ChemMedChem
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2018
·Vol. 13
·期 20
·2202-2207
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IF 3.009
Rong Zhou,Yueguang Sun,Hangbin Li,Weili Long,Xiaojian Liao,Pengju Feng,Shihai Xu
Graphical Sponging up SAR data : The marine sponge Reniochalina stalagmitis is the source of a set of cyclic peptides known as reniochalistatins. Herein we report the total synthesis of reniochalistatins A–E, along with evaluations of their anticancer and antitubercular activities. Our results pave the way for further investigations into the structure–activity relationships of this class of cyclic peptide. The total synthesis of reniochalistatins A–E, along with a reniochalistatin E analogue (inverso-E) was successfully achieved through Fmoc-based solid-phase peptide synthesis and subsequent macrolactamization with PyBOP and DIEA. The biological activities of these reniochalistatins and a key linear peptide intermediate were systematically evaluated. Among these seven synthesized compounds, linear reniochalistatin B was found to have potent activity against several cancer cell lines not shown by the cyclic reniochalistatin B counterpart. In addition, linear reniochalistatin B was found to have antitubercular activity (IC 50 =1.4 μ m ). Inverso-E possesses increasing cytotoxicity against the HeLa and LNCaP cell lines after simple alternation of the sequence of amino acids in reniochalistatin E. The results of these studies provide a feasible method to further investigate the structure–activity relationships (SARs) of reniochalistatins A–E.
研究领域:
有机化学
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药物化学
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生物化学
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DOI
PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
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2024
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IF 2.3
Yongchang Bi,Jingjun Wang,Xingyu Bian,Mingyue Chen,Guangyuan Zhu,Yumin Zhang,Qiang Gu
An efficient and green method for synthesizing 3-methyl-4-(hetero) arylmethylene isoxazole-5(4 H )-ones was developed using a recyclable and environmental–friendly catalyst, Na 2 S 2 O 3 , and 16 target compounds were successfully synthesized under the obtained optimal reaction condition. Using rifampicin as a positive control, the antibacterial activity of all synthesized compounds was tested by micro dilution method, among them, 3-methyl-4-[(2,4-dimethoxyphenyl) methylene]-isoxazole-5-one ( 4 m ) presented wonderful antimicrobial activity, which may contribute to the development of anti-tuberculosis drugs. Graphical
研究领域:
有机化学
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药物化学
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微生物学
✓ 已验证
DOI
PubMed
高影响因子
ACS Infectious Diseases
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2025
·
IF 3.8
Xingli Han,Zhiyong Liu,Biao Zhou,Yuanyuan Shi,H.M. Adnan Hameed,Yamin Gao,Cuiting Fang,Xiongfang Zhao,Linzhuan Wu,Xiaoli Xiong,Wei Yu,Bin Hong,Tianyu Zhang
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), represents a global health challenge, necessitating new treatments with distinct mechanisms of action (MOA) to combat drug resistance. Chuangxinmycin (CM), characterized by its indole-dihydrothiopyran heterocyclic skeleton, exhibits potent antibacterial activity both in vitro and in vivo, with a minimum inhibitory concentration (MIC) of 0.25 μg/mL against Mtb. However, the MOA of CM against Mtb has remained obscure. Through comprehensive genetic, chemical rescue, and protein-drug interaction studies, coupled with biochemical analyses, we reveal that CM selectively binds and inhibits tryptophanyl-tRNA synthetase (TrpRS) encoded by trpS, rather than anthranilate synthase (TrpE). Overexpression of trpS in Mtb results in a 128-fold increase in the MIC of CM, indicating a fundamental cause of resistance, whereas overexpression of trpE leads to modest resistance, suggesting a secondary effect. Conversely, knockdown of trpS or trpE enhances the susceptibility of Mtb to CM. Meanwhile, promoters of trpS in CM-resistant Mtb mutants exhibit increased activity compared to the wild type. Furthermore, drug–protein interaction and biochemical assays have confirmed that while CM effectively inhibits TrpRS, mutants of TrpE show decreased affinity for tryptophan. These results establish that CM exerts its anti-Mtb effects by interfering with the tryptophan-tRNA linkage essential for protein synthesis.
研究领域:
微生物学
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药理学
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DOI
PubMed
高影响因子
Journal of the Iranian Chemical Society
·
2025
·
IF 2.3
Xue Yafei,Bi Yongchang,Wang Jingjun,Zhu Guangyuan,Chen Mingyue,Bian Xingyu,Zhang Yumin,Gu Qiang
Isoxazole-containing compounds showed an array of biological activities relevant to pulmonary tuberculosis. A series of pyrrolopyrimidine and indole derivatives containing isoxazole rings were constructed and synthesized by employing substituted isoxazole, pyrrolopyrimidine and indole derivatives as raw materials under the optimal reaction condition. On the basis of confirming the structure of the synthesized compounds, their antibacterial activity against Mycobacteria smegmatis in vitro was evaluated using rifampin as a positive control. Two compounds showed excellent anti-mycobacterium activity, and their minimum inhibitory concentrations were respectively 10.67 ± 3.77 μg/mL and 8.00 μg/mL, which suggested that they can be regarded as candidates for development of anti-tuberculosis drugs. Graphical abstract
研究领域:
药理学
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有机化学
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传染病学
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产品关联
DOI
高影响因子
Frontiers in Cellular and Infection Microbiology
·
2019
·
IF 3.518
Chen Changming,Han Xiuyan,Yan Qiulong,Wang Chao,Jia Liqiu,Taj Ayaz,Zhao Lizhe,Ma Yufang
Mycobacterium tuberculosis bifunctional enzyme GlmU is a novel target for anti-TB drugs and is involved in glycosyl donor UDP-N-acetylglucosamine biosynthesis. Here, we found that TPSA (2-[5-(2-{[4-(2-thienyl)-2-pyrimidinyl]sulfanyl}acetyl)-2-thienyl]acetic acid) was a novel inhibitor for GlmU acetyltransferase activity (IC50: 5.3 μM). The interaction sites of GlmU and TPSA by molecular docking were confirmed by site-directed mutagenesis. TPSA showed an inhibitory effect on Mtb H37Ra growth and intracellular H37Ra in macrophage cells (MIC: 66.5 μM). To investigate why TPSA at a higher concentration (66.5 μM) was able to inhibit H37Ra growth, proteome and transcriptome of H37Ra treated with TPSA were analyzed. The expression of two methyltransferases MRA_0565 (Rv0558) and MRA_0567 (Rv0560c) were markedly increased. TPSA was pre-incubated with purified Rv0558 and Rv0560c in the presence of S-adenosylmethionine (methyl donor) respectively, resulting in its decreased inhibitory effect of GlmU on acetyltransferase activity. The inhibition of TPSA on growth of H37Ra with overexpressed Rv0558 and Rv0560c was reduced. These implied that methyltransferases could modify TPSA. The methylation of TPSA catalyzed by Rv0560c was subsequently confirmed by LC-MS. Therefore, TPSA as a GlmU acetyltransferase activity inhibitor may offer a structural basis for new anti-tuberculosis drugs. TPSA needs to be modified further by some groups to prevent its methylation by methyltransferases.
研究领域:
微生物学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
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2024
·
IF 3.3
Yanhong Niu,Zhili Wu,Qianfang Hu,Yuchen Wu,Qihua Jiang,Xiaolan Yang
Acetohydroxy acid synthase (AHAS) is a key enzyme that catalyzes the synthesis of branched-chain amino acids, which is indispensable for the survival and growth of Mycobacterium tuberculosis ( Mtb ). Aim to discover new AHAS inhibitors from natural products, here we performed computer assistant target-based screening for Mtb- AHAS inhibitors using Discovery Studio on TCMSP and SELLECK libraries. Mtb -AHAS structure was first simulated and verified for docking, and 80 compounds with top LIBDOCK and CDDOCK scores were obtained. By experimental verification, four compounds namely Salvianolic acid A, Embelin, Celastrol and Wushanicaritin showed inhibition potency against Mtb- AHAS with IC50 ranging from 805.5 nM–32.36 μM. The most potential inhibitor Celastrol exhibited bacteriostatic activity for both Mycobacterium smegmatis and Mycobacterium tuberculosis with MIC of 62.5 μM and 80 μM, respectively. This study revealed that Celastrol is the potential Mtb- AHAS inhibitor as an anti-tuberculosis lead compound.
研究领域:
药理学
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微生物学
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药物发现
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计算生物学
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产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
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2024
·
IF 5.2
Qiuwen Fei,Jian Zhang,Liangqiong Chen,Manqi Shi,Qinglan Wang,Feifan Xu,Jiahai Shi,Yongwei Qin
Background Mycobacterium tuberculosis infection triggers various forms of host cell death, including ferroptosis in lung epithelial cells; YY1, a critical transcription factor, plays a pivotal role in regulating ferroptosis, however, the underlying mechanisms are not fully understood. Methods To investigate Mycobacterium marinum ( M.marinum )infection in lung epithelial cells A549 and H1299, we utilized flow cytometry to evaluate cell death and measure reactive oxygen species (ROS). Colony-forming unit (CFU) assays determined the intracellular bacterial load. Ferroptosis was analyzed using a specific detection kit to measure malondialdehyde (MDA) and glutathione (GSH) levels. The interaction between the transcription factor YY1 and the iNOS promoter was assessed through a dual-luciferase reporter assay. Results M.marinum induced ferroptosis in lung epithelial cells through invasion. This effect is most pronounced at 8 h of infection and decreases over time but increased with a higher multiplicity of infection (MOI). YY1 knockdown decreases the expression of SLC7A11 and GPX4, attenuates cellular ferroptosis, while YY1 overexpression has the opposite phenomenon, enhancing the expression of bactericidal molecules such as iNOS and MPEG1, thereby markedly reducing the intracellular bacterial load. We identified substantial binding of YY1 to the iNOS promoter region (−655 to −1018 bp), enhancing mycobactericidal activity in YY1-overexpressing cells. Conclusions Our study demonstrates that YY1 inhibits ferroptosis induced by Mycobacterium marinum infection and reduces intracellular bacterial proliferation in lung epithelial cells. These findings provide a crucial basis for developing anti-tuberculosis therapies that target YY1 modulation, potentially offering new clinical avenues for the treatment of tuberculosis.
研究领域:
微生物学
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细胞生物学
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传染病学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
THERAPEUTIC DRUG MONITORING
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2024
·
IF 2.8
Fan Xudong,Guo Suhang,Zhang Ruoying,Cai Qingshan,Lang Yazhen,Huang Jinpeng,Chen Yuanyuan,Zhang Ying,Xu Yingying,Chen Meng,Yang Gaoyi,Cai Xinjun
Introduction: Linezolid, moxifloxacin, rifapentine, rifabutin, cycloserine, clofazimine, bedaquiline, levofloxacin, prothionamide, and ethionamide are commonly used second-line antituberculosis (anti-TB) drugs. To support therapeutic drug monitoring in regular clinical practice, the authors sought to develop a method based on ultra–high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) that would allow for the simultaneous quantification of multiple second-line anti-TB drugs in human serum. Methods: Analytes were extracted from human serum by protein precipitation. UHPLC-MS/MS was performed using a gradient at a flow rate of 0.3 mL/min, and each sample was taken for 7.5 minutes. The mass spectrometry scanning mode used was electrospray ionization with multiple reaction monitoring in the positive mode. Results: Validation showed that endogenous substances in the sample did not interfere with the assay, and the relationship between X and Y was highly linear, with a coefficient of determination (R 2 ) >0.9954 for each curve. The accuracy (85.0%–114.7%) and precision (intraday: 0.27%–9.32%; interday: 0.20%–7.66%) were less than 15.0%, and the internal standard-normalized matrix effects were consistent (coefficient of variation ≤4.40%). The analytes were stable in the final extract and human serum under various storage conditions (recovery: 87.0%–115.0%). The clinical applicability of the method was demonstrated by quantitative determination of analytes in serum samples obtained from patients with TB. Reproducibility of the drug concentrations measured in clinical samples was confirmed by incurred sample reanalysis. Conclusions: A simple and reliable analytical method was developed and validated for the simultaneous determination of 10 anti-TB drugs in human serum using UHPLC-MS/MS. Quantitation of anti-TB drugs in clinical samples confirmed that the assay is suitable for therapeutic drug monitoring in regular clinical practice.
研究领域:
药理学
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临床化学
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分析化学
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结核病治疗
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）