Pub Date : 2026-06-01Epub Date: 2026-02-05DOI: 10.1016/j.bmcl.2026.130573
Michael Burton , Chris Cains , Danielle J.C. Fenwick , Amy Foster , Clair L. Preece , Sidrah Saleem , Stephen P. Stanforth , Hayley J. Turner , Graeme Turnbull , John D. Perry
We describe the synthesis and evaluation of six halogenated nitrophenyl glycosides for detection of β-galactosidase and β-glucuronidase enzyme activity among Enterobacterales (“coliforms”) and Escherichia coli, respectively. These were evaluated alongside the established substrates; o-nitrophenyl-β-D-galactopyranoside (ONPG), p-nitrophenyl-β-D-galactopyranoside (PNPG) and p-nitrophenyl-β-D-glucuronide (PNP-GUR). The evaluation was performed using 30 isolates of Enterobacterales including 19 isolates of E. coli. Hydrolysis of 2-fluoro-p-nitrophenyl-β-D-galactopyranoside (2-fluoro-PNPG) yielded a significantly stronger yellow coloration after a six-hour incubation period compared to hydrolysis of ONPG and PNPG, potentially allowing for a more sensitive detection of Enterobacterales. Similarly, hydrolysis of the novel substrate 2-fluoro-p-nitrophenyl-β-D-glucuronide sodium salt (2-fluoro-PNP-GUR Na) by producers of β-glucuronidase also yielded a significantly stronger yellow colouration, potentially allowing for a more sensitive detection of E. coli. The yellow chromophore 2-fluoro-PNP retained high colour intensity at reduced pH when compared to o-nitrophenol and p-nitrophenol. Both substrates potentially offer enhanced sensitivity for the detection of Enterobacterales and E. coli in environmental samples as markers of faecal pollution.
本文报道了六种卤化硝基苯苷的合成和评价，分别用于肠杆菌（“大肠菌群”）和大肠杆菌中β-半乳糖苷酶和β-葡萄糖醛酸酶活性的检测。这些与确定的底物一起进行评估；邻硝基苯-β- d -半乳糖苷（ONPG）、对硝基苯-β- d -半乳糖苷（PNPG）和对硝基苯-β- d -葡萄糖醛酸（PNP-GUR）。对30株肠杆菌进行评价，其中包括19株大肠杆菌。与ONPG和PNPG的水解相比，2-fluoro-p-nitrophenyl-β-D-galactopyranoside （2-fluoro-PNPG）的水解在6小时的孵育期后产生了明显更强的黄色，可能允许更敏感的肠杆菌检测。同样，新型底物2-氟-对硝基苯-β- d -葡萄糖醛酸钠盐（2-氟- pnp - gur Na）由β-葡萄糖醛酸酶的生产者水解也产生了明显更强的黄色，可能允许更灵敏的大肠杆菌检测。与邻硝基酚和对硝基酚相比，黄色发色团2-氟- pnp在降低的pH下保持较高的显色强度。这两种底物都有可能提高环境样品中肠杆菌和大肠杆菌的检测灵敏度，作为粪便污染的标志物。
{"title":"Glycosides of fluorinated p-nitrophenol offer improved sensitivity for detection of β-galactosidase and β-glucuronidase in Escherichia coli and other Enterobacterales","authors":"Michael Burton , Chris Cains , Danielle J.C. Fenwick , Amy Foster , Clair L. Preece , Sidrah Saleem , Stephen P. Stanforth , Hayley J. Turner , Graeme Turnbull , John D. Perry","doi":"10.1016/j.bmcl.2026.130573","DOIUrl":"10.1016/j.bmcl.2026.130573","url":null,"abstract":"<div><div>We describe the synthesis and evaluation of six halogenated nitrophenyl glycosides for detection of β-galactosidase and β-glucuronidase enzyme activity among Enterobacterales (“coliforms”) and <em>Escherichia coli</em>, respectively. These were evaluated alongside the established substrates; <em>o</em>-nitrophenyl-β-D-galactopyranoside (ONPG), <em>p</em>-nitrophenyl-β-D-galactopyranoside (PNPG) and <em>p</em>-nitrophenyl-β-D-glucuronide (PNP-GUR). The evaluation was performed using 30 isolates of Enterobacterales including 19 isolates of <em>E. coli</em>. Hydrolysis of 2-fluoro-<em>p</em>-nitrophenyl-β-D-galactopyranoside (2-fluoro-PNPG) yielded a significantly stronger yellow coloration after a six-hour incubation period compared to hydrolysis of ONPG and PNPG, potentially allowing for a more sensitive detection of Enterobacterales. Similarly, hydrolysis of the novel substrate 2-fluoro-<em>p</em>-nitrophenyl-β-D-glucuronide sodium salt (2-fluoro-PNP-GUR Na) by producers of β-glucuronidase also yielded a significantly stronger yellow colouration, potentially allowing for a more sensitive detection of <em>E. coli</em>. The yellow chromophore 2-fluoro-PNP retained high colour intensity at reduced pH when compared to <em>o</em>-nitrophenol and <em>p</em>-nitrophenol. Both substrates potentially offer enhanced sensitivity for the detection of Enterobacterales and <em>E. coli</em> in environmental samples as markers of faecal pollution.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130573"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146136933","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 : 2026-06-01Epub Date: 2026-02-02DOI: 10.1016/j.bmcl.2026.130570
Die Sun , Meiyan Jiang , YongQuan Wei , Lisheng Wang
Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality and disease burden worldwide, and its clinical management continues to face substantial challenges. Sorafenib, a widely used systemic therapy for advanced HCC, frequently develops acquired resistance upon long-term treatment, in part due to the overexpression of anti-apoptotic Bcl-2 family proteins. Herein, guided by the structural features of Sorafenib, the selective Bcl-2 inhibitor Venetoclax, and the selective Mcl-1 inhibitor AZD5991, we designed and synthesized a series of novel Sophocarpine-derived analogues bearing a pyridylethyl moiety via a molecular-hybridization strategy. Molecular docking suggested a favorable binding mode, in which the resulting scaffold could occupy the hydrophobic binding pockets of both Bcl-2 and Mcl-1 and engage key residues through hydrogen-bond interactions. In vitro antiproliferative screening (MTT assay) against three human HCC cell lines (Huh-7, MHCC-97H, and HepG2) showed that most compounds exhibited moderate to good activity. Notably, compound S6 emerged as the most potent analogue, with IC₅₀ values of 9.13 ± 0.29 μM (Huh-7), 6.76 ± 0.06 μM (MHCC-97H), and 15.9 ± 0.98 μM (HepG2). Mechanistic studies demonstrated that S6 markedly suppressed proliferation and migration of MHCC-97H cells, induced G1-phase arrest, and promoted apoptosis. Western blot analysis revealed that S6 downregulated anti-apoptotic proteins Bcl-2 and Mcl-1, induced mitochondrial membrane potential (ΔΨm) depolarization, and activated the caspase-dependent apoptotic cascade, as evidenced by caspase-3 activation and PARP1 cleavage. In parallel, a 3D-QSAR (CoMFA) model was constructed to rationalize the structure–activity relationship and to inform further lead optimization. Collectively, these findings identify S6 as a promising Sophocarpine derivative with a putative dual Bcl-2/Mcl-1 targeting profile, with significant anti-HCC activity and potential for preclinical development.
{"title":"Discovery of novel sophocarpine derivatives as potential dual Bcl-2 and Mcl-1 inhibitors: design, synthesis and anti-hepatocellular carcinoma evaluation","authors":"Die Sun , Meiyan Jiang , YongQuan Wei , Lisheng Wang","doi":"10.1016/j.bmcl.2026.130570","DOIUrl":"10.1016/j.bmcl.2026.130570","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality and disease burden worldwide, and its clinical management continues to face substantial challenges. Sorafenib, a widely used systemic therapy for advanced HCC, frequently develops acquired resistance upon long-term treatment, in part due to the overexpression of anti-apoptotic Bcl-2 family proteins. Herein, guided by the structural features of Sorafenib, the selective Bcl-2 inhibitor Venetoclax, and the selective Mcl-1 inhibitor AZD5991, we designed and synthesized a series of novel Sophocarpine-derived analogues bearing a pyridylethyl moiety via a molecular-hybridization strategy. Molecular docking suggested a favorable binding mode, in which the resulting scaffold could occupy the hydrophobic binding pockets of both Bcl-2 and Mcl-1 and engage key residues through hydrogen-bond interactions. In vitro antiproliferative screening (MTT assay) against three human HCC cell lines (Huh-7, MHCC-97H, and HepG2) showed that most compounds exhibited moderate to good activity. Notably, compound S6 emerged as the most potent analogue, with IC₅₀ values of 9.13 ± 0.29 μM (Huh-7), 6.76 ± 0.06 μM (MHCC-97H), and 15.9 ± 0.98 μM (HepG2). Mechanistic studies demonstrated that S6 markedly suppressed proliferation and migration of MHCC-97H cells, induced G1-phase arrest, and promoted apoptosis. Western blot analysis revealed that S6 downregulated anti-apoptotic proteins Bcl-2 and Mcl-1, induced mitochondrial membrane potential (ΔΨm) depolarization, and activated the caspase-dependent apoptotic cascade, as evidenced by caspase-3 activation and PARP1 cleavage. In parallel, a 3D-QSAR (CoMFA) model was constructed to rationalize the structure–activity relationship and to inform further lead optimization. Collectively, these findings identify S6 as a promising Sophocarpine derivative with a putative dual Bcl-2/Mcl-1 targeting profile, with significant anti-HCC activity and potential for preclinical development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130570"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117097","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 : 2026-05-01Epub Date: 2026-01-27DOI: 10.1016/j.bmcl.2026.130564
Jonah Fine , John B. Perkins , Vincent Gullo , Ryan D. Cohen , Jun Lu , Sheo B. Singh
Kibdelomycin and kibdelomycin A are antibiotics biosynthesized by Kibdelosporangium banguiense CA-240109. Kibdelomycin demonstrates broad-spectrum activity, exhibiting significant activity against antibiotic-resistant Gram-positive bacteria. These compounds inhibit DNA GyrB and ParE through a distinct U-shaped multi-contact binding mechanism and do not display cross-resistance with established antibiotics. To investigate structure-activity relationships, various methodologies were employed to identify new congeners, including the implementation of repeat batch fermentation. This study presents the discovery, isolation, structural elucidation, and antibacterial assessment of two mono des-chloro congeners of kibdelomycin A produced via repeat batch fermentation. The newly discovered compounds displayed inhibitory effects on bacterial growth in Staphylococcus aureus and Escherichia coli, with minimum inhibitory concentrations (MIC) ranging from 16 to 64 μg/mL. The MIC values for E. coli are comparable to kibdelomycin, whereas for S. aureus the MIC is 64 times less potent than that of kibdelomycin. AI-assisted docking studies involving DNA gyrase B enzymes provide reasonable support for varying activities of the congeners.
{"title":"Discovery and antibacterial activity of kibdelomycin A-1 and A-2 from repeat batch fermentation of Kibdelosporangium banguiesne","authors":"Jonah Fine , John B. Perkins , Vincent Gullo , Ryan D. Cohen , Jun Lu , Sheo B. Singh","doi":"10.1016/j.bmcl.2026.130564","DOIUrl":"10.1016/j.bmcl.2026.130564","url":null,"abstract":"<div><div>Kibdelomycin and kibdelomycin A are antibiotics biosynthesized by <em>Kibdelosporangium banguiense</em> CA-240109. Kibdelomycin demonstrates broad-spectrum activity, exhibiting significant activity against antibiotic-resistant Gram-positive bacteria. These compounds inhibit DNA GyrB and ParE through a distinct U-shaped multi-contact binding mechanism and do not display cross-resistance with established antibiotics. To investigate structure-activity relationships, various methodologies were employed to identify new congeners, including the implementation of repeat batch fermentation. This study presents the discovery, isolation, structural elucidation, and antibacterial assessment of two mono des-chloro congeners of kibdelomycin A produced via repeat batch fermentation. The newly discovered compounds displayed inhibitory effects on bacterial growth in <em>Staphylococcus aureus</em> and <em>Escherichia coli</em>, with minimum inhibitory concentrations (MIC) ranging from 16 to 64 μg/mL. The MIC values for <em>E. coli</em> are comparable to kibdelomycin, whereas for <em>S. aureus</em> the MIC is 64 times less potent than that of kibdelomycin. AI-assisted docking studies involving DNA gyrase B enzymes provide reasonable support for varying activities of the congeners.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130564"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075044","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 : 2026-05-01Epub Date: 2026-01-13DOI: 10.1016/j.bmcl.2026.130541
Otília Höeller Guarnieri , Mariza Gabriela Faleiro de Moura Lodi Cruz , Daniela de Melo Resende , Carime L.M. Pontes , Igor Vivan Roberto , Luiza Schmidt D'Agostini , Bertha Chithambo , Niklas Ehlenz , Xavier Siwe-Noundou , Rui W.M. Krause , Maique W. Biavatti , Jaya R. Lakkakula , Nilesh Shirish Wagh , Mario Steindel , Till Opatz , Silvane M. Fonseca Murta , Louis P. Sandjo
Trypanosoma cruzi and Leishmania spp. are the protozoan parasites responsible for Chagas disease and leishmaniasis. The treatment of these neglected diseases relies on repurposed drugs and faces several challenges including high toxicity, and the emergence of resistant strain. Therefore, there is a constant demand for promising antiparasitic agents. The present work aimed to investigate seventeen prepared N1,N4-bisbenzylbutane-1,4-diamines against recombinant T. cruzi and L. infantum as well as their inhibitory effects against the T. cruzi recombinant trypanothione reductase (TcTR). N1,N4-bis(4-chlorobenzyl)butane-1,4-diamine showed significant trypanocidal activity with an IC50 of 6.0 ± 0.9 μM with a selectivity index of 4.3. This compound was more active than the positive control, benznidazole (IC50 of 14.6). It moderately inhibited TcTR with an IC50 of 55.6 ± 18.6 μM. N1,N4-bis(4-chlorobenzyl)butane-1,4-diamine also inhibited L. infantum with an IC50 of 19.3 ± 1.2 μM (SI of 3.4). N1,N4-bis((E)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine exhibited potent inhibitory effect against T. cruzi (2.4 ± 0.3 μM); However, it also turned out to be highly cytotoxic to the L929 fibroblast cell line. Its inhibitory effect against TcTR was also significant, with an IC50 of 3.9 ± 1.9 μM. Alongside the two diamines, nine other synthesized derivatives displayed antitrypanosomal activity with IC50 ranging from 8 to 150 μM. Concerning the leishmanicidal effects, all tested compounds were moderately active. Moreover, during in silico studies of the active compounds using TcTR (PDB ID 4NEW), N1,N4-bis((E)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine emerged as the most promising candidate, displaying both strong binding affinity and significant biological activity.
{"title":"Inhibitory effects against Trypanosoma cruzi, Leishmania infantum and trypanothione reductase of N1,N4-bisbenzylbutane-1,4-diamines","authors":"Otília Höeller Guarnieri , Mariza Gabriela Faleiro de Moura Lodi Cruz , Daniela de Melo Resende , Carime L.M. Pontes , Igor Vivan Roberto , Luiza Schmidt D'Agostini , Bertha Chithambo , Niklas Ehlenz , Xavier Siwe-Noundou , Rui W.M. Krause , Maique W. Biavatti , Jaya R. Lakkakula , Nilesh Shirish Wagh , Mario Steindel , Till Opatz , Silvane M. Fonseca Murta , Louis P. Sandjo","doi":"10.1016/j.bmcl.2026.130541","DOIUrl":"10.1016/j.bmcl.2026.130541","url":null,"abstract":"<div><div><em>Trypanosoma cruzi</em> and <em>Leishmania</em> spp. are the protozoan parasites responsible for Chagas disease and leishmaniasis. The treatment of these neglected diseases relies on repurposed drugs and faces several challenges including high toxicity, and the emergence of resistant strain. Therefore, there is a constant demand for promising antiparasitic agents. The present work aimed to investigate seventeen prepared <em>N</em><sup>1</sup>,<em>N</em><sup>4</sup>-bisbenzylbutane-1,4-diamines against recombinant <em>T. cruzi</em> and <em>L. infantum</em> as well as their inhibitory effects against the <em>T. cruzi</em> recombinant trypanothione reductase (TcTR). <em>N</em><sup>1</sup>,<em>N</em><sup>4</sup>-bis(4-chlorobenzyl)butane-1,4-diamine showed significant trypanocidal activity with an IC<sub>50</sub> of 6.0 ± 0.9 μM with a selectivity index of 4.3. This compound was more active than the positive control, benznidazole (IC<sub>50</sub> of 14.6). It moderately inhibited TcTR with an IC<sub>50</sub> of 55.6 ± 18.6 μM. <em>N</em><sup>1</sup>,<em>N</em><sup>4</sup>-bis(4-chlorobenzyl)butane-1,4-diamine also inhibited <em>L. infantum</em> with an IC<sub>50</sub> of 19.3 ± 1.2 μM (SI of 3.4). <em>N</em><sup>1</sup>,<em>N</em><sup>4</sup>-bis((<em>E</em>)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine exhibited potent inhibitory effect against <em>T. cruzi</em> (2.4 ± 0.3 μM); However, it also turned out to be highly cytotoxic to the L929 fibroblast cell line. Its inhibitory effect against TcTR was also significant, with an IC<sub>50</sub> of 3.9 ± 1.9 μM. Alongside the two diamines, nine other synthesized derivatives displayed antitrypanosomal activity with IC<sub>50</sub> ranging from 8 to 150 μM. Concerning the leishmanicidal effects, all tested compounds were moderately active. Moreover, during <em>in silico</em> studies of the active compounds using TcTR (PDB ID <span><span>4NEW</span><svg><path></path></svg></span>), <em>N</em><sup>1</sup>,<em>N</em><sup>4</sup>-bis((<em>E</em>)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine emerged as the most promising candidate, displaying both strong binding affinity and significant biological activity.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130541"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145963073","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 : 2026-05-01Epub Date: 2026-01-08DOI: 10.1016/j.bmcl.2026.130537
Xin-Yu Huang , Xiao-He Liu , Na Xu , Ting Peng , Xi-Yuan Hu , Min Su , Zhi-Yong Luo , Su-You Liu , Da-You Ma
Spinosad, a natural-origin pesticide, is extensively employed in agriculture and public health. Its primary component, Spinosyn A, has also attracted considerable interest due to its antiproliferative activity against various cancer cell lines. While ASS1 has emerged as a promising target for anticancer therapy, the development of ASS1 activators remains a largely unexplored research area. Previous work by our group identified Spinosyn A as the first-in-class ASS1 activator. In this study, to further elucidate the structure–activity relationship (SAR) of Spinosyn A as both an ASS1 activator and a tumor inhibitor, we introduced structural modifications at the nitrogen atom, yielding 25 novel derivatives. Biological evaluation revealed a strong correlation between the antitumor effects of these compounds and their ability to activate ASS1. For optimal activity, the introduction of a suitable aminoalkyl side chain at the nitrogen atom of dimethyl-Spinosyn A proved to be essential.
{"title":"Spinosyn A derivatives as ASS1 activators and tumor inhibitors","authors":"Xin-Yu Huang , Xiao-He Liu , Na Xu , Ting Peng , Xi-Yuan Hu , Min Su , Zhi-Yong Luo , Su-You Liu , Da-You Ma","doi":"10.1016/j.bmcl.2026.130537","DOIUrl":"10.1016/j.bmcl.2026.130537","url":null,"abstract":"<div><div>Spinosad, a natural-origin pesticide, is extensively employed in agriculture and public health. Its primary component, Spinosyn A, has also attracted considerable interest due to its antiproliferative activity against various cancer cell lines. While ASS1 has emerged as a promising target for anticancer therapy, the development of ASS1 activators remains a largely unexplored research area. Previous work by our group identified Spinosyn A as the first-in-class ASS1 activator. In this study, to further elucidate the structure–activity relationship (SAR) of Spinosyn A as both an ASS1 activator and a tumor inhibitor, we introduced structural modifications at the nitrogen atom, yielding 25 novel derivatives. Biological evaluation revealed a strong correlation between the antitumor effects of these compounds and their ability to activate ASS1. For optimal activity, the introduction of a suitable aminoalkyl side chain at the nitrogen atom of dimethyl-Spinosyn A proved to be essential.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130537"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948233","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 : 2026-05-01Epub Date: 2026-01-21DOI: 10.1016/j.bmcl.2026.130559
Paula Pérez-Ramos , Rogelio Gomez-Escobedo , Benjamín Nogueda-Torres , Adriana Moreno-Rodriguez , Alejandro Llamedo , Humberto Rodríguez-Solla , Sara M. Soto , Gildardo Rivera , Raquel G. Soengas
Chagas disease or American trypanosomiasis remains a serious public health concern with unsatisfactory treatment outcomes. The serious problems with the efficacy and toxicity of the drugs currently used to treat Chagas disease, along with the emergence of resistant strains, have made the development of new chemotherapy strategies a priority. In this work, fourteen (C^S)-cyclometallated gold(III) complexes were evaluated as potential trypanocidal agents. All the tested compounds had better trypanocidal activity against trypomastigotes than the reference drugs, with five complexes presenting an SI above ten for both strains, and two complexes displaying a SI value >200 for the NINOA strain. Among them, complex 6b was identified as a highly selective agent against T. cruzi amastigotes of the NINOA strain. Furthermore, cytotoxicity to mouse macrophage cells is very low for this compound, resulting in a better selectivity index than that of reference drugs Bnz and Nfx. These results suggest the potential of (C^S)-cyclometallated gold (III) complexes as promising antiparasitic drug candidates.
{"title":"Organometallic gold(III) (C^S)-cyclometallated complexes as candidates to new drugs against chagas disease","authors":"Paula Pérez-Ramos , Rogelio Gomez-Escobedo , Benjamín Nogueda-Torres , Adriana Moreno-Rodriguez , Alejandro Llamedo , Humberto Rodríguez-Solla , Sara M. Soto , Gildardo Rivera , Raquel G. Soengas","doi":"10.1016/j.bmcl.2026.130559","DOIUrl":"10.1016/j.bmcl.2026.130559","url":null,"abstract":"<div><div>Chagas disease or American trypanosomiasis remains a serious public health concern with unsatisfactory treatment outcomes. The serious problems with the efficacy and toxicity of the drugs currently used to treat Chagas disease, along with the emergence of resistant strains, have made the development of new chemotherapy strategies a priority. In this work, fourteen (C^S)-cyclometallated gold(III) complexes were evaluated as potential trypanocidal agents. All the tested compounds had better trypanocidal activity against trypomastigotes than the reference drugs, with five complexes presenting an SI above ten for both strains, and two complexes displaying a SI value >200 for the NINOA strain. Among them, complex <strong>6b</strong> was identified as a highly selective agent against <em>T. cruzi</em> amastigotes of the NINOA strain. Furthermore, cytotoxicity to mouse macrophage cells is very low for this compound, resulting in a better selectivity index than that of reference drugs Bnz and Nfx. These results suggest the potential of (C^S)-cyclometallated gold (III) complexes as promising antiparasitic drug candidates.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130559"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036240","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 : 2026-05-01Epub Date: 2026-01-21DOI: 10.1016/j.bmcl.2026.130558
Qingsu Cheng
Cancer remains one of the leading causes of mortality worldwide. As a result, bioactive compounds derived from herbal medicines have gained increasing attention in cancer research. Ardicrenin, extracted from Ardisia crenata, has been evaluated for its ability to suppress the growth of MG-63 cells. Remarkably, its inhibitory effect on MG-63 cell proliferation is comparable to that of Taxol. Unlike Taxol, which induces apoptosis by stabilizing microtubules, ardicrenin regulates cell proliferation and death through the integrin signaling pathway. These findings highlight ardicrenin as a promising candidate for anti-tumor drug development.
{"title":"Anti-tumor effect of ardicrenin against MG63 osteosarcoma cells","authors":"Qingsu Cheng","doi":"10.1016/j.bmcl.2026.130558","DOIUrl":"10.1016/j.bmcl.2026.130558","url":null,"abstract":"<div><div>Cancer remains one of the leading causes of mortality worldwide. As a result, bioactive compounds derived from herbal medicines have gained increasing attention in cancer research. Ardicrenin, extracted from <em>Ardisia crenata</em>, has been evaluated for its ability to suppress the growth of MG-63 cells. Remarkably, its inhibitory effect on MG-63 cell proliferation is comparable to that of Taxol. Unlike Taxol, which induces apoptosis by stabilizing microtubules, ardicrenin regulates cell proliferation and death through the integrin signaling pathway. These findings highlight ardicrenin as a promising candidate for anti-tumor drug development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130558"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040154","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 : 2026-05-01Epub Date: 2026-01-20DOI: 10.1016/j.bmcl.2026.130548
Hongyue Bu , Qi-Long Wu , Cun-Chen Wang , Qiaolu Guo , Shengqun Deng , Yiji Li , Shuojin Wang
To develop novel mosquito control agents, we designed and synthesized a series of derivatives based on the natural alkaloid arecoline as a lead compound, targeting muscarinic acetylcholine receptors (mAChRs). Using computer-aided drug design and docking techniques focused on mAChRs, we designed piperidine derivatives and screened for synthetically accessible candidates. The compounds were synthesized, structurally characterized, and evaluated for activity via a Fluo-4 calcium fluorescence assay using Chinese Hamster Ovary-K1 (CHO-K1) cells expressing the muscarinic acetylcholine receptor M1. Most compounds showed potent mAChRs agonist activity, with Half Maximal Effective Concentration (EC₅₀) values below 10 μM. In subsequent insecticidal activity tests, these piperidine derivatives exhibited strong larvicidal effects against Aedes aegypti. The Median Lethal Concentration (LC₅₀) values for compounds 1a, 2a, 3a, 4a, 13a, 22a, 2b, and 9b were 58.4, 29.6, 11.4, 21.7, 42.0, 61.7, 125.9, and 81.6 mg/L, respectively. Notably, compound 13a maintained high insecticidal activity even against pyrethroid-resistant mosquitoes, indicating a mode of action different from conventional neurotoxic insecticides. These results demonstrate that mAChR-targeting derivatives derived from betel alkaloids represent a promising strategy for developing new mosquito control agents and offer a novel approach to combating insecticide resistance.
{"title":"Design, synthesis and preliminary evaluation of mosquitoicidal activity of arecoline derivatives targeting muscarinic acetylcholine receptors","authors":"Hongyue Bu , Qi-Long Wu , Cun-Chen Wang , Qiaolu Guo , Shengqun Deng , Yiji Li , Shuojin Wang","doi":"10.1016/j.bmcl.2026.130548","DOIUrl":"10.1016/j.bmcl.2026.130548","url":null,"abstract":"<div><div>To develop novel mosquito control agents, we designed and synthesized a series of derivatives based on the natural alkaloid arecoline as a lead compound, targeting muscarinic acetylcholine receptors (mAChRs). Using computer-aided drug design and docking techniques focused on mAChRs, we designed piperidine derivatives and screened for synthetically accessible candidates. The compounds were synthesized, structurally characterized, and evaluated for activity via a Fluo-4 calcium fluorescence assay using Chinese Hamster Ovary-K1 (CHO-K1) cells expressing the muscarinic acetylcholine receptor M1. Most compounds showed potent mAChRs agonist activity, with Half Maximal Effective Concentration (EC₅₀) values below 10 μM. In subsequent insecticidal activity tests, these piperidine derivatives exhibited strong larvicidal effects against <em>Aedes aegypti</em>. The Median Lethal Concentration (LC₅₀) values for compounds <strong>1a</strong>, <strong>2a</strong>, <strong>3a</strong>, <strong>4a</strong>, <strong>13a</strong>, <strong>22a</strong>, <strong>2b</strong>, and <strong>9b</strong> were 58.4, 29.6, 11.4, 21.7, 42.0, 61.7, 125.9, and 81.6 mg/L, respectively. Notably, compound 13a maintained high insecticidal activity even against pyrethroid-resistant mosquitoes, indicating a mode of action different from conventional neurotoxic insecticides. These results demonstrate that mAChR-targeting derivatives derived from betel alkaloids represent a promising strategy for developing new mosquito control agents and offer a novel approach to combating insecticide resistance.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130548"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027932","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 : 2026-05-01Epub Date: 2026-01-30DOI: 10.1016/j.bmcl.2026.130562
Omaima F. Ibrahim , Rana M.I. Morsy , Varsha Menon , Wafaa S. Ramadan , Raafat El-Awady , Hajjaj H.M. Abdu-Allah , Etify A. Bakhite
Inspired by the known anticancer activities of hydroxychalcones and acetamidochalcones, a series of novel hybrid molecules integrating these motifs with a paracetamol core were designed and synthesized. The synthesized chalcone–paracetamol hybrids were evaluated for their antiproliferative activity against a panel of eight human cancer cell lines. Compounds 6a, 6b, and 9, showed good activity against four cancer cell lines (U937, Jurkat, HCT-116 and MCF-7 cells). Notably, derivative 9 was the most potent with IC50 ranging from 1.50 to 4.50 μM, while showing no significant toxicity toward normal cells. Mechanistic investigations revealed that compound 9 induced cell cycle arrest at G0/G1 phase and stimulated apoptosis. Further biochemical analysis identified it (9) as a multi-target agent, with significant inhibitory activity against EGFR (0.62 ± 0.02 μM), VEGFR-2 (2.26 ± 0.01 μM), COX-2 (17.38 ± 0.13 μM), and tubulin polymerization (19.31 ± 0.29 μM). Molecular docking analysis supported these results, showing strong binding affinities for the respective target proteins, with high binding scores of compound 9 ranging from (−9.2 to −10.0) kcal/mol. Collectively, these findings highlight that compound 9 is worthy of further investigation as a potential anticancer lead.
{"title":"Nature-inspired chalcone-functionalized paracetamol derivatives as potential anticancer leads: synthesis, biological evaluation, apoptotic mechanisms, and in silico docking studies","authors":"Omaima F. Ibrahim , Rana M.I. Morsy , Varsha Menon , Wafaa S. Ramadan , Raafat El-Awady , Hajjaj H.M. Abdu-Allah , Etify A. Bakhite","doi":"10.1016/j.bmcl.2026.130562","DOIUrl":"10.1016/j.bmcl.2026.130562","url":null,"abstract":"<div><div>Inspired by the known anticancer activities of hydroxychalcones and acetamidochalcones, a series of novel hybrid molecules integrating these motifs with a paracetamol core were designed and synthesized. The synthesized chalcone–paracetamol hybrids were evaluated for their antiproliferative activity against a panel of eight human cancer cell lines. Compounds <strong>6a</strong>, <strong>6b</strong>, and <strong>9</strong>, showed good activity against four cancer cell lines (U937, Jurkat, HCT-116 and MCF-7 cells). Notably, derivative <strong>9</strong> was the most potent with IC<sub>50</sub> ranging from 1.50 to 4.50 μM, while showing no significant toxicity toward normal cells. Mechanistic investigations revealed that compound <strong>9</strong> induced cell cycle arrest at G0/G1 phase and stimulated apoptosis. Further biochemical analysis identified it (<strong>9</strong>) as a multi-target agent, with significant inhibitory activity against EGFR (0.62 ± 0.02 μM), VEGFR-2 (2.26 ± 0.01 μM), COX-2 (17.38 ± 0.13 μM), and tubulin polymerization (19.31 ± 0.29 μM). Molecular docking analysis supported these results, showing strong binding affinities for the respective target proteins, with high binding scores of compound <strong>9</strong> ranging from (−9.2 to −10.0) kcal/mol. Collectively, these findings highlight that compound <strong>9</strong> is worthy of further investigation as a potential anticancer lead.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130562"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099822","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 : 2026-05-01Epub Date: 2026-01-22DOI: 10.1016/j.bmcl.2026.130560
Le Quoc Tien , Hien Thi Thanh Phung , Huy-Hoang Do , Tiep N. Khac , Pham Thi Ngoc Minh , Vu Ngoc Hai Linh , Nguyen Quoc Thang , Shuai Wang , Phuong-Thao Tran
In this study, a series of thirty-five novel imidazolium salts bearing a 2-oxindoles were designed and synthesized as potent acetylcholinesterase (AChE) inhibitors for Alzheimer's disease. Structural diversity was introduced through substituent variation on both the oxindole and phenyl rings to investigate structure–activity relationships. All compounds were evaluated in vitro by the modified Ellman assay, revealing several highly potent inhibitors in the nanomolar to subnanomolar range. The most active compound, 32, exhibited an IC50 of 0.17 nM, surpassing galantamine and donepezil. Enzyme kinetic study indicated that all compounds act as mixed-type AChE inhibitors. Machine learning–based binding affinity predictions (ΔGML = −10.30 to −8.18 kcal/mol) correlated well with experimental activity. Molecular docking against AChE (PDB ID: 4EY6 and 7E3H) revealed that compounds bearing electron-withdrawing substituents exhibited superior binding scores and favorable interactions with key catalytic residues and aromatic residues. Molecular dynamics (200 ns) simulations demonstrated that compound 32 maintained a highly stable conformation within the AChE active site, with consistent hydrogen bonding and low root-mean-square deviation (RMSD) fluctuations. In addition, MM-PBSA binding free energy analysis (ΔGtotal = −33.42 kcal/mol) further confirmed its strong and stable interactions compared with galantamine (−17.82 kcal/mol) and donepezil (−21.20 kcal/mol). Furthermore, in silico ADME predictions suggested favorable oral absorption and potential blood-brain barrier permeability for compound 32, while maintaining an acceptable safety profile compared to galantamine and donepezil. These promising findings highlight the potential of oxindole–imidazolium hybrids as effective AChE inhibitors and warrant further investigation for the development of novel anti-Alzheimer agents.
{"title":"Novel imidazolium salts bearing 2-oxindoles scaffold as potent acetylcholinesterase inhibitors for Alzheimer's disease: Design, synthesis, in vitro and in silico studies","authors":"Le Quoc Tien , Hien Thi Thanh Phung , Huy-Hoang Do , Tiep N. Khac , Pham Thi Ngoc Minh , Vu Ngoc Hai Linh , Nguyen Quoc Thang , Shuai Wang , Phuong-Thao Tran","doi":"10.1016/j.bmcl.2026.130560","DOIUrl":"10.1016/j.bmcl.2026.130560","url":null,"abstract":"<div><div>In this study, a series of thirty-five novel imidazolium salts bearing a 2-oxindoles were designed and synthesized as potent acetylcholinesterase (AChE) inhibitors for Alzheimer's disease. Structural diversity was introduced through substituent variation on both the oxindole and phenyl rings to investigate structure–activity relationships. All compounds were evaluated in vitro by the modified Ellman assay, revealing several highly potent inhibitors in the nanomolar to subnanomolar range. The most active compound, <strong>32</strong>, exhibited an IC<sub>50</sub> of 0.17 nM, surpassing galantamine and donepezil. Enzyme kinetic study indicated that all compounds act as mixed-type AChE inhibitors. Machine learning–based binding affinity predictions (ΔG<sub>ML</sub> = −10.30 to −8.18 kcal/mol) correlated well with experimental activity. Molecular docking against AChE (PDB ID: <span><span>4EY6</span><svg><path></path></svg></span> and <span><span>7E3H</span><svg><path></path></svg></span>) revealed that compounds bearing electron-withdrawing substituents exhibited superior binding scores and favorable interactions with key catalytic residues and aromatic residues. Molecular dynamics (200 ns) simulations demonstrated that compound <strong>32</strong> maintained a highly stable conformation within the AChE active site, with consistent hydrogen bonding and low root-mean-square deviation (RMSD) fluctuations. In addition, MM-PBSA binding free energy analysis (ΔG<sub>total</sub> = −33.42 kcal/mol) further confirmed its strong and stable interactions compared with galantamine (−17.82 kcal/mol) and donepezil (−21.20 kcal/mol). Furthermore, in silico ADME predictions suggested favorable oral absorption and potential blood-brain barrier permeability for compound <strong>32</strong>, while maintaining an acceptable safety profile compared to galantamine and donepezil. These promising findings highlight the potential of oxindole–imidazolium hybrids as effective AChE inhibitors and warrant further investigation for the development of novel anti-Alzheimer agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130560"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043622","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}
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