PKMYT1, a member of the WEE family, plays a crucial role in the cell cycle by specifically phosphorylating CDK1-CyclinB at Tyr15 and Thr14. Recent investigations have revealed that the amplification of CCNE1 and the inhibition of PKMYT1 kinase collectively result in synthetic lethality, further indicating that PKMYT1 is promising as an effective target for tumor therapy. Existing PKMYT1 inhibitors are mostly derivatives of RP-6306 or pan-inhibitors, limiting their further development. Herein, we conducted virtual screening of a natural product library, and in vitro enzyme experiments demonstrated that EGCG, GCG, and luteolin exhibited potent inhibitory activities with IC50 values of 0.137 μM, 0.159 μM, and 1.5 μM, respectively. Subsequently, analysis of the hit compounds and RP-6306, using different molecular simulation methods, revealed that stable hydrogen bonds with Asp251 and Glu157 in the DFG region were vital for binding to PKMYT1, more so than hydrogen bonds in the hinge and loop regions.
{"title":"Structure-based virtual screening discovers novel PKMYT1 inhibitors†","authors":"Haoyu Zhang, Jinyu Yu, Ziheng Yang, Zhiqiang Guo, Rui Liu, Qiaohua Qin, Yixiang Sun, Nian Liu, Zixuan Gao, Dongmei Zhao and Maosheng Cheng","doi":"10.1039/D4MD00389F","DOIUrl":"10.1039/D4MD00389F","url":null,"abstract":"<p >PKMYT1, a member of the WEE family, plays a crucial role in the cell cycle by specifically phosphorylating CDK1-CyclinB at Tyr15 and Thr14. Recent investigations have revealed that the amplification of CCNE1 and the inhibition of PKMYT1 kinase collectively result in synthetic lethality, further indicating that PKMYT1 is promising as an effective target for tumor therapy. Existing PKMYT1 inhibitors are mostly derivatives of RP-6306 or pan-inhibitors, limiting their further development. Herein, we conducted virtual screening of a natural product library, and <em>in vitro</em> enzyme experiments demonstrated that EGCG, GCG, and luteolin exhibited potent inhibitory activities with IC<small><sub>50</sub></small> values of 0.137 μM, 0.159 μM, and 1.5 μM, respectively. Subsequently, analysis of the hit compounds and RP-6306, using different molecular simulation methods, revealed that stable hydrogen bonds with Asp251 and Glu157 in the DFG region were vital for binding to PKMYT1, more so than hydrogen bonds in the hinge and loop regions.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141944949","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}
Hebatallah S. Ali, Hiba S. Al-Amodi, Shaimaa Hamady, Marian M. S. Roushdy, Amany Helmy Hasanin, Ghada Ellithy, Rasha A. Elmansy, Hagir H. T. Ahmed, Enshrah M. E. Ahmed, Doaa M. A. Elzoghby, Hala F. M. Kamel, Ghida Hassan, Hind A. ELsawi, Laila M. Farid, Mariam B. Abouelkhair, Eman K. Habib, Mohamed Esawie, Heba Fikry, Lobna A. Saleh and Marwa Matboli
Correction for ‘Rosavin improves insulin resistance and alleviates hepatic and kidney damage via modulating the cGAS-STING pathway and autophagy signaling in HFD/STZ-induced T2DM animals’ by Hebatallah S. Ali et al., RSC Med. Chem., 2024, 15, 2098–2113, https://doi.org/10.1039/D4MD00023D.
对 Hebatallah S. Ali 等人撰写的 "Rosavin 通过调节 cGAS-STING 通路和自噬信号,改善 HFD/STZ 诱导的 T2DM 动物的胰岛素抵抗,减轻肝脏和肾脏损伤 "的更正,RSC Med.Chem.,2024,15,2098-2113,https://doi.org/10.1039/D4MD00023D。
{"title":"Correction: Rosavin improves insulin resistance and alleviates hepatic and kidney damage via modulating the cGAS-STING pathway and autophagy signaling in HFD/STZ-induced T2DM animals","authors":"Hebatallah S. Ali, Hiba S. Al-Amodi, Shaimaa Hamady, Marian M. S. Roushdy, Amany Helmy Hasanin, Ghada Ellithy, Rasha A. Elmansy, Hagir H. T. Ahmed, Enshrah M. E. Ahmed, Doaa M. A. Elzoghby, Hala F. M. Kamel, Ghida Hassan, Hind A. ELsawi, Laila M. Farid, Mariam B. Abouelkhair, Eman K. Habib, Mohamed Esawie, Heba Fikry, Lobna A. Saleh and Marwa Matboli","doi":"10.1039/D4MD90030H","DOIUrl":"10.1039/D4MD90030H","url":null,"abstract":"<p >Correction for ‘Rosavin improves insulin resistance and alleviates hepatic and kidney damage <em>via</em> modulating the cGAS-STING pathway and autophagy signaling in HFD/STZ-induced T2DM animals’ by Hebatallah S. Ali <em>et al.</em>, <em>RSC Med. Chem.</em>, 2024, <strong>15</strong>, 2098–2113, https://doi.org/10.1039/D4MD00023D.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md90030h?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141886139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chien Van Tran, Thao Thi Phuong Tran, Anh The Nguyen, Loc Van Tran, Ninh Thi Pham, Luu Thi Nguyen, Dung Thi Nguyen, Michelle D Garrett, Nga Thi Nguyen, Thao Thi Do, Christopher J Serpell, Sung Van Tran
A series of 14 conjugates of 2α,3β,23-triacetyl-madecassic acid and silybin were designed and synthesized. The madecassic acid unit was linked to silybin either directly at position C-7 or C-3; or through an amino acid linker (glycine, β-alanine, or 11-aminoundecanoic acid) at position C-3. The conjugates were tested in vitro for their cytotoxic effect on HepG2 cells using the MTT assay. The results confirmed that the conjugated compounds demonstrated a stronger cytotoxic effect compared to the parent compounds. Of these compounds, the most promising conjugate, compound 8, was evaluated for cytotoxic activity in the additional Hep3B, Huh7, and Huh7R human hepatocellular carcinoma cell lines and also for cell cycle changes and induction of apoptosis in HepG2 cells. This compound caused a rapid and significant induction of caspase 3 activity and induced cell cycle arrest in the S phase - effects distinct from the activity of madecassic acid. This is the first study on the synthesis and cytotoxicity of madecassic acid-silybin conjugates, and of their testing against liver cancer cell lines and provides evidence for a distinct biological profile versus madecassic acid alone.
{"title":"Synthesis and cytotoxic activity of madecassic acid-silybin conjugate compounds in liver cancer cells.","authors":"Chien Van Tran, Thao Thi Phuong Tran, Anh The Nguyen, Loc Van Tran, Ninh Thi Pham, Luu Thi Nguyen, Dung Thi Nguyen, Michelle D Garrett, Nga Thi Nguyen, Thao Thi Do, Christopher J Serpell, Sung Van Tran","doi":"10.1039/d4md00170b","DOIUrl":"10.1039/d4md00170b","url":null,"abstract":"<p><p>A series of 14 conjugates of 2α,3β,23-triacetyl-madecassic acid and silybin were designed and synthesized. The madecassic acid unit was linked to silybin either directly at position C-7 or C-3; or through an amino acid linker (glycine, β-alanine, or 11-aminoundecanoic acid) at position C-3. The conjugates were tested <i>in vitro</i> for their cytotoxic effect on HepG2 cells using the MTT assay. The results confirmed that the conjugated compounds demonstrated a stronger cytotoxic effect compared to the parent compounds. Of these compounds, the most promising conjugate, compound 8, was evaluated for cytotoxic activity in the additional Hep3B, Huh7, and Huh7R human hepatocellular carcinoma cell lines and also for cell cycle changes and induction of apoptosis in HepG2 cells. This compound caused a rapid and significant induction of caspase 3 activity and induced cell cycle arrest in the S phase - effects distinct from the activity of madecassic acid. This is the first study on the synthesis and cytotoxicity of madecassic acid-silybin conjugates, and of their testing against liver cancer cell lines and provides evidence for a distinct biological profile <i>versus</i> madecassic acid alone.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11343037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rho-associated coiled-coil containing kinase (ROCK) plays an important role in inflammation. Herein, a series of compounds were designed and synthesized as ROCK inhibitors based on the structure-based drug design (SBDD) strategy and were evaluated for cytotoxicity, antioxidant activity and anti-inflammatory activity. Among them, compound DC24 was identified as the optimal hit in enzymatic screening with an IC50 value of 0.124 μM against ROCK2 and 50-fold selectivity over ROCK1. DC24 has a novel lipid amide scaffold with a bis(4-fluorophenyl)methyl substituent, and DC24 is the first ROCK2 inhibitor interacting with the hinge region of ROCK2 via the 1,2-dithiolan-3-yl motif, which has been confirmed by the binding model of DC24 with ROCK2. In a complete Freund's adjuvant (CFA) induced acute inflammation model, DC24 at a dose of 5 mg kg−1 exhibited an anti-inflammatory effect better than that of belumosudil. Furthermore, DC24 exhibits good safety in vivo.
{"title":"The synthesis and bioactivities of ROCK2 inhibitors with 1,2-dithiolan-3-yl motif","authors":"Ruolin Cao, Fangyu Du, Zhiqiang Liu, Pengcheng Cai, Minggang Qi, Wei Xiao, Xuefei Bao, Guoliang Chen","doi":"10.1039/d4md00438h","DOIUrl":"https://doi.org/10.1039/d4md00438h","url":null,"abstract":"Rho-associated coiled-coil containing kinase (ROCK) plays an important role in inflammation. Herein, a series of compounds were designed and synthesized as ROCK inhibitors based on the structure-based drug design (SBDD) strategy and were evaluated for cytotoxicity, antioxidant activity and anti-inflammatory activity. Among them, compound <strong>DC24</strong> was identified as the optimal hit in enzymatic screening with an IC<small><sub>50</sub></small> value of 0.124 μM against ROCK2 and 50-fold selectivity over ROCK1. <strong>DC24</strong> has a novel lipid amide scaffold with a bis(4-fluorophenyl)methyl substituent, and <strong>DC24</strong> is the first ROCK2 inhibitor interacting with the hinge region of ROCK2 <em>via</em> the 1,2-dithiolan-3-yl motif, which has been confirmed by the binding model of <strong>DC24</strong> with ROCK2. In a complete Freund's adjuvant (CFA) induced acute inflammation model, <strong>DC24</strong> at a dose of 5 mg kg<small><sup>−1</sup></small> exhibited an anti-inflammatory effect better than that of belumosudil. Furthermore, <strong>DC24</strong> exhibits good safety <em>in vivo</em>.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222000","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}
Colorectal cancer represents the over-expression of TMEM16A and COX-2, offering a promising therapeutic strategy. Two Pt(IV) conjugates derived from Pt(II) drug (cisplatin or oxaliplatin) and niflumic acid, complexes 1 and 2, were designed and prepared to exert the positive impact of multiple biological targets of DNA/TMEM16A/COX-2 against colorectal cancer. Complex 2 afforded higher cytotoxicity than 1 and the combination of an intermediate of oxidized oxaliplatin and NFA against cancer cells A549, HeLa, MCF-7, and HCT116. Especially for colorectal cancer cells HCT116, 2 was significantly more toxic (22-fold) and selective to cancer cells against normal HUVEC cells (4-fold) than first-line oxaliplatin. The outstanding anticancer activity of 2 is partly attributed to its dramatic increase in cellular uptake, DNA damage, and apoptosis. Mechanistic studies indicated that 2 inhibited HCT116 cell metastasis by triggering TMEM16A, COX-2, and their downstream signaling pathways, including EGFR, STAT3, E-cadherin and N-cadherin.
{"title":"Pt(iv) derivatives of cisplatin and oxaliplatin bearing an EMT-related TMEM16A/COX-2-selective dual inhibitor against colorectal cancer cells HCT116†","authors":"Zhong-Ying Ma, Xiao-Jing Ding, Zhen-Zhen Zhu, Qian Chen, Dong-Bo Wang, Xin Qiao and Jing-Yuan Xu","doi":"10.1039/D4MD00327F","DOIUrl":"10.1039/D4MD00327F","url":null,"abstract":"<p >Colorectal cancer represents the over-expression of TMEM16A and COX-2, offering a promising therapeutic strategy. Two Pt(<small>IV</small>) conjugates derived from Pt(<small>II</small>) drug (cisplatin or oxaliplatin) and niflumic acid, complexes <strong>1</strong> and <strong>2</strong>, were designed and prepared to exert the positive impact of multiple biological targets of DNA/TMEM16A/COX-2 against colorectal cancer. Complex <strong>2</strong> afforded higher cytotoxicity than <strong>1</strong> and the combination of an intermediate of oxidized oxaliplatin and NFA against cancer cells A549, HeLa, MCF-7, and HCT116. Especially for colorectal cancer cells HCT116, <strong>2</strong> was significantly more toxic (22-fold) and selective to cancer cells against normal HUVEC cells (4-fold) than first-line oxaliplatin. The outstanding anticancer activity of <strong>2</strong> is partly attributed to its dramatic increase in cellular uptake, DNA damage, and apoptosis. Mechanistic studies indicated that <strong>2</strong> inhibited HCT116 cell metastasis by triggering TMEM16A, COX-2, and their downstream signaling pathways, including EGFR, STAT3, E-cadherin and N-cadherin.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056379","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}
Hugo Kocek, Dominika Chalupská, Milan Dejmek, Alexandra Dvořáková, Michala Zgarbová, Michal Šála, Karel Chalupský, Petra Krafčíková, Tomáš Otava, Matúš Drexler, Eliška Procházková, Blanka Klepetářová, Milan Štefek, Ján Kozic, Helena Mertlíková-Kaiserová, Evzen Boura, Jan Weber, Radim Nencka
The emergence of SARS-CoV-2, the causative agent of COVID-19, has highlighted the need for advanced antiviral strategies. Targeting the coronaviral methyltransferase nsp14, which is essential for RNA capping, offers a promising approach for the development of small-molecule inhibitors. We designed and synthesized a series of adenosine 5'-carboxamide derivatives as potential nsp14 inhibitors and identified coumarin analogs to be particularly effective. Structural modifications revealed the importance of the 5'-carboxyl moiety for the inhibitory activity, showing superior efficacy compared to other modifications. Notably, compound 18l (HK370) demonstrated high selectivity and favorable in vitro pharmacokinetic properties and exhibited moderate antiviral activity in cell-based assays. These findings provide a robust foundation for developing targeted nsp14 inhibitors as a potential treatment for COVID-19 and related diseases.
{"title":"Discovery of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors based on adenosine 5'-carboxamides.","authors":"Hugo Kocek, Dominika Chalupská, Milan Dejmek, Alexandra Dvořáková, Michala Zgarbová, Michal Šála, Karel Chalupský, Petra Krafčíková, Tomáš Otava, Matúš Drexler, Eliška Procházková, Blanka Klepetářová, Milan Štefek, Ján Kozic, Helena Mertlíková-Kaiserová, Evzen Boura, Jan Weber, Radim Nencka","doi":"10.1039/d4md00422a","DOIUrl":"10.1039/d4md00422a","url":null,"abstract":"<p><p>The emergence of SARS-CoV-2, the causative agent of COVID-19, has highlighted the need for advanced antiviral strategies. Targeting the coronaviral methyltransferase nsp14, which is essential for RNA capping, offers a promising approach for the development of small-molecule inhibitors. We designed and synthesized a series of adenosine 5'-carboxamide derivatives as potential nsp14 inhibitors and identified coumarin analogs to be particularly effective. Structural modifications revealed the importance of the 5'-carboxyl moiety for the inhibitory activity, showing superior efficacy compared to other modifications. Notably, compound 18l (<b>HK370</b>) demonstrated high selectivity and favorable <i>in vitro</i> pharmacokinetic properties and exhibited moderate antiviral activity in cell-based assays. These findings provide a robust foundation for developing targeted nsp14 inhibitors as a potential treatment for COVID-19 and related diseases.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142111559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Apoptosis is programmed cell death that eliminates undesired cells to maintain homeostasis in metazoan. Aberration of this process may lead to cancer genesis. The tumor necrosis factor related apoptosis inducing ligand (TRAIL) induces apoptosis in cancer cells after ligation with death receptors (DR4/DR5) while sparing most normal cells. Therefore, strategies to induce apoptosis in cancer cells by mimicking the TRAIL emerge as a promising therapeutic tool. Hence, approaches are taken to develop TRAIL/DR-based cancer therapeutics. The recombinant soluble TRAIL (rhTRAIL) and death receptor agonistic antibodies were produced and tested pre-clinically and clinically. Pre-clinical and clinical trial data demonstrate that these therapeutics are safe and relatively well tolerated. But some of these therapeutics failed to exert adequate efficacy in clinical settings. Besides these biotechnologically derived therapeutics, a few chemically synthesized therapeutics are reported. Some of these therapeutics exert considerable efficacy in vitro and in vivo. In this review, we will discuss chemically synthesized TRAIL/DR-based therapeutics, their chemical and biological behaviour, design concepts and strategies that may contribute to further improvement of TRAIL/DR-based therapeutics.
{"title":"Chemical synthetic approaches to mimic the TRAIL: promising cancer therapeutics.","authors":"Abdullah-Al Masum, Shin Aoki, Md Mahbubur Rahman, Yosuke Hisamatsu","doi":"10.1039/d4md00183d","DOIUrl":"10.1039/d4md00183d","url":null,"abstract":"<p><p>Apoptosis is programmed cell death that eliminates undesired cells to maintain homeostasis in metazoan. Aberration of this process may lead to cancer genesis. The tumor necrosis factor related apoptosis inducing ligand (TRAIL) induces apoptosis in cancer cells after ligation with death receptors (DR4/DR5) while sparing most normal cells. Therefore, strategies to induce apoptosis in cancer cells by mimicking the TRAIL emerge as a promising therapeutic tool. Hence, approaches are taken to develop TRAIL/DR-based cancer therapeutics. The recombinant soluble TRAIL (rhTRAIL) and death receptor agonistic antibodies were produced and tested pre-clinically and clinically. Pre-clinical and clinical trial data demonstrate that these therapeutics are safe and relatively well tolerated. But some of these therapeutics failed to exert adequate efficacy in clinical settings. Besides these biotechnologically derived therapeutics, a few chemically synthesized therapeutics are reported. Some of these therapeutics exert considerable efficacy <i>in vitro</i> and <i>in vivo</i>. In this review, we will discuss chemically synthesized TRAIL/DR-based therapeutics, their chemical and biological behaviour, design concepts and strategies that may contribute to further improvement of TRAIL/DR-based therapeutics.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11376135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiang Wang, Jing-Yi Yang, Pradeepraj Durairaj, Wei-Huan Wen, Nadana Sabapathi, Liang Yang, Bo Wang and Ai-Qun Jia
Quorum sensing (QS) inhibition stands out as an innovative therapeutic strategy for combating infections caused by drug-resistant pathogens. In this study, we assessed the potential of 3-(2-isocyanobenzyl)-1H-indole derivatives as novel quorum sensing inhibitors (QSIs). Initial screenings of their QS inhibitory activities were conducted against Pseudomonas aeruginosa PAO1 and Chromobacterium violaceum CV026. Notably, six 3-(2-isocyanobenzyl)-1H-indole derivatives (4, 12, 25, 28, 32, and 33) exhibited promising QS, biofilms, and pyocyanin inhibitory activities under minimum inhibitory concentrations (MICs) against P. aeruginosa PAO1. Among them, 3-(2-isocyano-6-methylbenzyl)-1H-indole (IMBI, 32) emerged as the most promising candidate, demonstrating superior biofilm and pyocyanin inhibition. Further comprehensive studies revealed that derivative 32 at 25 μg mL−1 inhibited biofilm formation by 70% against P. aeruginosa PAO1, as confirmed by scanning electron microscopy (SEM). Additionally, derivative 32 substantially increased the susceptibility of mature biofilms, leading to a 57% destruction of biofilm architecture. In terms of interfering with virulence factors in P. aeruginosa PAO1, derivative 32 (25 μg mL−1) displayed remarkable inhibitory effects on pyocyanin, protease, and extracellular polysaccharides (EPS) by 73%, 51%, and 37%, respectively, exceeding the positive control resveratrol (RSV). Derivative 32 at 25 μg mL−1 also exhibited effective inhibition of swimming and swarming motilities. Moreover, it downregulated the expressions of QS-related genes, including lasI, lasR, rhlI, rhlR, pqsR, sdhB, sucD, sodB, and PA5439, by 1.82- to 10.87-fold. Molecular docking, molecular dynamics simulations (MD), and energy calculations further supported the stable binding of 32 to LasR, RhlI, RhlR, EsaL, and PqsR antagonizing the expression of QS-linked traits. Evaluation of the toxicity of derivative 32 on HEK293T cells via CCK-8 assay demonstrated low cytotoxicity. Overall, this study underscores the efficacy of derivative 32 in inhibiting virulence factors in P. aeruginosa. Derivative 32 emerges as a potential QSI for controlling P. aeruginosa PAO1 infections in vitro and an anti-biofilm agent for restoring or enhancing drug sensitivity in drug-resistant pathogens.
{"title":"Discovery and evaluation of 3-(2-isocyanobenzyl)-1H-indole derivatives as potential quorum sensing inhibitors for the control of Pseudomonas aeruginosa infections in vitro†","authors":"Jiang Wang, Jing-Yi Yang, Pradeepraj Durairaj, Wei-Huan Wen, Nadana Sabapathi, Liang Yang, Bo Wang and Ai-Qun Jia","doi":"10.1039/D4MD00354C","DOIUrl":"10.1039/D4MD00354C","url":null,"abstract":"<p >Quorum sensing (QS) inhibition stands out as an innovative therapeutic strategy for combating infections caused by drug-resistant pathogens. In this study, we assessed the potential of 3-(2-isocyanobenzyl)-1<em>H</em>-indole derivatives as novel quorum sensing inhibitors (QSIs). Initial screenings of their QS inhibitory activities were conducted against <em>Pseudomonas aeruginosa</em> PAO1 and <em>Chromobacterium violaceum</em> CV026. Notably, six 3-(2-isocyanobenzyl)-1<em>H</em>-indole derivatives (4, 12, 25, 28, 32, and 33) exhibited promising QS, biofilms, and pyocyanin inhibitory activities under minimum inhibitory concentrations (MICs) against <em>P. aeruginosa</em> PAO1. Among them, 3-(2-isocyano-6-methylbenzyl)-1<em>H</em>-indole (IMBI, 32) emerged as the most promising candidate, demonstrating superior biofilm and pyocyanin inhibition. Further comprehensive studies revealed that derivative 32 at 25 μg mL<small><sup>−1</sup></small> inhibited biofilm formation by 70% against <em>P. aeruginosa</em> PAO1, as confirmed by scanning electron microscopy (SEM). Additionally, derivative 32 substantially increased the susceptibility of mature biofilms, leading to a 57% destruction of biofilm architecture. In terms of interfering with virulence factors in <em>P. aeruginosa</em> PAO1, derivative 32 (25 μg mL<small><sup>−1</sup></small>) displayed remarkable inhibitory effects on pyocyanin, protease, and extracellular polysaccharides (EPS) by 73%, 51%, and 37%, respectively, exceeding the positive control resveratrol (RSV). Derivative 32 at 25 μg mL<small><sup>−1</sup></small> also exhibited effective inhibition of swimming and swarming motilities. Moreover, it downregulated the expressions of QS-related genes, including <em>lasI</em>, <em>lasR</em>, <em>rhlI</em>, <em>rhlR</em>, <em>pqsR</em>, <em>sdhB</em>, <em>sucD</em>, <em>sodB</em>, and <em>PA5439</em>, by 1.82- to 10.87-fold. Molecular docking, molecular dynamics simulations (MD), and energy calculations further supported the stable binding of 32 to LasR, RhlI, RhlR, EsaL, and PqsR antagonizing the expression of QS-linked traits. Evaluation of the toxicity of derivative 32 on HEK293T cells <em>via</em> CCK-8 assay demonstrated low cytotoxicity. Overall, this study underscores the efficacy of derivative 32 in inhibiting virulence factors in <em>P. aeruginosa</em>. Derivative 32 emerges as a potential QSI for controlling <em>P. aeruginosa</em> PAO1 infections <em>in vitro</em> and an anti-biofilm agent for restoring or enhancing drug sensitivity in drug-resistant pathogens.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056377","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}
Madison Frazier, Jay S. Wright, David M. Raffel, Jenelle Stauff, Wade P. Winton, Peter J. H. Scott and Allen F. Brooks
The most prominent myocardial voltage-gated sodium channel, NaV1.5, is a major drug target for treating cardiovascular disease. However, treatment determination and therapeutic development are complicated partly by an inadequate understanding of how the density of SCN5A, the gene that encodes NaV1.5, relates to treatment response and disease prognosis. To address these challenges, imaging agents derived from NaV1.5 blocking therapeutics have been employed in positron emission tomography (PET) imaging to infer how SCN5A expression relates to human disease in vivo. Herein, we describe the preparation of a novel fluorine-18 labelled analogue of lidocaine, a known NaV1.5 inhibitor, and compare this agent to a previously described analogue. Evidence from rodent and non-human primate PET imaging experiments suggests that the imaging utility of these agents may be limited by rapid metabolism and clearance.
{"title":"Automated radiosynthesis and preclinical imaging of a novel [18F]fluorolidocaine analogue via sequential C–H radiolabelling†","authors":"Madison Frazier, Jay S. Wright, David M. Raffel, Jenelle Stauff, Wade P. Winton, Peter J. H. Scott and Allen F. Brooks","doi":"10.1039/D4MD00293H","DOIUrl":"10.1039/D4MD00293H","url":null,"abstract":"<p >The most prominent myocardial voltage-gated sodium channel, Na<small><sub>V</sub></small>1.5, is a major drug target for treating cardiovascular disease. However, treatment determination and therapeutic development are complicated partly by an inadequate understanding of how the density of SCN5A, the gene that encodes Na<small><sub>V</sub></small>1.5, relates to treatment response and disease prognosis. To address these challenges, imaging agents derived from Na<small><sub>V</sub></small>1.5 blocking therapeutics have been employed in positron emission tomography (PET) imaging to infer how SCN5A expression relates to human disease <em>in vivo</em>. Herein, we describe the preparation of a novel fluorine-18 labelled analogue of lidocaine, a known Na<small><sub>V</sub></small>1.5 inhibitor, and compare this agent to a previously described analogue. Evidence from rodent and non-human primate PET imaging experiments suggests that the imaging utility of these agents may be limited by rapid metabolism and clearance.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11339636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Preeti Rana, Rahul Maitra, Deepanshi Saxena, Abdul Akhir, Manasa Vadakattu, Abdul Kalam, Swanand Vinayak Joshi, Ramulu Parupalli, Vasundhra Bhandari, Y V Madhavi, Arunava Dasgupta, Sidharth Chopra, Srinivas Nanduri
In this work, a novel series of naphthalimide hydrazide derivatives were designed, synthesized and evaluated against a bacterial pathogen panel. Most of the compounds were found to exhibit potent antibacterial activity against carbapenem-resistant A. baumannii BAA 1605, with MIC ranging from 0.5 to 16 μg mL-1. Compounds 5b, 5c, 5d and 5e showed the most potent antibacterial activity, with an MIC range of 0.5-1 μg mL-1. These compounds were also found to be non-toxic to Vero cells with a high selectivity index. Further, they were active against 24 clinical isolates of MDR-AB with potent antibacterial activity. In addition, synergistic studies revealed that compound 5d exhibited synergism with FDA-approved drugs, as further validated through time-kill kinetic studies. These results highlight the potential of the synthesized compounds as promising leads for the development of novel and selective agents against carbapenem-resistant A. baumannii.
本研究设计、合成并评估了一系列新型萘二甲酰亚胺酰肼衍生物对细菌病原体的抗菌活性。结果发现,大多数化合物对耐碳青霉烯类的鲍曼尼氏菌 BAA 1605 具有强效抗菌活性,MIC 值范围为 0.5 至 16 μg mL-1。化合物 5b、5c、5d 和 5e 的抗菌活性最强,MIC 范围为 0.5-1 μg mL-1。研究还发现,这些化合物对 Vero 细胞无毒,且具有较高的选择性。此外,这些化合物对 24 种临床分离的 MDR-AB 具有很强的抗菌活性。此外,协同作用研究表明,化合物 5d 与美国 FDA 批准的药物具有协同作用,这一点通过时间致死动力学研究得到了进一步验证。这些结果凸显了合成化合物作为新型选择性抗耐碳青霉烯类鲍曼尼菌药物开发先导的潜力。
{"title":"Development of naphthalimide hydrazide derivatives as potent antibacterial agents against carbapenem-resistant <i>A. baumannii</i>.","authors":"Preeti Rana, Rahul Maitra, Deepanshi Saxena, Abdul Akhir, Manasa Vadakattu, Abdul Kalam, Swanand Vinayak Joshi, Ramulu Parupalli, Vasundhra Bhandari, Y V Madhavi, Arunava Dasgupta, Sidharth Chopra, Srinivas Nanduri","doi":"10.1039/d4md00368c","DOIUrl":"https://doi.org/10.1039/d4md00368c","url":null,"abstract":"<p><p>In this work, a novel series of naphthalimide hydrazide derivatives were designed, synthesized and evaluated against a bacterial pathogen panel. Most of the compounds were found to exhibit potent antibacterial activity against carbapenem-resistant <i>A. baumannii</i> BAA 1605, with MIC ranging from 0.5 to 16 μg mL<sup>-1</sup>. Compounds 5b, 5c, 5d and 5e showed the most potent antibacterial activity, with an MIC range of 0.5-1 μg mL<sup>-1</sup>. These compounds were also found to be non-toxic to Vero cells with a high selectivity index. Further, they were active against 24 clinical isolates of MDR-AB with potent antibacterial activity. In addition, synergistic studies revealed that compound 5d exhibited synergism with FDA-approved drugs, as further validated through time-kill kinetic studies. These results highlight the potential of the synthesized compounds as promising leads for the development of novel and selective agents against carbapenem-resistant <i>A. baumannii</i>.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142353064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}