Cyclic diguanosine monophosphate (c-di-GMP) is the key second messenger regulating bacterial biofilm formation related genes. Several c-di-GMP analogues have demonstrated biofilm inhibition activity. In this study, ribose-phosphate macrocyclic skeleton containing 1′-azido groups was constructed, and CDN analogues were prepared via click chemistry. The biofilm formation inhibition activity of the analogues was evaluated, and compound 17 illustrated better activity than c-di-GMP. This high-throughput strategy could be extended to synthesize cyclic analogues for biological research and immunotherapeutic development.
{"title":"Synthesis and biofilm inhibitory activity of cyclic dinucleotide analogues prepared with macrocyclic ribose-phosphate skeleton","authors":"Di Xie, Lingyun Xu, Shuwei Yuan, Jiayin Yan, Peng Zhou, Wenpei Dong, Jinliang Ma, Changpo Chen","doi":"10.1016/j.bmcl.2025.130107","DOIUrl":"10.1016/j.bmcl.2025.130107","url":null,"abstract":"<div><div>Cyclic diguanosine monophosphate (c-di-GMP) is the key second messenger regulating bacterial biofilm formation related genes. Several c-di-GMP analogues have demonstrated biofilm inhibition activity. In this study, ribose-phosphate macrocyclic skeleton containing 1′-azido groups was constructed, and CDN analogues were prepared via click chemistry. The biofilm formation inhibition activity of the analogues was evaluated, and compound <strong>17</strong> illustrated better activity than c-di-GMP. This high-throughput strategy could be extended to synthesize cyclic analogues for biological research and immunotherapeutic development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130107"},"PeriodicalIF":2.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997190","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}
Pub Date : 2025-01-13DOI: 10.1016/j.bmcl.2025.130106
Yongjian Liu , Hao Liu , Shuqi Li , Shaojun Yu , Heng Chen , Jinling Ge , Yonggang Liu
Harmaline as a natural compound possessed a wide range of pharmacological activities. In this study, 22 novel harmaline-based derivatives were synthesized and screened for in vitro anti-proliferation activity against three cancer cell lines, HCT116, MCF7, and MGC803. The modification site was at the position N-9 of harmaline. The 24-hour IC50 of compound HL22 against HCT116, MGC803, and MCF7 was 3.84 ± 0.11 μM, 5.26 ± 0.46 μM, and 8.67 ± 0.13 μM, respectively. Compound HL22 significantly reduced the migratory ability of MGC803 cells. The monoclonal formation of MGC803 cells was also inhibited by HL22. The 1H NMR metabolomics analysis suggested that the antiproliferative mechanism could be associated for the metabolism of glycine, serine and threonine, the metabolism of taurine and hypotaurine, glutathione metabolism, and the metabolism of nicotinic acid and nicotinamide. The significance of this study is that the anti-cancer activity of the modified N-9 derivatives of harmaline has been explored for the first time.
{"title":"Synthesis of harmaline N-9 derivatives and investigation of in vitro anticancer activity","authors":"Yongjian Liu , Hao Liu , Shuqi Li , Shaojun Yu , Heng Chen , Jinling Ge , Yonggang Liu","doi":"10.1016/j.bmcl.2025.130106","DOIUrl":"10.1016/j.bmcl.2025.130106","url":null,"abstract":"<div><div>Harmaline as a natural compound possessed a wide range of pharmacological activities. In this study, 22 novel harmaline-based derivatives were synthesized and screened for <em>in vitro</em> anti-proliferation activity against three cancer cell lines, HCT116, MCF7, and MGC803. The modification site was at the position N-9 of harmaline. The 24-hour IC<sub>50</sub> of compound <strong>HL22</strong> against HCT116, MGC803, and MCF7 was 3.84 ± 0.11 μM, 5.26 ± 0.46 μM, and 8.67 ± 0.13 μM, respectively. Compound <strong>HL22</strong> significantly reduced the migratory ability of MGC803 cells. The monoclonal formation of MGC803 cells was also inhibited by <strong>HL22</strong>. The <sup>1</sup>H NMR metabolomics analysis suggested that the antiproliferative mechanism could be associated for the metabolism of glycine, serine and threonine, the metabolism of taurine and hypotaurine, glutathione metabolism, and the metabolism of nicotinic acid and nicotinamide. The significance of this study is that the anti-cancer activity of the modified N-9 derivatives of harmaline has been explored for the first time.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130106"},"PeriodicalIF":2.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997192","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}
Current CML treatments often suffer from undesired side effects. Herein we report the computation-assisted optimization of Bcr-Abl/C-Src dual kinase inhibitor. We surmised the improved toxicity profile was achieved via disrupted ligand-target binding. The development of compound 21b highlighted our strategy with ∼1000-fold weaker Bcr-Abl/C-Src inhibition but same level of antiproliferation compared to that of bosutinib. We demonstrated that the introduction of acryloyl group could serves as a potential strategy to maintain antitumor activity.
{"title":"Disrupted target binding with acryloyl group as potential Bcr-Abl/C-Src dual kinase inhibitor optimization strategies with maintained antitumor activity","authors":"Ching Lin , Hsin-Yi Chiang , Grace Shiahuy Chen , Ji-Wang Chern , Chao-Wu Yu","doi":"10.1016/j.bmcl.2025.130105","DOIUrl":"10.1016/j.bmcl.2025.130105","url":null,"abstract":"<div><div>Current CML treatments often suffer from undesired side effects. Herein we report the computation-assisted optimization of Bcr-Abl/C-Src dual kinase inhibitor. We surmised the improved toxicity profile was achieved via disrupted ligand-target binding. The development of compound <strong>21b</strong> highlighted our strategy with ∼1000-fold weaker Bcr-Abl/C-Src inhibition but same level of antiproliferation compared to that of bosutinib. We demonstrated that the introduction of acryloyl group could serves as a potential strategy to maintain antitumor activity.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130105"},"PeriodicalIF":2.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997191","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}
Pub Date : 2025-01-09DOI: 10.1016/j.bmcl.2025.130096
Han Wang , Xiaolong Ma , Longkang Sun , Tongyu Bi , Weibo Yang
The discovery of novel anticancer agents remains a critical goal in medicinal chemistry, with innovative synthetic methodologies playing a pivotal role in advancing this field. Recent breakthroughs in CH activation reactions, cyclization reactions, multicomponent reactions, cross-coupling reactions, and photo- and electro-catalytic reactions have enabled the efficient synthesis of new molecular scaffolds exhibiting potent biological activities, including anticancer properties. These methodologies have facilitated the functionalization of natural products, the modification of bioactive molecules, and the generation of entirely new compounds, many of which demonstrate strong antitumor activity. This review summarizes the latest synthetic strategies employed over the past five years for discovering anticancer agents, focusing on their influence on drug design. Additionally, the role of new chemical reactions in expanding chemical space and overcoming challenges, such as drug resistance and selectivity, is highlighted, further emphasizing the importance of discovering novel reactions as a key trend in future drug development.
{"title":"Applications of innovative synthetic strategies in anticancer drug discovery: The driving force of new chemical reactions","authors":"Han Wang , Xiaolong Ma , Longkang Sun , Tongyu Bi , Weibo Yang","doi":"10.1016/j.bmcl.2025.130096","DOIUrl":"10.1016/j.bmcl.2025.130096","url":null,"abstract":"<div><div>The discovery of novel anticancer agents remains a critical goal in medicinal chemistry, with innovative synthetic methodologies playing a pivotal role in advancing this field. Recent breakthroughs in C<img>H activation reactions, cyclization reactions, multicomponent reactions, cross-coupling reactions, and photo- and electro-catalytic reactions have enabled the efficient synthesis of new molecular scaffolds exhibiting potent biological activities, including anticancer properties. These methodologies have facilitated the functionalization of natural products, the modification of bioactive molecules, and the generation of entirely new compounds, many of which demonstrate strong antitumor activity. This review summarizes the latest synthetic strategies employed over the past five years for discovering anticancer agents, focusing on their influence on drug design. Additionally, the role of new chemical reactions in expanding chemical space and overcoming challenges, such as drug resistance and selectivity, is highlighted, further emphasizing the importance of discovering novel reactions as a key trend in future drug development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130096"},"PeriodicalIF":2.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968977","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}
Pub Date : 2025-01-08DOI: 10.1016/j.bmcl.2025.130093
Srinivas Kantham , Hongbing Yu , Christophe R. Cantelli , Gang Chen , Caixia Ma , Jocelyn J. Chan , Hyungjun Yang , Kevin Tsai , Kristiana Lassueur , Bruce A. Vallance , Kevan Jacobson , Robert N. Young
Prostaglandin E2 receptor type 4 (EP4) agonists have been shown to be effective in treating experimental ulcerative colitis (UC) in animals and in human clinical trials, but their development has been impeded by unacceptable systemic side effects. In this study, a series of methylene phosphate prodrugs of a highly potent and selective prostaglandin EP4 receptor agonist were designed to target and remain localized in the gastrointestinal (GI) tract after either oral or rectal instillation. The prodrugs were designed to be converted to liberate active EP4 agonist by intestinal alkaline phosphate (IAP), a ubiquitous enzyme found at the luminal of the intestinal wall thus exposing the colon epithelial barrier while reducing systemic exposure to the active agonist. The prodrugs were shown to hydrolyze in plasma and after contact with GI tissue slices from ileum and colon. When optimized prodrugs were dosed orally, systemic peak exposure to the active agonist was not reduced, presumably due to IAP activity in the duodenum and small intestine. However, when dosed rectally, the prodrugs gave much reduced levels of EP4 agonist in the blood. An optimized prodrug was shown to be retained in the colon, when compared with free agonist after rectal administration in healthy mice and to be efficacious in a model of UC (the DSS mouse model). Plasma exposure to the active agonist was also much reduced in the mouse model of UC after 4 days of rectal dosing but after 7 days, one DSS mouse showed elevated systemic levels of the free agonist in the blood.
The concept of efficacy and intestinal retention of an EP4 agonist-methylene phosphate prodrug was proven for rectal instillation but in DSS treated mice, severe disease appears to compromise the epithelia barrier sufficiently to allow some absorption of the prodrug to occur. Thus, further optimization of these prodrugs is required before a candidate can be selected for development for treating severe ulcerative colitis.
{"title":"Development of novel GI-centric prostaglandin E2 receptor type 4 (EP4) agonist prodrugs as treatment for ulcerative colitis and other intestinal inflammatory diseases","authors":"Srinivas Kantham , Hongbing Yu , Christophe R. Cantelli , Gang Chen , Caixia Ma , Jocelyn J. Chan , Hyungjun Yang , Kevin Tsai , Kristiana Lassueur , Bruce A. Vallance , Kevan Jacobson , Robert N. Young","doi":"10.1016/j.bmcl.2025.130093","DOIUrl":"10.1016/j.bmcl.2025.130093","url":null,"abstract":"<div><div>Prostaglandin E<sub>2</sub> receptor type 4 (EP4) agonists have been shown to be effective in treating experimental ulcerative colitis (UC) in animals and in human clinical trials, but their development has been impeded by unacceptable systemic side effects. In this study, a series of methylene phosphate prodrugs of a highly potent and selective prostaglandin EP4 receptor agonist were designed to target and remain localized in the gastrointestinal (GI) tract after either oral or rectal instillation. The prodrugs were designed to be converted to liberate active EP4 agonist by intestinal alkaline phosphate (IAP), a ubiquitous enzyme found at the luminal of the intestinal wall thus exposing the colon epithelial barrier while reducing systemic exposure to the active agonist. The prodrugs were shown to hydrolyze in plasma and after contact with GI tissue slices from ileum and colon. When optimized prodrugs were dosed orally, systemic peak exposure to the active agonist was <em>not</em> reduced, presumably due to IAP activity in the duodenum and small intestine. However, when dosed rectally, the prodrugs gave much reduced levels of EP4 agonist in the blood. An optimized prodrug was shown to be retained in the colon, when compared with free agonist after rectal administration in healthy mice and to be efficacious in a model of UC (the DSS mouse model). Plasma exposure to the active agonist was also much reduced in the mouse model of UC after 4 days of rectal dosing but after 7 days, one DSS mouse showed elevated systemic levels of the free agonist in the blood.</div><div>The concept of efficacy and intestinal retention of an EP4 agonist-methylene phosphate prodrug was proven for rectal instillation but in DSS treated mice, severe disease appears to compromise the epithelia barrier sufficiently to allow some absorption of the prodrug to occur. Thus, further optimization of these prodrugs is required before a candidate can be selected for development for treating severe ulcerative colitis.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130093"},"PeriodicalIF":2.5,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963332","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}
Pub Date : 2025-01-06DOI: 10.1016/j.bmcl.2025.130094
Ren-Feng An , Kai-Tian Wu , Jie Pan , Wen-Jin Zhang , Hui-Ying Qin , Xiao-Rui Li , Wei Liu , Xue-Feng Huang
Novel lipophilic cationic derivatives including quaternary ammonium salt and triphenylphosphine series were designed and synthesized using diosgenin (1) and sarsasapogenin (2) as substrates to improve the cytotoxicity and selectivity. Most of the derivatives showed higher cytotoxicity against all cancer cell lines tested, compound 13 exhibited the most superior activity against A549 cells with an IC50 value of 0.95 μM, which was 34-fold of diosgenin. Preliminary cellular mechanism studies elucidated that compound 13 might arrest cell cycle at G0/G1 phase, trigger apoptosis via up-regulating the expression of Bax, down-regulating the expression of Bcl-2 and caspase-3, and induce an increase in the generation of intracellular reactive oxygen species (ROS) in A549 cells. In addition, molecular docking analysis revealed that compound 13 could occupy the active site of p38α-MAPK well and interact to the surrounding amino acids by salt bridge and conjugation. These results suggested that compound 13 had the potential to serve as an antitumor lead agent, probably exert antitumor effect through mitochondrial pathway and p38α MAPK pathway.
{"title":"Design, synthesis and cytotoxic activity of novel lipophilic cationic derivatives of diosgenin and sarsasapogenin","authors":"Ren-Feng An , Kai-Tian Wu , Jie Pan , Wen-Jin Zhang , Hui-Ying Qin , Xiao-Rui Li , Wei Liu , Xue-Feng Huang","doi":"10.1016/j.bmcl.2025.130094","DOIUrl":"10.1016/j.bmcl.2025.130094","url":null,"abstract":"<div><div>Novel lipophilic cationic derivatives including quaternary ammonium salt and triphenylphosphine series were designed and synthesized using diosgenin (<strong>1</strong>) and sarsasapogenin (<strong>2</strong>) as substrates to improve the cytotoxicity and selectivity. Most of the derivatives showed higher cytotoxicity against all cancer cell lines tested, compound <strong>13</strong> exhibited the most superior activity against A549 cells with an IC<sub>50</sub> value of 0.95 μM, which was 34-fold of diosgenin. Preliminary cellular mechanism studies elucidated that compound <strong>13</strong> might arrest cell cycle at G0/G1 phase, trigger apoptosis via up-regulating the expression of Bax, down-regulating the expression of Bcl-2 and caspase-3, and induce an increase in the generation of intracellular reactive oxygen species (ROS) in A549 cells. In addition, molecular docking analysis revealed that compound <strong>13</strong> could occupy the active site of p38α-MAPK well and interact to the surrounding amino acids by salt bridge and conjugation. These results suggested that compound <strong>13</strong> had the potential to serve as an antitumor lead agent, probably exert antitumor effect through mitochondrial pathway and p38α MAPK pathway.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130094"},"PeriodicalIF":2.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941928","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}
Pub Date : 2025-01-06DOI: 10.1016/j.bmcl.2025.130095
George Procopiou, Paul J.M. Jackson, Paolo Andriollo, Md. Mahbub Hasan, Nicolas Veillard, Khondaker Miraz Rahman, David E. Thurston
The pyrrolobenzodiazepines (PBDs) represent a major class of sequence-selective DNA-alkylating molecules, one example of which, in its dimeric DNA-cross-linking form, is employed as the payload in the anticancer Antibody Drug Conjugate (ADC) loncastuximab tesirine-lpyl. To date, PBD analogues have been produced with substituents at every position of the tricyclic skeleton except the C1-position. We report here the first synthesis of a C1-subsitituted PBD monomer and dimer, both of which possess DNA-binding activity and cytotoxicity in a cancer cell line.
{"title":"Synthesis of novel pyrrolobenzodiazepine (PBD) C1-substituted monomers and dimers with DNA-binding activity and cytotoxicity","authors":"George Procopiou, Paul J.M. Jackson, Paolo Andriollo, Md. Mahbub Hasan, Nicolas Veillard, Khondaker Miraz Rahman, David E. Thurston","doi":"10.1016/j.bmcl.2025.130095","DOIUrl":"10.1016/j.bmcl.2025.130095","url":null,"abstract":"<div><div>The pyrrolobenzodiazepines (PBDs) represent a major class of sequence-selective DNA-alkylating molecules, one example of which, in its dimeric DNA-cross-linking form, is employed as the payload in the anticancer Antibody Drug Conjugate (ADC) loncastuximab tesirine-lpyl. To date, PBD analogues have been produced with substituents at every position of the tricyclic skeleton except the C1-position. We report here the first synthesis of a C1-subsitituted PBD monomer and dimer, both of which possess DNA-binding activity and cytotoxicity in a cancer cell line.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130095"},"PeriodicalIF":2.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941936","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}
Pub Date : 2025-01-06DOI: 10.1016/j.bmcl.2025.130092
Dilep K. Sigalapalli , Sophia Groustra , Michael K. Fenwick , Rachael Zigweid , Matthew A. Hulverson , Eric Owsley , Monique Khim , Sayaka Shibata , Wesley C. Van Voorhis , Bart L. Staker , Erkang Fan
Cryptosporidium parvum is a protozoan parasite that causes severe diarrheal illness in children and each year nearly 50,000 children under age 5 die due to the disease. Despite tremendous research efforts, there remains a lack of effective therapies and vaccines. Novel inhibitors against N-myristoyltransferase of C. parvum (CpNMT) are potential starting points towards the development of effective therapies. In quest of promising selective CpNMT inhibitors, structure guided modifications of compound 1 (2-chloro-5-(ethyl-phenyl-sulfamoyl)-N-[2-(2-oxo-pyrrolidin-1-yl)-phenyl]-benzamide) were performed. The resulting compounds were evaluated for selective inhibition of CpNMT over the host enzyme HsNMT1. Compounds 11e and 11f exhibited good inhibition, with IC50 values of 2.5 and 2.8 μM, respectively. While 11e was slightly more selective towards CpNMT over HsNMT1 (∼5-fold), compound 11f showed >40-fold selectivity, validating our structure-based design approaches. Compounds 11e and 11f were also found to be efficacious against C. parvum growth, with EC50 values of 6.9 and 16.4 μM, respectively.
{"title":"Structure guided modification of 2-chloro-5-(ethyl-phenyl-sulfamoyl)-N-[2-(2-oxo-pyrrolidin-1-yl)-phenyl]-benzamide to afford selective inhibitors of Cryptosporidium parvum N-myristoyltransferase","authors":"Dilep K. Sigalapalli , Sophia Groustra , Michael K. Fenwick , Rachael Zigweid , Matthew A. Hulverson , Eric Owsley , Monique Khim , Sayaka Shibata , Wesley C. Van Voorhis , Bart L. Staker , Erkang Fan","doi":"10.1016/j.bmcl.2025.130092","DOIUrl":"10.1016/j.bmcl.2025.130092","url":null,"abstract":"<div><div><em>Cryptosporidium parvum</em> is a protozoan parasite that causes severe diarrheal illness in children and each year nearly 50,000 children under age 5 die due to the disease. Despite tremendous research efforts, there remains a lack of effective therapies and vaccines. Novel inhibitors against <em>N</em>-myristoyltransferase of <em>C. parvum</em> (<em>Cp</em>NMT) are potential starting points towards the development of effective therapies. In quest of promising selective <em>Cp</em>NMT inhibitors, structure guided modifications of compound <strong>1</strong> (2-chloro-5-(ethyl-phenyl-sulfamoyl)-<em>N</em>-[2-(2-oxo-pyrrolidin-1-yl)-phenyl]-benzamide) were performed. The resulting compounds were evaluated for selective inhibition of <em>Cp</em>NMT over the host enzyme <em>Hs</em>NMT1. Compounds <strong>11e</strong> and <strong>11f</strong> exhibited good inhibition, with IC<sub>50</sub> values of 2.5 and 2.8 μM, respectively. While <strong>11e</strong> was slightly more selective towards <em>Cp</em>NMT over <em>Hs</em>NMT1 (∼5-fold), compound <strong>11f</strong> showed >40-fold selectivity, validating our structure-based design approaches. Compounds <strong>11e</strong> and <strong>11f</strong> were also found to be efficacious against <em>C. parvum</em> growth, with EC<sub>50</sub> values of 6.9 and 16.4 μM, respectively.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130092"},"PeriodicalIF":2.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941930","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}
Pub Date : 2024-12-28DOI: 10.1016/j.bmcl.2024.130090
Yong Wang , He Wu , Guangguang Yang, Karuppu Selvaraj, Gang Chen
A novel and new type of tetracycline with a different mechanism of action was necessary, due to the drug resistance of existing tetracyclines. This study outlines the synthesis and antibacterial evaluation of anhydro-tetracycline derivatives, which are unconventional tetracyclines with unique mechanisms of action. These derivatives include C4-NH2, C4-OH, and C9-substituted variations, and our synthetic approach focuses on semi-synthesis using natural tetracyclines as the starting precursors. Several derivatives of C4-NH2, C4-OH, and C9-substituted compounds have demonstrated effective antibiotic activity against both Gram-positive and Gram-negative bacteria.
{"title":"Synthesis and antibacterial study of anhydrotetracycline derivatives","authors":"Yong Wang , He Wu , Guangguang Yang, Karuppu Selvaraj, Gang Chen","doi":"10.1016/j.bmcl.2024.130090","DOIUrl":"10.1016/j.bmcl.2024.130090","url":null,"abstract":"<div><div>A novel and new type of tetracycline with a different mechanism of action was necessary, due to the drug resistance of existing tetracyclines. This study outlines the synthesis and antibacterial evaluation of anhydro-tetracycline derivatives, which are unconventional tetracyclines with unique mechanisms of action. These derivatives include C4-NH<sub>2</sub>, C4-OH, and C9-substituted variations, and our synthetic approach focuses on semi-synthesis using natural tetracyclines as the starting precursors. Several derivatives of C4-NH<sub>2</sub>, C4-OH, and C9-substituted compounds have demonstrated effective antibiotic activity against both Gram-positive and Gram-negative bacteria.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"118 ","pages":"Article 130090"},"PeriodicalIF":2.5,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906419","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}
Pub Date : 2024-12-28DOI: 10.1016/j.bmcl.2024.130088
Alize Hoepfner , Anél Petzer , Jacobus P. Petzer , Theunis T. Cloete
This study aimed to design and synthesise novel guaiacol–chalcone and nitroguaiacol–chalcone derivatives and determine their in vitro antibacterial activity against five pathogens viz. Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella aerogenes. The checkerboard assay was used to explore potential synergism with existing antibiotics to shed light on a possible antibacterial mechanism of action. A pharmacophore model was constructed to identify key chemical entities the derivatives had which are necessary for activity. The pharmacophore model was validated utilising the enrichment factor (EF10 %) and the area under the receiver operating characteristic (ROC-AUC) curve metrics. The most active derivative was nitroguaiacol–chalcone derivative 2c (8 µg/ml), with activity against susceptible and methicillin-resistant strains of S. aureus. The checkerboard assay showed that one nitroguaiacol–chalcone derivative (2a) had a synergistic effect when combined with chloramphenicol (FICImin: 0.45 ± 0.09), implying its antibacterial mechanism of action might also target bacterial protein synthesis. Active guaiacol–chalcone and nitroguaiacol–chalcone derivatives were accurately identified by the common feature pharmacophore model (max. fit: 4, rank score: 52.34). The leading pharmacophore model, i.e., hypothesis 1 (EF10 %: 8, ROC-AUC: 0.95 ± 0.02) indicated that four features are important for antibacterial activity i.e., a ring aromatic, a hydrophobic moiety and two hydrogen bond acceptors.
{"title":"Guaiacol–chalcone and nitroguaiacol–chalcone derivatives: In vitro and in silico antibacterial evaluation","authors":"Alize Hoepfner , Anél Petzer , Jacobus P. Petzer , Theunis T. Cloete","doi":"10.1016/j.bmcl.2024.130088","DOIUrl":"10.1016/j.bmcl.2024.130088","url":null,"abstract":"<div><div>This study aimed to design and synthesise novel guaiacol–chalcone and nitroguaiacol–chalcone derivatives and determine their <em>in vitro</em> antibacterial activity against five pathogens <em>viz. Staphylococcus aureus, Klebsiella pneumoniae</em>, <em>Acinetobacter baumannii, Pseudomonas aeruginosa</em> and <em>Klebsiella aerogenes.</em> The checkerboard assay was used to explore potential synergism with existing antibiotics to shed light on a possible antibacterial mechanism of action. A pharmacophore model was constructed to identify key chemical entities the derivatives had which are necessary for activity. The pharmacophore model was validated utilising the enrichment factor (EF<sup>10 %</sup>) and the area under the receiver operating characteristic (ROC-AUC) curve metrics. The most active derivative was nitroguaiacol–chalcone derivative <strong>2c</strong> (8 µg/ml), with activity against susceptible and methicillin-resistant strains of <em>S. aureus</em>. The checkerboard assay showed that one nitroguaiacol–chalcone derivative (<strong>2a</strong>) had a synergistic effect when combined with chloramphenicol (FICI<sub>min</sub>: 0.45 ± 0.09), implying its antibacterial mechanism of action might also target bacterial protein synthesis. Active guaiacol–chalcone and nitroguaiacol–chalcone derivatives were accurately identified by the common feature pharmacophore model (max. fit: 4, rank score: 52.34). The leading pharmacophore model, <em>i.e</em>., hypothesis 1 (EF<sup>10 %</sup>: 8, ROC-AUC: 0.95 ± 0.02) indicated that four features are important for antibacterial activity <em>i.e</em>., a ring aromatic, a hydrophobic moiety and two hydrogen bond acceptors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"118 ","pages":"Article 130088"},"PeriodicalIF":2.5,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143130658","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}
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