Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Development of coumarin-3-thiosemicarbazones and coumarin-3-oximes as potent inhibitors of mushroom tyrosinase/tyrosine hydroxylase","authors":"Luiz Alberto Ferreira ,&nbsp;Angelo Matheus Torres Santos ,&nbsp;Rodrigo Cabral de Araújo-Filho ,&nbsp;Emanuelly Karla Araújo-Padilha ,&nbsp;Clara Andrezza Crisóstomo Bezerra Costa ,&nbsp;Johnnatan Duarte de Freitas ,&nbsp;Joanna Cytarska ,&nbsp;Krzysztof Z. Łączkowski ,&nbsp;Edeildo Ferreira da Silva-Júnior ,&nbsp;Silvia Helena Cardoso","doi":"10.1016/j.bmcl.2026.130583","DOIUrl":"10.1016/j.bmcl.2026.130583","url":null,"abstract":"<div><div>Tyrosinase is a copper-dependent oxidase that catalyzes the rate-limiting steps of melanogenesis, directly linking its overexpression to hyperpigmentation disorders and melanoma progression. Previously our researcher team found that a coumarin–thiosemicarbazone analog exhibited potent anti-tyrosinase activity (IC₅₀ = 42.16 ± 5.16 μM). Herein, as part of our efforts in this field of study, we report the synthesis and biological evaluation of a new series of coumarin derivatives functionalized with thiosemicarbazone and/or oxime moieties as potent tyrosinase inhibitors. The most active compound, <strong>B5</strong>, exhibited an IC₅₀ value of 21.91 ± 0.26 μM, showing 3.3- and 17.6-fold higher inhibitory potency than kojic and ascorbic acids, respectively. Kinetic studies revealed a mixed inhibition pattern, suggesting multiple enzyme–inhibitor interactions. <em>In silico</em> 100-ns molecular dynamics simulations against <em>Agaricus bisporus</em> tyrosinase (PDB ID: <span><span>2Y9X</span><svg><path></path></svg></span>) confirmed the structural stability of the <strong>B5</strong>–tyrosinase complex, with a mean RMSD of 1.85 Å for the enzyme and 0.3 Å for the ligand. The thiosemicarbazone moiety played a pivotal role in complex stabilization through hydrogen bonding and coordination with catalytic Cu²⁺ ions, while hydrophobic and π-stacking contacts contributed to binding persistence. Altogether, these findings highlight compound <strong>B5</strong> as a promising lead compound for developing next-generation tyrosinase inhibitors with potential dermatological and photoprotective applications.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130583"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171822","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":"Novel anticancer paeonol derivatives possessing a nitric oxide donor moiety as TrxR inhibitors: design, synthesis, biological evaluation","authors":"Ce Shi ,&nbsp;Weisen Zhong ,&nbsp;Guowei Qiang ,&nbsp;Panjunjie Ying ,&nbsp;Junyu Guo ,&nbsp;Yameng Si ,&nbsp;Jie Mou","doi":"10.1016/j.bmcl.2026.130555","DOIUrl":"10.1016/j.bmcl.2026.130555","url":null,"abstract":"<div><div>The tumor microenvironment (TME) plays a pivotal role in determining tumor progression and treatment response. Within the TME, redox processes mediated by reactive oxygen species (ROS) and nitric oxide (NO) are critically involved in regulating intercellular and intracellular signaling. In this study, we hypothesized that conjugating an NO-releasing moiety to paeonol derivatives and introducing a chalcone structure to enhance thioredoxin reductase (TrxR) targeting would yield compounds with potent anticancer activity. Accordingly, a series of mono- and di-substituted nitrate derivatives were synthesized. The inhibitory activities of all synthesized compounds were evaluated against BGC823, HCT116, Hep G2, and MCF-7 cell lines using the CCK-8 assay. Among the paeonol chalcone derivatives, compound <strong>11f</strong> exhibited significant antiproliferative activity across the tested cancer cell panel. It was identified as a promising candidate with potent TrxR inhibitory activity (IC₅₀ = 0.26 ± 0.17 μM in vitro; IC₅₀ = 0.33 μM in vivo). Furthermore, compound <strong>11f</strong> induced S-phase arrest and promoted apoptosis in MCF-7 cells. These findings underscore the enhanced anticancer potential of paeonol chalcone derivatives, attributable to the synergistic effects of NO and ROS.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130555"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146045921","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":"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 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":"Nature-inspired chalcone-functionalized paracetamol derivatives as potential anticancer leads: synthesis, biological evaluation, apoptotic mechanisms, and in silico docking studies","authors":"Omaima F. Ibrahim ,&nbsp;Rana M.I. Morsy ,&nbsp;Varsha Menon ,&nbsp;Wafaa S. Ramadan ,&nbsp;Raafat El-Awady ,&nbsp;Hajjaj H.M. Abdu-Allah ,&nbsp;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 IC₅₀ 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}