MedChemComm最新文献

{"title":"Thiochromenes and thiochromanes: a comprehensive review of their diverse biological activities and structure–activity relationship (SAR) insights","authors":"Jatin, Solai Murugappan, Shivani Kirad, Chandu Ala, Pranali Vijaykumar Kuthe, Chandra Sekhar Venkata Gowri Kondapalli and Murugesan Sankaranarayanan","doi":"10.1039/D4MD00995A","DOIUrl":"10.1039/D4MD00995A","url":null,"abstract":"<p >Thiochromene and thiochromane scaffolds, sulfur containing heterocycles, have gained significant attention in medicinal chemistry due to their diverse pharmacological activities. This review provides a comprehensive analysis of their antibacterial, antifungal, antiviral, anti-parasitic, and anticancer properties, emphasizing their therapeutic potential. SAR studies highlight key molecular modifications such as electron withdrawing substituents, sulfur oxidation, and tailored ring substitutions that enhance bioactivity, potency, and target specificity. Mechanistic insights reveal their ability to inhibit microbial enzymes, disrupt cellular pathways, and modulate key biological targets. By summarizing recent advancements, this review underscores the potential of thiochromene and thiochromane based therapeutics and encourages further research to address existing limitations and enhance their drug development prospects.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1941-1968"},"PeriodicalIF":3.597,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Near-infrared photochemical internalization: design of a distorted zinc phthalocyanine for efficient intracellular delivery of immunotoxins†","authors":"Mikako Hamabe, Wakako Dewa, Mizue Yuki, Eriko Yamada, Tamako Aiba, Keisuke Horikoshi, Takao Hamakubo, Riuko Ohashi and Akimitsu Okamoto","doi":"10.1039/D4MD00931B","DOIUrl":"10.1039/D4MD00931B","url":null,"abstract":"<p >In the treatment of cancer, the physical and mental stress on patients and the potential for strong side effects are serious problems; therefore, reliable delivery of drugs into cancer tissue cells is required. We have developed a near-infrared (NIR) photosensitizing dye, Zn6PTPc, for NIR-photochemical internalization (PCI) to achieve gentle and efficient endosomal escape and delivery of antibody drugs, which are known to have high targeting ability but low intracellular activity, into target cancer cells. Zn6PTPc allowed longer wavelengths to be used to achieve higher singlet oxygen generation efficiency by the molecular design based on a distorted π-electron system. The system effectively introduced immunotoxins into cells to significantly inhibit tumor tissue growth. The developed potent NIR photosensitizers facilitated NIR-PCI with high tumor-targeting ability.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2615-2626"},"PeriodicalIF":3.597,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methods for kinetic evaluation of reversible covalent inhibitors from time-dependent IC50 data†","authors":"Lavleen K. Mader and Jeffrey W. Keillor","doi":"10.1039/D5MD00050E","DOIUrl":"10.1039/D5MD00050E","url":null,"abstract":"<p >Potent reversible covalent inhibitors are often slow in establishing their covalent modification equilibrium, resulting in time-dependent inhibition. While these inhibitors are commonly assessed using IC<small>₅₀</small> values, there are no methods available to analyze their time-dependent IC<small>₅₀</small> data to provide their inhibition (<em>K</em><small>_i</small> and <img>) and covalent modification rate (<em>k</em><small>₅</small> and <em>k</em><small>₆</small>) constants, leading to difficulty in accurately ranking drug candidates. Herein, we present an implicit equation that can estimate these constants from incubation time-dependent IC<small>₅₀</small> values and a numerical modelling method, EPIC-CoRe, that can fit these kinetic parameters from pre-incubation time-dependent IC<small>₅₀</small> data. The application of these new methods is demonstrated by the evaluation of a known inhibitor, saxagliptin, providing results consistent with those obtained by other known methods. This work introduces two new practical methods of evaluation for time-dependent reversible covalent inhibitors, allowing for rigorous characterization to enable the fine-tuning of their binding and reactivity.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2517-2531"},"PeriodicalIF":3.597,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the in vitro anticancer potential of bis(imino)acenaphthene–N-heterocyclic carbene transition metal complexes revealed TrxR inhibition and triggering of immunogenic cell death (ICD) for allyl palladates†","authors":"Chiara Donati, Ishfaq Ibni Hashim, Nestor Bracho Pozsoni, Laurens Bourda, Kristof Van Hecke, Catherine S. J. Cazin, Fabiano Visentin, Steven P. Nolan, Valentina Gandin and Thomas Scattolin","doi":"10.1039/D5MD00039D","DOIUrl":"10.1039/D5MD00039D","url":null,"abstract":"<p >Immunogenic cell death (ICD) is a regulated form of cell death that activates an immune response through the release of danger-associated molecular patterns (DAMPs), including calreticulin, ATP, and HMGB1. Gold complexes are known to induce ICD, but the ICD-inducing potential of palladium complexes remains largely unexplored. We report the first examples of palladium compounds capable of inducing ICD, specifically allyl palladates bearing bis(imino)acenaphthene–NHC (BIAN–NHC) ligands. Cytotoxicity tests on human cancer cell lines revealed that allyl palladates outperform their cinnamyl analogues and gold(<small>I</small>)/copper(<small>I</small>) BIAN–NHC complexes. Notably, [BIAN–IMes·H][PdCl<small>₂</small>(allyl)] <strong>2a</strong> showed excellent TrxR inhibition, reducing activity by 67% and surpassing auranofin. This inhibition strongly correlates with ICD induction, as evidenced by enhanced DAMP marker expression, including superior ATP and HMGB1 release compared to doxorubicin. These findings establish allyl palladates as a novel class of ICD inducers with dual anticancer activity and immune activation potential.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2592-2602"},"PeriodicalIF":3.597,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and biological evaluation of naphthalene-1,4-dione analogues as anticancer agents†","authors":"Yao Cheng, Tsz Tin Yu, Ellen M. Olzomer, Martina Beretta, Alice Katen, Jacky Su, John Patrick Jones, David StC Black, Kyle L. Hoehn, Frances L. Byrne and Naresh Kumar","doi":"10.1039/D4MD00987H","DOIUrl":"10.1039/D4MD00987H","url":null,"abstract":"<p >The increased metabolism of glucose <em>via</em> aerobic glycolysis, known as the Warburg effect, is a hallmark of most cancers. Identifying molecules that disrupt the Warburg effect may allow for selective cytotoxicity towards cancer cells and reduce side effects compared to current chemotherapy agents. Our initial hit compound, <strong>BH10</strong>, which potentially targets Kelch-like ECH-associated protein 1 (Keap1), increased oxygen consumption rate and displayed increased cytotoxicity towards cancer cells over normal cells <em>in vitro</em>. In this project, a library of analogues based on the <strong>BH10</strong> scaffold was prepared with the aim of improving potency and cancer-cell specificity. Among these analogues, several compounds showed notable potency, with activity (IC<small>₅₀</small>) observed around 1 μM. However, when considering selectivity, the imidazole derivative, compound <strong>44</strong>, exhibited the most optimal balance, achieving an IC<small>₅₀</small> of 6.4 μM and selectivity ratio of 3.6 which indicates greater toxicity to cancer cells <em>vs.</em> normal cells.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2677-2696"},"PeriodicalIF":3.597,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11986672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Minimalistic bis-triarylpyridinium cations: effective antimicrobials against bacterial and fungal pathogens†","authors":"Ana M. López-Fernández, Jean C. Neto, Rosa de Llanos, Juan F. Miravet and Francisco Galindo","doi":"10.1039/D4MD00902A","DOIUrl":"10.1039/D4MD00902A","url":null,"abstract":"<p >A series of twelve compounds from the family of 2,4,6-triarylpyridinium cations have been synthesized, chemically characterized (<small>¹</small>H, <small>¹³</small>C NMR, HRMS), and microbiologically evaluated (MIC determination against <em>S. aureus</em>, <em>E. faecalis</em>, <em>E. coli</em>, <em>P. aeruginosa</em>, and <em>C. albicans</em>). These compounds are quaternary ammonium cations (QACs), classified as either mono-QACs or bis-QACs. The mono-QACs are further divided into those with short (three-carbon) and long (twelve-carbon) pendant chains. An additional structural variable is the number of bromine atoms attached to the aromatic rings, ranging from zero to three. The major findings of this study are: (a) bis-QACs exhibit notably higher antimicrobial activity than mono-QACs; (b) an increased number of bromine atoms on the structure appears to diminish antimicrobial properties and (c) one of the compounds (<strong>1a</strong>) shows particularly promising properties as a broad spectrum antimicrobial, given its low MICs across all five pathogenic microorganisms studied. Preliminary assays with <em>C. albicans</em> show that <strong>1a</strong> has a strong mitochondrial activity, causing a remarkable mitochondrial membrane depolarization in this organelle. Taken together, this study positions triarylpyridinium cations—previously unexplored as antimicrobials—as promising candidates for future drug development, especially in light of the growing concern over drug-resistant microorganisms.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2641-2650"},"PeriodicalIF":3.597,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indolylmaleimide derivatives as a new class of anti-leishmanial agents: synthesis and biological evaluation†","authors":"Samarpita Das, Neerupudi Kishore Babu, Priyanka Mazire, Amit Roy, Rohit Kumar, Sushma Singh and Deepak K. Sharma","doi":"10.1039/D5MD00132C","DOIUrl":"10.1039/D5MD00132C","url":null,"abstract":"<p >Leishmaniasis is a neglected tropical disease, primarily affecting poor and developing countries. The present therapeutic approach faces various limitations, such as concerns regarding toxicity, route of administration, and the emergence of drug resistance. Therefore, there is a critical need to identify novel scaffolds to combat this fatal parasitic infection. Leishmanial DNA topoisomerase 1B is a heterodimeric protein and plays a crucial role in resolving topological problems during various biological processes. It is structurally distinct from its human counterparts, making it an attractive target for drug discovery. In this study, we synthesized various aminated indolylmaleimide derivatives targeting the leishmanial topoisomerase 1B enzyme. <em>In vitro</em> leishmanicidal assays on <em>Leishmania promastigotes</em> identified one highly potent hit (<strong>3m</strong>), showing considerable inhibition with single-digit micromolar IC<small>₅₀</small> values. Moreover, molecular docking analysis of the potent hit (<strong>3m</strong>) confirmed its strong binding affinity with the enzyme. Thus, the hit molecule (<strong>3m</strong>) holds promise as a lead for developing novel therapeutic strategies against leishmaniasis.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2808-2818"},"PeriodicalIF":3.597,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development, biological evaluation, and molecular modelling of novel isocytosine and guanidine derivatives as BACE1 inhibitors using a fragment growing strategy†","authors":"Asmaa M. Atta, Nouran Rihan, Ahmad M. Abdelwaly, Mohamed S. Nafie, Mohamed S. Elgawish, Samia M. Moustafa, Mohamed A. Helal and Khaled M. Darwish","doi":"10.1039/D4MD00698D","DOIUrl":"10.1039/D4MD00698D","url":null,"abstract":"<p >Alzheimer's disease (AD) is a neurodegenerative condition characterized by significant synaptic loss and neuronal death in brain regions critical for cognitive functions. The disease is characterized by the formation of amyloid plaques, which are extracellular constructs consisting mainly of aggregated Aβ42. The latter is a peptide formed by the proteolytic cleavage of β-amyloid precursor protein (APP) by two enzymes, β- and γ-secretase. Therefore, inhibition of the aspartic protease β-secretase (BACE1) is considered a promising therapeutic approach for the treatment and prevention of Alzheimer's disease. Unfortunately, a limited number of β-secretase inhibitors have reached human trials and eventually failed due to inconclusive therapeutic and/or safety profiles. In this study, we developed drug-like molecules with a β-secretase inhibitory activity using a fragment growing strategy on isocytosine and acyl guanidine warheads. Our approach is based on optimizing the hydrophobic part of the molecules to obtain a conformationally restrained scaffold complementary to the hydrophobic pockets within the enzyme active site. We developed 32 compounds with promising <em>in vitro</em> inhibitory activity against BACE1 down to sub-micromolar IC<small>₅₀</small>. Docking simulation studies were performed to understand the mode of binding of the prepared compounds. We demonstrated that compounds with superior activities, such as <strong>16b</strong> and <strong>16g</strong>, are able to provide the best balance between the steric shape and position of the polar substituent for achieving preferential anchoring into the S1, S3, S1′, and S2′ sub-pockets. Further, <em>in vivo</em> characterization of selected drug-like candidates of the benzimidazole series AMK-IV, namely <strong>16a</strong> and <strong>16k</strong>, demonstrated their ability to reduce oxidation stress and their safety within brain and liver tissues.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 2202-2230"},"PeriodicalIF":3.597,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and SAR of antiproliferative activity of trioxatriangulene derivatives†","authors":"Mohinder Maheshbhai Naiya, Ivy A. Guan, Matthew Sullivan, Chatchakorn Eurtivong, Euphemia Leung, Lisa I. Pilkington and David Barker","doi":"10.1039/D4MD00867G","DOIUrl":"10.1039/D4MD00867G","url":null,"abstract":"<p >Trioxatriangulene (TOTA<small>⁺</small>) and its derivatives, which are primarily used as dyes in biological systems, have received considerable attention owing to their photophysical and electronic properties. Notably, their DNA-intercalating properties have been well established. Previous studies have identified TOTA<small>⁺</small> derivatives, particularly ADOTA<small>⁺</small> (R = –C<small>₃</small>H<small>₇</small>) and DAOTA<small>⁺</small> (R = R′ = –C<small>₃</small>H<small>₇</small>), as potent antiproliferative agents in triple-negative breast cancer (MDA-MB-231) and colorectal cancer (HCT-116) cell lines. However, the potential to enhance antiproliferative activity through different side chains prompted further investigation. In addition, partially cyclized tetramethoxyphenyl acridinium ion (TMPA<small>⁺</small><strong>8</strong>) and dimethoxy quinacridinium ion (DMQA<small>⁺</small><strong>9</strong>) intermediates were assessed to elucidate the structure–activity relationship (SAR) of the triangulenium core for antiproliferative activity. In this study, 83 molecules with various side chains were synthesized, including planar, partially planar, and non-planar derivatives. Evaluation of their antiproliferative activity in MDA-MB-231 and HCT-116 cell lines revealed that compound <strong>6l</strong> (R = –C<small>₄</small>H<small>₉</small>, R′ = –C<small>₂</small>H<small>₄</small>N(Me)<small>₂</small>) was the most potent inhibitor, with IC<small>₅₀</small> values of 18 ± 3 nM and 32 ± 14 nM, respectively. A new one-pot method was developed to synthesize symmetrically and asymmetrically substituted DAOTA<small>⁺</small> molecules, enabling the introduction of acid-labile functional groups, such as alcohols, ethers, and alkylamines, in moderate to good yields.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2627-2640"},"PeriodicalIF":3.597,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and evaluation of acetylcholine-antitumor lipid hybrids led to identification of a potential anticancer agent disrupting the CDK4/6-Rb pathway in lung cancer†","authors":"Ahmed H. E. Hassan, Eun Seo Bae, Youngdo Jeong, Chae Won Ock, Selwan M. El-Sayed, Minji Kim, Mohamed F. Radwan, Tarek S. Ibrahim, Jun-Young Cho, Boyoung Y. Park, Jaehoon Sim, Sang Kook Lee and Yong Sup Lee","doi":"10.1039/D4MD01007H","DOIUrl":"10.1039/D4MD01007H","url":null,"abstract":"<p >Hybridization of acetylcholine with antitumor lipids (ATLs) was explored to achieve novel potential anticancer agents. The combination with a 2-stearoxyphenyl moiety substantially enhanced the anticancer activity of the acetylcholine hybrids. Compounds <strong>6</strong>, <strong>8</strong>, <strong>9</strong> and <strong>10</strong> exhibited pronounced anticancer activities higher than edelfosine and stPEPC and NSC43067. Compounds <strong>6</strong>, <strong>8</strong>, <strong>9</strong> and <strong>10</strong> also showed broad-spectrum anticancer activity against diverse cancer cells including lung, ovarian, renal, prostate, leukaemia, colon, CNS, melanoma, and breast cancer cells. Compounds <strong>6</strong> and <strong>8</strong> were potent compounds eliciting single digit low micromolar GI<small>₅₀</small> values. Compound <strong>6</strong> was the most potent against non-small cell lung cancer, ovarian cancer, renal cancer, and prostate cancer. Meanwhile, compound <strong>8</strong> was the most potent against leukaemia, colon cancer, CNS cancer, melanoma, and breast cancer. Exploration of the mechanism of action of compound <strong>6</strong> in A549 non-small cell lung cancer cells showed that it triggers cell cycle arrest in the G<small>₀</small>/G<small>₁</small> phase <em>via</em> disruption of the CDK4/6-Rb pathway and induces apoptosis <em>via</em> the activation of caspases, upregulation of BAX and cleavage of PARP. Overall, the results present acetylcholine-ATL hybrids <strong>6</strong> and <strong>8</strong> as potential anticancer agents for possible further development.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 2281-2296"},"PeriodicalIF":3.597,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}