeting androgen receptor for castration-resistant prostate cancer therapy 针对雄激素受体的姜黄素衍生物的合成，用于治疗耐阉割性前列腺癌。

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2024-07-11 DOI: 10.1111/cbdd.14583

Jiangfei Liu, Yaohui Ni, Keyun Zhou, Guanzhao Wu, Liangyong Hu, Tianyu Zhu, Defeng Xu, Hang Hu

{"title":"Synthesis of curcumin derivatives targeting androgen receptor for castration-resistant prostate cancer therapy","authors":"Jiangfei Liu, Yaohui Ni, Keyun Zhou, Guanzhao Wu, Liangyong Hu, Tianyu Zhu, Defeng Xu, Hang Hu","doi":"10.1111/cbdd.14583","DOIUrl":"10.1111/cbdd.14583","url":null,"abstract":"In this work, a series of curcumin derivatives (1a–1h, 2a–2g, and 3a–3c) were synthesized for the suppression of castration-resistant prostate cancer cells. All synthesized compounds were characterized by 1H NMR, 13C NMR, HRMS, and melting point. The in vitro cytotoxicity study shows that compounds 1a, 1e, 1f, 1h, 2g, 3a, and 3c display similar or enhanced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9, other synthesized compounds display reduced cytotoxicity against 22Rv1 and C4-2 cells as compared to ASC-J9. Molecular docking simulation was performed to study the binding affinity and probable binding modes of the synthesized compounds with androgen receptor. The results show that all synthesized compounds exhibit higher cdocker interaction energies as compared to ASC-J9. Compounds 1h, 2g, and 3c not only show strong cytotoxicity against 22Rv1 and C4-2 cells but also exhibit high binding affinity with androgen receptor. In androgen receptor suppression study, compounds 1f and 2g show similar androgen receptor suppression effect as compared to ASC-J9 on C4-2 cells, compound 3c displays significantly enhanced AR suppression effect as compared to ASC-J9, 1f and 2g. Compounds 1a, 1e, 1f, 1h, 2g, 3a and 3c prepared in this work have significant potential for castration-resistant prostate cancer therapy.","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141592428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to Silencing PCMT1 enhances the sensitivity of breast cancer cells to paclitaxel through the PI3K/Akt/STMN1 pathway 更正为沉默 PCMT1 可通过 PI3K/Akt/STMN1 途径提高乳腺癌细胞对紫杉醇的敏感性。

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2024-07-09 DOI: 10.1111/cbdd.14577

引用次数: 0

A hybrid evaluation of the intestinal absorption performance of compounds from molecular structure 从分子结构对化合物的肠道吸收性能进行混合评估。

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2024-07-05 DOI: 10.1111/cbdd.14576

Mengke Sheng, Lina Ma, Zhixun Li, Xinhui Peng, Shuai Cen, Minfang Feng, Yuting Tian, Xingxing Dai, Xinyuan Shi

{"title":"A hybrid evaluation of the intestinal absorption performance of compounds from molecular structure","authors":"Mengke Sheng, Lina Ma, Zhixun Li, Xinhui Peng, Shuai Cen, Minfang Feng, Yuting Tian, Xingxing Dai, Xinyuan Shi","doi":"10.1111/cbdd.14576","DOIUrl":"10.1111/cbdd.14576","url":null,"abstract":"Intestinal absorption of compounds is significant in drug research and development. To evaluate this efficiently, a method combining mathematical modeling and molecular simulation was proposed, from the perspective of molecular structure. Based on the quantitative structure–property relationship study, the model between molecular structure and their apparent permeability coefficients was successfully constructed and verified, predicting intestinal absorption of drugs and interpreting decisive structural factors, such as AlogP98, Hydrogen bond donor and Ellipsoidal volume. The molecules with strong lipophilicity, less hydrogen bond donors and receptors, and small molecular volume are more easily absorbed. Then, the molecular dynamics simulation and molecular docking were utilized to study the mechanism of differences in intestinal absorption of drugs and investigate the role of molecular structure. Results indicated that molecules with strong lipophilicity and small volume interacted with the membrane at a lower energy and were easier to penetrate the membrane. Likewise, they had weaker interaction with P-glycoprotein and were easier to escape from it and harder to export from the body. More in, less out, is the main reason these molecules absorb well.","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141539042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advancements in inhibitors of crucial enzymes in the cysteine biosynthetic pathway: Serine acetyltransferase and O-acetylserine sulfhydrylase 半胱氨酸生物合成途径中关键酶抑制剂的研究进展：丝氨酸乙酰转移酶和 O-乙酰丝氨酸巯基酶。

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2024-07-04 DOI: 10.1111/cbdd.14573

Yinhui Qin, Yuetai Teng, Yan Yang, Zhenkun Mao, Shengyu Zhao, Na Zhang, Xu Li, Weihong Niu

{"title":"Advancements in inhibitors of crucial enzymes in the cysteine biosynthetic pathway: Serine acetyltransferase and O-acetylserine sulfhydrylase","authors":"Yinhui Qin, Yuetai Teng, Yan Yang, Zhenkun Mao, Shengyu Zhao, Na Zhang, Xu Li, Weihong Niu","doi":"10.1111/cbdd.14573","DOIUrl":"10.1111/cbdd.14573","url":null,"abstract":"Infectious diseases have been jeopardized problem that threaten public health over a long period of time. The growing prevalence of drug-resistant pathogens and infectious cases have led to a decrease in the number of effective antibiotics, which highlights the urgent need for the development of new antibacterial agents. Serine acetyltransferase (SAT), also known as CysE in certain bacterial species, and O-acetylserine sulfhydrylase (OASS), also known as CysK in select bacteria, are indispensable enzymes within the cysteine biosynthesis pathway of various pathogenic microorganisms. These enzymes play a crucial role in the survival of these pathogens, making SAT and OASS promising targets for the development of novel anti-infective agents. In this comprehensive review, we present an introduction to the structure and function of SAT and OASS, along with an overview of existing inhibitors for SAT and OASS as potential antibacterial agents. Our primary focus is on elucidating the inhibitory activities, structure–activity relationships, and mechanisms of action of these inhibitors. Through this exploration, we aim to provide insights into promising strategies and prospects in the development of antibacterial agents that target these essential enzymes.","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141536236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0