Medicinal Chemistry Research最新文献

{"title":"The anti-inflammatory effects of iridoid glycosides: a comprehensive review of mechanisms of action and structure-activity relationships","authors":"Xinyue Zheng,&nbsp;Wenwen Li,&nbsp;Mingtao Wang,&nbsp;Haiyi Gao,&nbsp;Yian Zhao,&nbsp;Peiliang Dong,&nbsp;Hua Han","doi":"10.1007/s00044-025-03456-8","DOIUrl":"10.1007/s00044-025-03456-8","url":null,"abstract":"<div><p>Inflammation plays a crucial role in the onset and progression of various diseases. However, current anti-inflammatory therapies often produce adverse effects that limit their clinical utility. This review focuses on the therapeutic potential of iridoid glycosides, a class of monoterpenoid compounds known for their anti-inflammatory properties. Drawing on literature from PubMed and Google Scholar, this study comprehensively examines eight well-studied iridoid glycosides in terms of their sources, administration methods, dosages, target inflammatory models, and mechanisms of action. The compounds were found to modulate critical signaling pathways, including NF-κB, NLRP3 inflammasome, MAPK, and JAK-STAT, thereby suppressing key inflammatory cytokines such as TNF-α, IL-1β, and IL-6, while also activating antioxidant defenses. Structure–activity relationship analysis suggests that glycosyl, ester, and epoxy groups are essential pharmacophores for their bioactivity. Collectively, these findings underscore the promise of iridoid glycosides as effective and safer alternatives for managing inflammatory diseases.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 9","pages":"1833 - 1854"},"PeriodicalIF":3.1,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028184","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":"Nano-TPD: Using nanoparticle-based systems to improve the delivery and therapeutic effect of targeted protein degraders","authors":"Kuntala Dey,&nbsp;Nina Erwin,&nbsp;Nicolas Molina,&nbsp;Hui Chen,&nbsp;Mei He,&nbsp;Guangrong Zheng","doi":"10.1007/s00044-025-03454-w","DOIUrl":"10.1007/s00044-025-03454-w","url":null,"abstract":"<div><p>As a novel therapeutic strategy, targeted protein degradation (TPD) enables the selective elimination of disease-driving proteins through endogenous degradation pathways such as the ubiquitin-proteasome system and lysosomal trafficking. However, the therapeutic potential of TPD agents is often limited by poor solubility, low bioavailability, off-target toxicity, and inefficient intracellular delivery. Nanocarrier-based delivery systems offer a promising solution to these challenges by enabling controlled release, enhanced pharmacokinetics, and precise intracellular trafficking of TPD agents, including PROteolysis TArgeting Chimera (PROTACs), LYsosome-TArgeting Chimeras (LYTACs), or AUtophagy-TArgeting Chimeras (AUTACs). These systems can be engineered to respond to tumor-specific internal stimuli (e.g., pH, redox environment, enzymes) or external triggers (e.g., light, ultrasound, magnetic fields), enabling spatiotemporal control of drug release while minimizing systemic toxicity. Furthermore, modular nanocarrier designs allow for co-delivery with synergistic therapeutics, improved endosomal escape, and surface modification for cell-specific targeting. Recent innovations, including the development of exosome-based and carrier-free nanotechnology-enabled TPD platforms (Nano-TPDs), further expand the landscape of degradable targets and therapeutic indications. This review highlights the design principles, current advances, and future directions of nano-TPD systems, with an emphasis on their potential to overcome delivery barriers and redefine precision oncology.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 in","pages":"2205 - 2227"},"PeriodicalIF":3.1,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145493357","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":"Biocatalytic potential of microbial CYP450s in the degradation of selected environmental pollutants","authors":"Vanisa Petriti,&nbsp;Amit Mondal,&nbsp;Yousong Ding","doi":"10.1007/s00044-025-03457-7","DOIUrl":"10.1007/s00044-025-03457-7","url":null,"abstract":"<div><p>Cytochrome P450s (CYP450s) are a diverse and functionally rich family of heme-containing enzymes that play vital roles in the metabolism of endogenous and xenobiotic compounds. In recent years, microbial CYP450s have gained attention for their potential in environmental bioremediation due to their ability to oxidize a wide range of chemically complex and recalcitrant pollutants. This mini-review provides an overview of CYP450s and highlights their emerging roles in the degradation of selected environmental pollutants, including pharmaceuticals, personal care products (PPCPs), polycyclic aromatic hydrocarbons (PAHs), and polychlorinated biphenyls (PCBs). We further discuss recent advances in CYP450 discovery enabled by metagenomic mining, sequence similarity networks, and machine learning/artificial intelligence (ML/AI), along with innovations in enzyme engineering through rational design, site-directed mutagenesis, and ML/AI-guided directed evolution. Collectively, these developments illustrate the growing potential of microbial CYP450s as sustainable biocatalysts for tackling complex environmental contaminants.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 in","pages":"2228 - 2238"},"PeriodicalIF":3.1,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145493522","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":"Identification and evaluation of potent AAK1 inhibitors through structure-based pharmacophores, virtual screening and bioassay screening","authors":"Mahmoud A. Al-Sha’er,&nbsp;Afnan A. Alzaghari,&nbsp;Mutasem O. Taha","doi":"10.1007/s00044-025-03455-9","DOIUrl":"10.1007/s00044-025-03455-9","url":null,"abstract":"<div><p>This study employed structure-based drug design to discover novel inhibitors of Adaptor Associated Kinase 1 (AAK1) as potential anticancer agents. A total of 300 pharmacophore models were generated from AAK1 co-crystallized protein structures, from which the optimal model (<b>Hypo1</b>) was selected based on receiver operating characteristic (ROC) analysis (AUC = 82.3%) and further refined using shape-based alignment. Virtual screening of the National Cancer Institute (NCI) database yielded 7399 initial hits, which were narrowed down to 3481 compounds through Lipinski’s rule of five and SMARTS pattern filtering. Subsequent molecular docking against the AAK1 active site identified 438 candidates, of which the top 40 were selected for biological evaluation. Among these, Hit 5 (NCI 157865) exhibited the most potent AAK1 inhibition (IC₅₀ = 1.03 µM), with other active hits showing IC₅₀ values ranging from 1.87 to 7.49 µM. MTT assays confirmed the anticancer activity of Compound 5, with IC₅₀ values of 11.46 µM against MCF7 and 69.37 µM against A549 cell lines. The compound’s potency is attributed to key hydrophobic interactions and hydrogen bond acceptor features. These results highlight Compound 5 as a promising lead candidate for further development as an anticancer agent.</p><div><figure><div><div><picture><source><img></source></picture></div><div><p><b>Hypo1</b> fitted against hit <b>5</b> as compared to its 2D interactions within AAK1 binding site with IC₅₀ = 1.05 μM</p></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 9","pages":"1945 - 1957"},"PeriodicalIF":3.1,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028421","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":"Translational insights from species differences in the metabolism of triclosan","authors":"Swati Nagar,&nbsp;Upendra Argikar,&nbsp;Ken Korzekwa","doi":"10.1007/s00044-025-03458-6","DOIUrl":"10.1007/s00044-025-03458-6","url":null,"abstract":"","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 in","pages":"2200 - 2204"},"PeriodicalIF":3.1,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145493523","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":"Advancements in saponin-based vaccine adjuvants","authors":"Linggai Cao,&nbsp;Ping Dong,&nbsp;Jie Liu,&nbsp;Jie Zhang,&nbsp;He Xie,&nbsp;Shizhou Yu,&nbsp;Jianfeng Zhang","doi":"10.1007/s00044-025-03453-x","DOIUrl":"10.1007/s00044-025-03453-x","url":null,"abstract":"<div><p>Saponin-based adjuvants have emerged as promising candidates for enhancing vaccine efficacy by modulating immune responses. Derived primarily from plant and marine sources, saponins possess unique amphiphilic structures that contribute to their potent immunostimulatory properties. This review explores the advancements in saponin-based vaccine adjuvants, focusing on their immunomodulatory mechanisms, structural diversity, and applications. QS-21, a triterpenoid saponin from <i>Quillaja saponaria</i>, is the most extensively studied and has been incorporated into licensed vaccines such as Shingrix, Mosquirix, and Arexvy. However, the limitations of natural saponin-derived adjuvants, including hemolytic toxicity, hydrolytic instability, and low yield, have driven research toward semi-synthetic and synthetic analogs. Advances in synthetic biology and biosynthetic pathway elucidation have enabled the development of next-generation saponin-based adjuvants with enhanced potency and reduced toxicity. This review provides a comprehensive overview of the current state of saponin-based adjuvant research, highlighting their potential to revolutionize vaccine formulations and contribute to global public health initiatives.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 9","pages":"1817 - 1832"},"PeriodicalIF":3.1,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-025-03453-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carbon atom σ-hole tetrel bonding – a non-bonded interaction with potential application in drug design","authors":"Nicholas A. Meanwell","doi":"10.1007/s00044-025-03440-2","DOIUrl":"10.1007/s00044-025-03440-2","url":null,"abstract":"<div><p>The non-bonded interaction between the positive electrostatic potential associated with a σ*-orbital (the σ hole) of a substituted carbon atom and an atom with a lone pair of electrons is referred to as tetrel bonding and can be expressed in both intermolecular and intramolecular manifolds. Intermolecular tetrel bonding can contribute to the inventory of interactions that convene protein-ligand complexes while intramolecular tetrel bonds can influence the conformation of a molecule. While the energy associated with a carbon-based tetrel bond is calculated to be of a modest value, ranging from ~5 kcal/mole for a close contact between optimal partners to ~1 kcal/mole for a more relaxed and what is perhaps the more typical interaction, the prevalence of carbon tetrel bonding in drug design may be underappreciated. The energy of a carbon-based σ-hole tetrel bonding interaction has been equated with that calculated for the more prominent n→π* multipolar-type of tetrel bonding interaction or a C-H→π bond, both of which are recognized as interactions of value in drug design. In this review, we provide a perspective on the evidence in support of intermolecular and intramolecular σ-hole tetrel bonding interactions in the context of geometric parameters associated with drug and drug-like molecule structures deposited in the Cambridge Structural Database (CSD) and the Protein Data Bank (PDB).</p><div><figure><div><div><picture><img></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 in","pages":"2414 - 2471"},"PeriodicalIF":3.1,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600931","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":"Antidiabetic evaluation of novel thienopyrimidinone-thiazolidinedione hybrids complemented with kinetic and computational investigations","authors":"Pule Seboletswe,&nbsp;Gobind Kumar,&nbsp;Nontobeko Gcabashe,&nbsp;Sanjeev Dhawan,&nbsp;Neha Manhas,&nbsp;Lungisani Khubone,&nbsp;ALmahi Idris,&nbsp;Md. Shahidul Islam,&nbsp;Parvesh Singh","doi":"10.1007/s00044-025-03449-7","DOIUrl":"10.1007/s00044-025-03449-7","url":null,"abstract":"<div><p>Diabetes mellitus (DM) is a complex disease, and its treatment/management frequently requires the use of different drugs with distinct modes of action. Unfortunately, many of the current medications come with an increasing plethora of adverse effects. Consequently, DM poses a significant challenge to the global health system. Carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase have emerged as well-known therapeutic targets for the regulation of postprandial glucose levels. Herein, we report the design and synthesis of 20 novel molecular hybrids encompassing thienopyrimidinone and thiazolidinedione pharmacophores that can inhibit α-amylase and α-glucosidase and prevent oxidative stress. Several derivatives showed more potency than the standard drug acarbose. Compound <b>12q</b> (IC₅₀ = 38.89 ± 0.50 µM) with alkyl chain length <i>n</i> = 4 exhibited four-fold superior potency to acarbose (IC₅₀ = 174.40 ± 2.63 µM) against α-amylase, while compound <b>12t</b> (IC₅₀ = 41.94 ± 4.76 µM) also with alkyl chain length <i>n</i> = 4 exhibited seven-fold higher activity than acarbose (IC₅₀ = 282.80 ± 1.46 µM) against α-glucosidase. Enzyme kinetic studies further revealed these compounds (<b>12q</b> and <b>12t</b>) to be mixed inhibitors of the respective enzymes and were extensively engaged in interactions with their targets based on molecular docking simulations.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 9","pages":"1929 - 1944"},"PeriodicalIF":3.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-025-03449-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and biological evaluation of coumarin derivatives as anti-lung adenocarcinoma agents via induction of apoptosis and autophagy: in vitro and in vivo studies","authors":"Shi Yin,&nbsp;Pengyu Zhao,&nbsp;Qi Liao,&nbsp;Debin Chen,&nbsp;Chenjuan Zeng,&nbsp;Yuefei Geng,&nbsp;Funeng Geng","doi":"10.1007/s00044-025-03451-z","DOIUrl":"10.1007/s00044-025-03451-z","url":null,"abstract":"<div><p>Lung cancer represents a significant public health challenge, with non-small cell lung cancer (NSCLC) being the predominant subtype, underscoring the urgent need for improved therapeutic strategies. The limited efficacy of conventional chemotherapy has catalyzed the exploration of alternative treatment modalities. Natural products play a pivotal role in drug discovery, with structural modifications being integral to pharmaceutical research. This study presents novel coumarin derivatives that exhibit potential as candidate molecules for the treatment of lung adenocarcinoma. Among the synthesized compounds, compound <b>4f</b> demonstrated potent inhibitory effects on PC9 cells, with an IC₅₀ value of 4.08 μM. In vitro analyses demonstrated that <b>4f</b> significantly inhibited the proliferation and migration of PC9 cells by downregulating the expression of mTOR, which subsequently induced autophagic cell death. In vivo studies indicated that <b>4f</b> effectively targets mTOR, leading to the suppression of tumor growth while exhibiting a favorable safety profile. These findings support the advancement of new coumarin derivatives as promising therapeutic agents for lung adenocarcinoma.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 9","pages":"1914 - 1928"},"PeriodicalIF":3.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028304","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 evaluation of benzoxathiolone derivatives as monoamine oxidase inhibitors and antibacterial agents","authors":"Bianca Coetzee,&nbsp;Stephanus J. Cloete,&nbsp;Anél Petzer,&nbsp;Jacobus P. Petzer,&nbsp;Theunis T. Cloete","doi":"10.1007/s00044-025-03450-0","DOIUrl":"10.1007/s00044-025-03450-0","url":null,"abstract":"<div><p>Benzoxathiolone derivatives have in vitro activity against monoamine oxidase A (MAO-A) and MAO-B, making them potential lead compounds for the treatment of neuropsychiatric and neurodegenerative disorders. They also have antibacterial activity against numerous bacteria. The aim of this study was to synthesise two series of benzoxathiolone derivatives with different ester (series 1) and sulfonic ester (series 2) substitutions on position C6. The in vitro half-maximal inhibitory concentration (IC₅₀) of these derivatives was determined against both MAO-A and MAO-B, after which their mode of inhibition was determined by constructing Lineweaver-Burk graphs. Additionally, the minimum inhibitory concentration (MIC) of these derivatives was also determined against <i>Staphylococcus aureus</i>, <i>Acinetobacter baumannii</i>, <i>Pseudomonas aeruginosa</i>, and <i>Escherichia coli</i>. All derivatives had activity against both MAO-A and MAO-B. With regards to MAO-A, derivatives <b>1c</b> (0.054 µM), <b>1f</b> (0.052 µM), and <b>2a</b> (0.072 µM) were the most active. The positive control, harmine (0.003 µM), was however more active. With regards to MAO-B, derivatives <b>2a</b> (0.001 µM), <b>2b</b> (0.003 µM), <b>2c</b> (0.010 µM) and <b>2d</b> (0.012 µM), were more active than both positive controls, i.e., safinamide (0.088 µM) and isatin (2.80 µM). Comparing the activity of the derivatives against MAO-A <i>versus</i> MAO-B, the sulfonic ester derivatives were more active against MAO-A while the ester derivatives were more active against MAO-B. Halide substituents on the phenyl ring notably increased MAO-A activity. For MAO-B, enhanced activity was specifically observed with <i>para</i>-position substitution on the ester derivatives. As for the antibacterial assays, only <b>1d</b> (16 µg/ml) had activity against <i>S. aureus</i>.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 9","pages":"1903 - 1913"},"PeriodicalIF":3.1,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-025-03450-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145171877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}