Bioorganic & Medicinal Chemistry Letters最新文献

{"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 ,&nbsp;Chris Cains ,&nbsp;Danielle J.C. Fenwick ,&nbsp;Amy Foster ,&nbsp;Clair L. Preece ,&nbsp;Sidrah Saleem ,&nbsp;Stephen P. Stanforth ,&nbsp;Hayley J. Turner ,&nbsp;Graeme Turnbull ,&nbsp;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}

{"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 ,&nbsp;Meiyan Jiang ,&nbsp;YongQuan Wei ,&nbsp;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}

{"title":"Discovery of GSI526: a potent IRAK4-targeting PROTAC degrader with efficient degradation and suppression of inflammatory signaling.","authors":"Bingjie Yin, Zhishuo Gao, Yan Ma, Zhuoyue Li, Mengjun Ma","doi":"10.1016/j.bmcl.2026.130680","DOIUrl":"https://doi.org/10.1016/j.bmcl.2026.130680","url":null,"abstract":"<p><p>Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target for inflammatory diseases. However, inhibition of its kinase activity alone often results in incomplete blockade of inflammatory signaling and limited therapeutic efficacy. To address this limitation, we designed and synthesized a novel proteolysis-targeting chimera (PROTAC) aimed at degrading IRAK4. Among the synthesized compounds, GSI526 emerged as a potent degrader, demonstrating efficient IRAK4 degradation in THP-1 cells with a DC₅₀ of 40.17 nM. Mechanistic studies confirmed that GSI526 acts via the ubiquitin-proteasome system, effectively suppressing the IRAK4-mediated NF-κB and MAPK signaling pathways. Furthermore, GSI526 exhibited a favorable preliminary safety profile. Collectively, these findings identify GSI526 as a promising IRAK4-targeting degrader, offering an alternative therapeutic strategy and a candidate for further drug development.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130680"},"PeriodicalIF":2.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831719","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}

{"title":"Development of isoxazole tethered 1,2,3-triazoles and sulphonamide derivatives as potent anti-bacterial and anti-cancer agents.","authors":"Priyanuj Krishnann Hazarika, Sanjeeb Kalita, Debajit Mahanta, Dhrubajyoti Gogoi, Babulal Das, Diganta Sarma","doi":"10.1016/j.bmcl.2026.130681","DOIUrl":"https://doi.org/10.1016/j.bmcl.2026.130681","url":null,"abstract":"<p><p>This study addresses the design and development of novel isoxazole molecules tethered with triazole and sulphonamide derivatives to elucidate their pharmacological response for antibacterial and anticancer activities. The ionic liquid mediated protocol garners the respective derivatives tolerating an array of functionalised and substituted molecular hybrids. Antimicrobial exploration performed against six bacterial strains with antibiotic associated resistance mechanisms, identified five scaffold that exhibited significant inhibitory activity. The sulphonamide-isoxazole moiety demonstrated cross-species effectiveness encompassing both the resistant and non-resistant bacterial strains. ScXRD provides the exact molecular conformation and regioselective formation of 3,5-disubstituted isoxazole-sulphonamide hybrid. The heterocyclic conjugates also elicit a concentration- and time-dependent reduction in hepatocellular carcinoma cell (HepG2) with pronounced cell death observed for triazole hybrids bearing chloro substituents. The binding affinities of these compounds with the microbial protein targets and their interactions with Heat Shock Protein 90 (Hsp90) for the cancer cell line probed by the docking studies corroborates with the experimental findings.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130681"},"PeriodicalIF":2.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831684","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}

{"title":"Discovery and antibacterial activity of kibdelomycin A-1 and A-2 from repeat batch fermentation of Kibdelosporangium banguiesne","authors":"Jonah Fine ,&nbsp;John B. Perkins ,&nbsp;Vincent Gullo ,&nbsp;Ryan D. Cohen ,&nbsp;Jun Lu ,&nbsp;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}

{"title":"Inhibitory effects against Trypanosoma cruzi, Leishmania infantum and trypanothione reductase of N1,N4-bisbenzylbutane-1,4-diamines","authors":"Otília Höeller Guarnieri ,&nbsp;Mariza Gabriela Faleiro de Moura Lodi Cruz ,&nbsp;Daniela de Melo Resende ,&nbsp;Carime L.M. Pontes ,&nbsp;Igor Vivan Roberto ,&nbsp;Luiza Schmidt D'Agostini ,&nbsp;Bertha Chithambo ,&nbsp;Niklas Ehlenz ,&nbsp;Xavier Siwe-Noundou ,&nbsp;Rui W.M. Krause ,&nbsp;Maique W. Biavatti ,&nbsp;Jaya R. Lakkakula ,&nbsp;Nilesh Shirish Wagh ,&nbsp;Mario Steindel ,&nbsp;Till Opatz ,&nbsp;Silvane M. Fonseca Murta ,&nbsp;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>¹,<em>N</em>⁴-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>¹,<em>N</em>⁴-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. <em>N</em>¹,<em>N</em>⁴-bis(4-chlorobenzyl)butane-1,4-diamine also inhibited <em>L. infantum</em> with an IC₅₀ of 19.3 ± 1.2 μM (SI of 3.4). <em>N</em>¹,<em>N</em>⁴-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 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 <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>¹,<em>N</em>⁴-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}

{"title":"Spinosyn A derivatives as ASS1 activators and tumor inhibitors","authors":"Xin-Yu Huang ,&nbsp;Xiao-He Liu ,&nbsp;Na Xu ,&nbsp;Ting Peng ,&nbsp;Xi-Yuan Hu ,&nbsp;Min Su ,&nbsp;Zhi-Yong Luo ,&nbsp;Su-You Liu ,&nbsp;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}

{"title":"Organometallic gold(III) (C^S)-cyclometallated complexes as candidates to new drugs against chagas disease","authors":"Paula Pérez-Ramos ,&nbsp;Rogelio Gomez-Escobedo ,&nbsp;Benjamín Nogueda-Torres ,&nbsp;Adriana Moreno-Rodriguez ,&nbsp;Alejandro Llamedo ,&nbsp;Humberto Rodríguez-Solla ,&nbsp;Sara M. Soto ,&nbsp;Gildardo Rivera ,&nbsp;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 &gt;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}

{"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}

{"title":"Design, synthesis and preliminary evaluation of mosquitoicidal activity of arecoline derivatives targeting muscarinic acetylcholine receptors","authors":"Hongyue Bu ,&nbsp;Qi-Long Wu ,&nbsp;Cun-Chen Wang ,&nbsp;Qiaolu Guo ,&nbsp;Shengqun Deng ,&nbsp;Yiji Li ,&nbsp;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}