European Journal of Medicinal Chemistry最新文献

{"title":"Discovery and optimization of 2-pyridones as dual h-DHFR/EGFRTK inhibitors with immunomodulatory potential; design, synthesis, anti-proliferative activity, and apoptosis inducer","authors":"Ahmed Ragab ,&nbsp;Reham R. Raslan ,&nbsp;Moustafa S. Abusaif ,&nbsp;Hamdy Khamees Thabet ,&nbsp;Yousry A. Ammar ,&nbsp;Nirvana A. Gohar","doi":"10.1016/j.ejmech.2025.117751","DOIUrl":"10.1016/j.ejmech.2025.117751","url":null,"abstract":"<div><div>Liver and colorectal cancers present considerable health challenges, underscoring the need to identify innovative targeted therapeutics. Tumor progression can be prevented by targeting EGFR-TK and <em>h</em>-DHFR as essential molecular targets. In this context, we synthesized a new series of 2-pyridones from the reaction of 2-cyanoacrylamide with active methylene or 2-cyanoacetanilide with activated double bonds under basic conditions. The structure of the synthesized 2-pyridones was confirmed through microanalysis and spectroscopic data. In comparison to doxorubicin, the spiro 2-pyridine derivative <strong>9b</strong> exhibited the highest anti-proliferative activity, demonstrating IC₅₀ values of 6.89 ± 0.4 μM and 5.68 ± 0.3 μM against HepG-2 and Caco-2 cell lines, respectively, with nearly 2-fold increase in efficacy observed in Caco-2 cells. Additionally, compound <strong>9b</strong> demonstrated a significant safety profile concerning normal cells (WI-38), as indicated by selectivity index values of 14.66 and 12.09 against the Caco-2 and HepG-2 cell lines, respectively. Moreover, flow cytometry analysis revealed that compound <strong>9b</strong> halted the cell cycle at the G1/S phase in Caco-2 treated cells, demonstrating an increase in the percentage of cells undergoing both early and late apoptosis. The apoptotic potential was corroborated by the up-regulation of BAX and the down-regulation of Bcl-2 levels. Compound <strong>9b</strong> exhibited significant inhibitory activity against <em>h</em>-DHFR, with an IC₅₀ value of 0.192 ± 0.011 μM, compared to methotrexate (IC₅₀ = 0.191 ± 0.011 μM). Furthermore, compound <strong>9b</strong> demonstrated EGFR inhibitory activity, with IC₅₀ of 0.109 ± 0.005 μM, which is close to the inhibition observed with Lapatinib (IC₅₀ = 0.044 ± 0.002 μM). Compound <strong>9b</strong> had better immunomodulatory properties with significant inhibitory efficacy on TNF-α and IL-6, with IC₅₀ values of 0.40 ± 0.03 pg/mL and 0.60 ± 0.02 pg/mL, respectively. These values indicate a greater potency than the positive control drug Lapatinib, which displayed IC₅₀ values of 0.41 ± 0.03 pg/mL and 0.74 ± 0.05 pg/mL for TNF-α and IL-6, respectively. In addition, in silico metabolism prediction using SwissADME and BioTransformer tools revealed that compound <strong>9b</strong> is a potential inhibitor of CYP2C9 and CYP3A4, and is predicted to undergo metabolic transformations primarily via aromatic hydroxylation and ketone reduction, while maintaining acceptable stability of its ester moiety. Finally, the molecular docking assessment, together with the direct in vitro enzymatic inhibition results, confirmed that the 2-pyridone derivative <strong>9b</strong> can potently bind to and inhibit both EGFR and h-DHFR through favorable binding interactions.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"294 ","pages":"Article 117751"},"PeriodicalIF":6.0,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic potential of dual HDAC6/SIRT2 inhibition in Alzheimer's disease","authors":"Xingyu Wang ,&nbsp;Cunjiang Li ,&nbsp;Lei Chen ,&nbsp;Bin He ,&nbsp;Yan Li","doi":"10.1016/j.ejmech.2025.117733","DOIUrl":"10.1016/j.ejmech.2025.117733","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by hallmark pathological changes such as amyloid β (Aβ) plaques, neurofibrillary tangles (NFTs) due to tau hyperphosphorylation, and neuroinflammation. Current therapeutic approaches focusing on single-target strategies exhibit limited efficacy, necessitating the exploration of novel multi-target approaches. Histone deacetylase 6 (HDAC6) and SIRT2, as two types of cytosolic histone deacetylases, have emerged as promising targets for AD treatment. HDAC6 plays a role in tau protein phosphorylation, while SIRT2 is involved in Aβ production. Both enzymes regulate microtubule proteins, impacting the formation of NFTs and Aβ plaques. Inhibition of HDAC6 reduces tau hyperphosphorylation, improves microtubule stability, and mitigates neuroinflammation, whereas SIRT2 inhibition attenuates Aβ accumulation and neuroinflammation. Recent studies indicate that dual-targeted inhibition of HDAC6 and SIRT2 may exhibit synergistic effects, suggesting it as a promising strategy for AD treatment. This review summarizes the biological roles of HDAC6 and SIRT2 in AD pathology and examines the development of dual-target inhibitors. It also discusses the challenges, including selectivity and toxicity, emphasizing that the development of combined HDAC6 and SIRT2 inhibitors represents a new direction for future AD treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"294 ","pages":"Article 117733"},"PeriodicalIF":6.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rationally designed Pyrazolo[1,5-a]pyrimidines as dual inhibitors of CA IX/XII and CDK6: A novel approach for NSCLC treatment","authors":"Mahmoud S. Elkotamy ,&nbsp;Islam A. Elkelesh ,&nbsp;Simone Giovannuzzi ,&nbsp;Rania S.M. Ismail ,&nbsp;Wessam M. El-Refaie ,&nbsp;Abdulrahman A. Almehizia ,&nbsp;Ahmed M. Naglah ,&nbsp;Alessio Nocentini ,&nbsp;Claudiu T. Supuran ,&nbsp;Mohamed Fares ,&nbsp;Hazem A. Ghabbour ,&nbsp;Rofaida Salem ,&nbsp;Wagdy M. Eldehna ,&nbsp;Hatem A. Abdel-Aziz","doi":"10.1016/j.ejmech.2025.117752","DOIUrl":"10.1016/j.ejmech.2025.117752","url":null,"abstract":"<div><div>Developing novel anticancer agents that target critical pathways in non-small cell lung cancer (NSCLC) presents a considerable challenge. This study synthesized 16 pyrazolo[1,5-<em>a</em>]pyrimidine derivatives with zinc-binding groups through molecular hybridization to achieve dual-target inhibition of tumor-associated carbonic anhydrase (CA) isoforms IX/XII and cyclin-dependent kinase 6 (CDK6). <em>In-vitro</em> assays indicated that sulfonamide-bearing compounds displayed enhanced CA inhibition, with compounds <strong>7d</strong>, <strong>11b</strong>, and <strong>11d</strong> presenting K_i values of 11.2, 18.4, and 19.7 nM for CA IX, while compounds <strong>11a</strong> and <strong>11c</strong> exhibited K_i values of 14.8 and 8.7 nM for CA XII. Cytotoxicity assays conducted on NSCLC cell lines A549 and NCI–H1734 demonstrated that compounds <strong>7c</strong>, <strong>7d</strong>, <strong>7i</strong>, and <strong>11d</strong> exhibited superior activity relative to <strong>Roscovitine</strong> in both cell lines. While these compounds demonstrated limited inhibition of cyclin-dependent kinase 4 (CDK4), <strong>7d</strong> and <strong>11d</strong> effectively inhibited CDK6, with IC₅₀ values of 0.054 and 0.069 μM, respectively, which are comparable to <strong>Palbociclib</strong>. Analyses of the cell cycle and apoptosis demonstrated a strong G1 arrest and a notable induction of apoptosis. Molecular docking confirmed essential binding interactions with CA IX/XII and CDK6, while <em>in-silico</em> ADMET predictions suggested favorable pharmacokinetics, despite potential toxicity concerns. Compounds <strong>7d</strong> and <strong>11d</strong> represent potential dual-target inhibitors for the treatment of NSCLC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117752"},"PeriodicalIF":6.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of isoxazole-based TRPA1 inhibitors with analgesic effects in vivo","authors":"Valentina Albanese ,&nbsp;Matilde Marini ,&nbsp;Martina Tesi ,&nbsp;Lorenzo Landini ,&nbsp;Elisa Bellantoni ,&nbsp;Sandro Cosconati ,&nbsp;Michele Roggia ,&nbsp;Lorenzo Tagliazucchi ,&nbsp;Lorenzo Gnudi ,&nbsp;Valentina Puscio ,&nbsp;Chiara Sturaro ,&nbsp;Chiara Ruzza ,&nbsp;Remo Guerrini ,&nbsp;Pierangelo Geppetti ,&nbsp;Romina Nassini ,&nbsp;Delia Preti ,&nbsp;Francesco De Logu ,&nbsp;Salvatore Pacifico","doi":"10.1016/j.ejmech.2025.117732","DOIUrl":"10.1016/j.ejmech.2025.117732","url":null,"abstract":"<div><div>The transient receptor potential ankyrin 1 (TRPA1) channel has been extensively studied as a potential therapeutic target for the treatment of different pain types, with better efficacy and safety profiles compared to current therapies. Because TRPA1 is implicated in different pathophysiological processes, selective antagonists of this channel could provide therapeutic benefits beyond pain relief. In this study, we report the design and synthesis of a novel series of carboxamide derivatives incorporating an isoxazole moiety, which were evaluated for their ability to inhibit TRPA1-mediated signalling. Among these, we identified the TRPA1 antagonists <strong>12</strong> and <strong>13</strong> displaying nanomolar potency <em>in vitro</em> and significant analgesic effects against the TRPA1 agonist, allyl isothiocyanate and in the formalin test in mice. Docking analyses were also conducted to explore the binding modes of the most representative compounds with the proposed pharmacological target.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"294 ","pages":"Article 117732"},"PeriodicalIF":6.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the classical chiral resolution: Modern enantioselective synthetic strategies used in the preparation of new chiral kinase inhibitors including drugs for autoimmune diseases and antitumoral drugs","authors":"Cesar Emiliano Hoffmann da Silva ,&nbsp;Grace Gosmann ,&nbsp;Rafael Roesler ,&nbsp;Marcela Silva Lopes ,&nbsp;Saulo Fernandes de Andrade","doi":"10.1016/j.ejmech.2025.117730","DOIUrl":"10.1016/j.ejmech.2025.117730","url":null,"abstract":"<div><div>Kinase inhibitors is one of the most approved class by FDA in this century. These proteins are versatile targets that have a huge impact in several pharmacotherapy including against cancer, autoimunne and rare diseases. Thus, the number of patents that aim these targets are increasing and is becoming harder to be innovative in this field. Furthermore, the design of ATP-competitive inhibitors is the major strategy used to develop new kinase inhibitors and there are few regions in the ATP cleft or around it, which are generally explored by the commercially available inhibitor drugs. In this way in this review, we focused in the use of modern enantioselective strategies that were carried out in the last years to prepare new chiral kinase inhibitors as an emerging field that resulted in several new potent innovative approved drugs. Also we suggested new trends in this modern relevant topic and analyzed kinase-drug complexes highlighting the interactions that support the importance of the stereochemistry.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117730"},"PeriodicalIF":6.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of 3-methacylic acid substituted benzoxaboroles as dual metallo- and serine-β-lactamase inhibitors","authors":"Guo-Qing Liang,&nbsp;Ying-Ying Jiang,&nbsp;Cheng-Long Han,&nbsp;Yao Wang,&nbsp;Si-Yao Wang,&nbsp;Yi-Ting Chen,&nbsp;Gen Li,&nbsp;Guo-Bo Li,&nbsp;You-Cai Xiao","doi":"10.1016/j.ejmech.2025.117723","DOIUrl":"10.1016/j.ejmech.2025.117723","url":null,"abstract":"<div><div>Carbapenem resistance is an ongoing clinical problem, largely driven by production of evolved serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs). We here report a series of new 3-methacrylic acid-substituted benzoxaboroles as dual MBL/SBL inhibitors. Structure-activity relationship studies showed that the new compounds manifested nanomolar inhibition to the SBLs KPC-2 and OXA-48, and single-digit micromolar inhibition to the MBLs VIM-2, NDM-1, and NDM-5. Co-crystallographic analyses revealed their binding modes with VIM-2 and OXA-48, which are similar as those of taniborbactam and xeruborbactam. Bacterial assays demonstrated that compound <strong>10</strong> can potentiate meropenem against multidrug-resistant Gram-negative strains. This work provides new lead compounds and structural basis for developing new drug candidates against MBL/SBL-mediated carbapenem resistance.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117723"},"PeriodicalIF":6.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Design and synthesis of novel styrylquinolinium derivatives for the treatment of breast cancer: Targeting the c-Myc G-Quadruplex” [Europ. J. Med. Chem. 291 (2025) 117663]","authors":"Xutong Wang ,&nbsp;Yu Liu ,&nbsp;Zeyu Gao ,&nbsp;Xiaodong Fang ,&nbsp;Kejing Ma ,&nbsp;Meng Sun ,&nbsp;Qiming Li ,&nbsp;Bing Wang ,&nbsp;Yong Zhang ,&nbsp;Xin Zhao ,&nbsp;Weina Han","doi":"10.1016/j.ejmech.2025.117719","DOIUrl":"10.1016/j.ejmech.2025.117719","url":null,"abstract":"","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117719"},"PeriodicalIF":6.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-class dual inhibitors of MASTL and Aurora A kinase: Discovery of selective cyclohexa[b]thiophenes with potent anticancer activity","authors":"Somaya A. Abdel-Rahman ,&nbsp;Hossam Nada ,&nbsp;Moustafa T. Gabr","doi":"10.1016/j.ejmech.2025.117729","DOIUrl":"10.1016/j.ejmech.2025.117729","url":null,"abstract":"<div><div>The dysregulation of mitotic kinases, particularly Microtubule Associated Serine/Threonine Kinase Like (MASTL) and Aurora A kinase, play pivotal roles in tumor progression and resistance to therapy. Herein, we report cyclohexa[<em>b</em>]thiophenes as first-in-class dual inhibitors of MASTL and Aurora A kinase. The lead compound, <strong>MA4</strong>, demonstrated potent inhibition of both kinases with IC₅₀ values of 0.16 ± 0.01 μM for Aurora A and 0.56 ± 0.16 μM for MASTL. Kinase selectivity profiling against a panel of 277 kinases revealed a high degree of specificity against both targets. In vitro antiproliferative screening using the NCI-60 human cancer cell line panel revealed broad-spectrum cytotoxicity, with <strong>MA4</strong> exhibiting submicromolar GI₅₀ values across multiple malignancies, outperforming previously reported cyclohexa[<em>b</em>]thiophenes in the multidose screening. Mechanistic studies, including microscale thermophoresis (MST) and NanoBRET target engagement assays, confirmed direct binding to both kinases. Computational studies, including molecular docking and molecular dynamics simulations, revealed key interactions stabilizing <strong>MA4</strong> within the ATP-binding sites of both kinases. We demonstrated the potent anticancer activity of <strong>MA4</strong> in 3D tumor spheroids, along with its favorable pharmacokinetic profile. Additionally, <strong>MA4</strong> exhibited no inhibitory activity against hERG and demonstrated selectivity toward cancer cells over normal cell lines, further supporting its potential for in vivo applications. These findings establish cyclohexa[<em>b</em>]thiophenes as promising dual kinase inhibitors with high selectivity, offering a compelling strategy for targeting mitotic dysregulation in cancer therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117729"},"PeriodicalIF":6.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The anti-neoplastic potency of epoxy-substituted polyaromatic platinum(II) and platinum(IV) complexes against A549 lung cancer cells","authors":"Rouba Al Sayegh ,&nbsp;Aleen Khoury ,&nbsp;Maria George Elias ,&nbsp;Najwa Mansour ,&nbsp;Stephanie Mehanna ,&nbsp;Amjad Slika ,&nbsp;Costantine F. Daher ,&nbsp;Janice R. Aldrich-Wright ,&nbsp;Robin I. Taleb","doi":"10.1016/j.ejmech.2025.117734","DOIUrl":"10.1016/j.ejmech.2025.117734","url":null,"abstract":"<div><div>A novel platinum(II) complex, <strong>Pt^II56O<em>SS</em></strong>, coordinated to 5,6-epoxy-5,6-dihydro-1,10-phenanthroline and its platinum(IV) di-hydroxido derivative (<strong>Pt^IV56O<em>SS</em></strong>) were synthesized and successfully characterised via NMR spectroscopy, HPLC, ESI-MS, UV, and CD spectroscopy. The cytotoxic activity of <strong>Pt^II56O<em>SS</em></strong> and <strong>Pt^IV56O<em>SS</em></strong> against A549, A375 and MDA-MB-231 cancer cells was investigated, and the results showed that both complexes exhibit dose dependent growth inhibition against all three cancer cell lines. In addition, <strong>Pt^IV56O<em>SS</em></strong> displayed significantly less toxicity against mesenchymal cells (MCs; &gt;100 μM) compared to both <strong>Pt^II56O<em>SS</em></strong> (6.5 μM) and cisplatin (2.0 μM). A Dose Escalation Study on Balb/c mice showed that the most tolerated dose (MTD) for <strong>Pt^II56O<em>SS</em></strong> and <strong>Pt^IV56O<em>SS</em></strong> were 140 and 200 mg/kg.b.w., respectively (which were ∼23-fold and 33-fold more tolerated than cisplatin). Cellular uptake experiments in A549 cells after 1, 3, 6, 12, 24 and 30 h of incubation, showed that both complexes are actively transported into the cells with <strong>Pt^II56O<em>SS</em></strong> exhibiting a similar uptake rate to cisplatin and approximately a 3-fold higher uptake than <strong>Pt^IV56O<em>SS</em></strong>. Intracellular distribution showed that while <strong>Pt^II56O<em>SS</em></strong> resides primarily in the Cytoplasmic Fraction) while (CF), the <strong>Pt^IV56O<em>SS</em></strong> resides heavily in the nucleus and cytoskeleton (NC) fraction. A549 cells treated with <strong>Pt^II56O<em>SS</em></strong> and <strong>Pt^IV56O<em>SS</em></strong> also showed a significant increase in the production of cellular ROS at all-time points (24, 48 and 72 h). Flow cytometry results demonstrated that <strong>Pt^II56O<em>SS</em></strong> and <strong>Pt^IV56O<em>SS</em></strong> caused significant increase in apoptotic cell death. Western blot assays exhibited an upregulation of cytochrome c, cleaved Parp, and the ratio of Bax/Bcl-2 when A549 cells were treated with either <strong>Pt^II56O<em>SS</em></strong> and <strong>Pt^IV56O<em>SS</em></strong>. These results distinguish <strong>Pt^II56O<em>SS</em></strong> and <strong>Pt^IV56O<em>SS</em></strong> as promising candidates for further investigation both <em>in vitro</em> and <em>in vivo</em> against several cancer models with the platinum(IV) analogue showing more promise due to its low cytotoxicity against normal cells coupled with its high <em>in vivo</em> tolerability.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"294 ","pages":"Article 117734"},"PeriodicalIF":6.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 biological evaluation of isoxazole-dihydropyrimidinone hybrids as potential modulators of adipogenesis and dyslipidemia","authors":"Alisha Ansari ,&nbsp;Nilesh Khandelwal ,&nbsp;Jay Gupta ,&nbsp;Prashant Rai ,&nbsp;Arvind Kumar Jaiswal ,&nbsp;Astha Singh ,&nbsp;Sarita Katiyar ,&nbsp;Ajay Kishor Kushawaha ,&nbsp;Vinita Kushwaha ,&nbsp;Anuradha Vishwakarma ,&nbsp;Divyanshi Singh ,&nbsp;Arpon Biswas ,&nbsp;Ravi Kumar ,&nbsp;Rabi Sankar Bhatta ,&nbsp;Anil Nilkanth Gaikwad ,&nbsp;Koneni V. Sashidhara","doi":"10.1016/j.ejmech.2025.117746","DOIUrl":"10.1016/j.ejmech.2025.117746","url":null,"abstract":"<div><div>The prevalence of obesity and its accompanying metabolic disorders necessitates innovative strategies to modulate adipocyte energy homeostasis. Adipose tissue, vital in energy metabolism, influences various physiological processes. Excessive energy storage leading to obesity exacerbates conditions like insulin resistance, dyslipidemia, and type-2 diabetes. Targeting adipogenic processes becomes crucial in mitigating obesity associated health risks. In this study, a series of 35 compounds integrating isoxazole and dihydropyrimidinone pharmacophores were synthesized and evaluated for their anti-adipogenic potential. Further refinement using structure-activity relationship led to the design of additional compounds, revealing promising anti-adipogenic properties. Among these, compound <strong>10g</strong> demonstrated notable efficacy and was studied for further mechanistic investigation. Compound <strong>10g</strong> targets the early stage of adipogenesis, including mitotic clonal expansion to inhibit the differentiation. It activates the AMPK pathway to exert anti-adipogenic potential and improve mitochondrial function and fatty acid oxidation in mature adipocytes. Treatment of compound <strong>10g</strong> in HFD-fed hamsters results in reduced adipose mass and body weight without altering the calorie intake. Compound <strong>10g</strong> ameliorated dyslipidemia by activating the reverse cholesterol transport machinery in hamsters. These results highlight isoxazole-dihydropyrimidinone hybrids, as a potential pharmacophore for developing drugs for obesity and dyslipidemia.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"294 ","pages":"Article 117746"},"PeriodicalIF":6.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}