Future medicinal chemistry最新文献

{"title":"Integrated <i>in vitro</i> and <i>in silico</i> evaluation of adamantane-1,2,3-triazole hybrids as potential <i>α</i>-glucosidase inhibitors.","authors":"Aman Ragshaniya, Vivek Asati, Jayant Sindhu, Sonika Asija, Kashmiri Lal","doi":"10.1080/17568919.2026.2699685","DOIUrl":"10.1080/17568919.2026.2699685","url":null,"abstract":"<p><strong>Aims: </strong>To find for lead compounds, efficiently defeating diabetes mellitus, prompted us to the synthesis of a new library of adamantane‑appended 1,2,3-triazole hybrid conjugates (<b>AT1-AT18</b>).</p><p><strong>Material and methods: </strong>The current synthesis of adamantane-appended 1,2,3-triazoles was performed by using Cu(I)-catalyzed azide-alkyne cycloaddition reaction. The hybrids were structurally characterized <i>via</i> ¹H, ¹³C NMR, FTIR, and mass spectrometry. The hybrids were evaluated for their inhibitory potential for <i>α</i>-glucosidase enzyme, along with <i>in silico</i> activity, <i>i.e</i>., molecular docking, molecular dynamics simulations, and ADME (absorption, distribution, metabolism, and excretion).</p><p><strong>Results: </strong>Hybrid <b>AT5</b> (<i>IC</i>_<i>50</i> 5.5 <b>±</b> 0.87 µM) showed maximum inhibition potential against <i>α</i>-glucosidase enzyme, which may be risen from the methyl substitution on phenyl ring. The results were compared with the reference, acarbose (<i>IC</i>_<i>50</i> 13.5 ± 0.32 µM). The docking studies using PDB:3L4U revealed that the hybrid <b>AT5</b> demonstrated a docking score -7.656, which was better than alkyne, <i>i.e</i>., -3.894. Ligand stability analysis explored by using molecular dynamics demonstrated the useful findings such as RMSD <2 Å, 0-2 <i>H</i>-bonds, for hybrid <b>AT5</b>, highlighting the stabilization contribution of triazole unit.</p><p><strong>Conclusion: </strong>The hybrid <b>AT5</b> may be used as potential lead compound after necessary structural modifications.</p>","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"2135-2146"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435810","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":"Butenolide-based human carbonic anhydrase (hCA) I/II inhibitors: integrated computational and biological evaluation.","authors":"Songul Bayrak, Cansu Ozturk, Serpil Gerni, Ufuk Atmaca, Namik Kilinc","doi":"10.1080/17568919.2026.2688861","DOIUrl":"10.1080/17568919.2026.2688861","url":null,"abstract":"<p><strong>Aims: </strong>This study aimed to evaluate the inhibitory effects of a series of butenolide derivatives on human carbonic anhydrase isoenzymes I and II (hCA I and hCA II) and to investigate their antioxidant and antimicrobial properties through experimental and computational approaches.</p><p><strong>Materials and methods: </strong>Butenolide derivatives (<b>2a-2j</b>) were evaluated for their inhibitory activity against hCA I and hCA II using in vitro enzyme inhibition assays. Antioxidant activities were assessed using ABTS•⁺ radical scavenging and Fe³⁺ reducing assays, while antimicrobial activities were determined using the disc diffusion method against selected Gram-positive, Gram-negative bacteria and fungal strains. Molecular docking, Prime/MM-GBSA binding free energy calculations, and molecular dynamics simulations were performed to investigate ligand - enzyme interactions and binding stability.</p><p><strong>Results: </strong>Among the tested compounds, derivative <b>2c</b> showed the most potent inhibition against hCA I and hCA II with K_i values of 0.212 ± 0.018 μM and 0.051 ± 0.015 μM, respectively, exceeding the activity of the reference inhibitor acetazolamide. Antioxidant assays indicated that compound <b>2h</b> exhibited the strongest radical scavenging and reducing activity. Several derivatives demonstrated moderate antibacterial activity, whereas limited antifungal activity was observed. Computational studies supported the experimental findings and revealed stable ligand - enzyme interactions.</p><p><strong>Conclusions: </strong>The results suggest that butenolide derivatives represent promising multifunctional scaffolds for the development of new carbonic anhydrase inhibitors with additional antioxidant and antimicrobial potential.</p>","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"1963-1978"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13432884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148250250","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":"LSD1-based dual-target inhibitors as emerging anticancer agents: pharmacological perspectives and SAR exploration.","authors":"Pitam Ghosh, Ryena Dhir, Dinki Sharma, Subhadip Maity, Sanjay Kumar Bharti, Vivek Asati","doi":"10.1080/17568919.2026.2699684","DOIUrl":"10.1080/17568919.2026.2699684","url":null,"abstract":"<p><p>LSD1 is a key epigenetic eraser that demethylates the histone proteins and regulates transcription. Overexpression of LSD1 drives the development of multiple cancers, such as prostate, breast, gastric, lung, colorectal cancers, and acute myeloid leukemia. Although several LSD1 inhibitors have shown promise for cancer therapy, monotherapy faces challenges such as low selectivity, high toxicity, and drug resistance. To overcome these drawbacks and achieve synergistic anticancer effects, researchers have focused on dual inhibitors that target LSD1 along with other oncogenic partners, including HDAC, EGFR, EZH2, tubulin, ERα, G9a, JmjC, DCN1, and SMOX. This review aims to provide recent design strategies and SAR for LSD1-based dual inhibitors, emphasizing the fusion of different LSD1 pharmacophore (tranylcypromine, pargyline, pyridine, 5-cyano-3-phenylindole, indole, benzyl/aryl piperazine, triazole-dithiocarbamate and substituted triazole scaffold) with various heterocyclic and zinc-binding cores such as hydroxamic acids, bipyridine, hydroxy quinoline to generate hybrids capable of inducing apoptosis, blocking cell-cycle, differentiation. This review explores the pharmacological role of LSD1 in oncogenesis and offers structural and SAR insights to guide the design of LSD1-based dual inhibitors.</p>","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"2203-2225"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13557592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148420039","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, characterization & molecular docking studies of rationally designed azobenzene-Derived 5-oxoimidazoline derivatives as potent antimicrobial agents.","authors":"Vipasha Sharma, Sumitra Nain","doi":"10.1080/17568919.2026.2628548","DOIUrl":"10.1080/17568919.2026.2628548","url":null,"abstract":"<p><strong>Aim: </strong>The study aimed to design the series of azobenzene-induced 5-oxoimidazoline moiety, represents as a promising structural framework for the development of a new class of antimicrobial agents, supported by molecular docking studies.</p><p><strong>Materials & methods: </strong>Two series of compounds (10 in each series) were synthesized through a multistep procedure beginning with diazotization of 2-nitroaniline, followed by coupling with methyl paraben to yield azobenzene compound <b>(9)</b>, which were subsequently refluxed with hydrazine hydrate to afford the hydrazide intermediate (11). Reaction of compound <b>(11)</b> with substituted acetophenones <b>12(A1-A5)</b> and aldehydes <b>12(A6-A10)</b> produced schiff bases <b>13(S1-S10)</b>, which upon refluxing with amino acids (glycine and alanine) furnished the desired final compounds <b>14(M1-M10)</b>and <b>15(M1-M10)</b>. The compounds were screened for in-vitro antimicrobial activity & molecular docking studies were carried out to investigate ligand - protein interactions and to predict the most probable binding conformations.</p><p><strong>Results: </strong>Compounds <b>14M6</b> (MIC = 0.55 & 0.45 µg/ml, ΔG = -6.093), <b>14M9</b> (MIC = 0.38 µg/ml, ΔG = -5.928), <b>15M9</b> (MIC = 0.40 µg/ml, ΔG = -6.084) showed best anti-fungal activity displaying best docking score (PDB ID: 3LD6). The most active anti-bacterial compounds included <b>14M8</b> (MIC = 0.70 & 0.88 µg/ml, ΔG = -5.832), <b>14M9</b> (MIC = 0.54, 0.72& 0.39 µg/ml, ΔG = -5.755 & -5.845), <b>15M8</b> (MIC = 0.34, 0.75& 0.55 µg/ml, ΔG = -5.683 &-5.894), <b>15M9</b> (MIC = 0.65& 0.44 µg/ml, ΔG = -5.573) with best docking score (PDB ID: 2XCT & 6M1S).</p><p><strong>Conclusion: </strong>Compounds <b>14M6</b>, <b>14M8</b>, <b>14M9</b>, <b>15M8</b> & <b>15M9</b> emerged as the most promising antimicrobial candidates, establishing them as potential lead molecules for further optimization and drug development.</p>","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"2107-2125"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13568568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147431527","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":"Biological evaluation and molecular docking of previously reported pyrazolo-thiazole derivatives as dual α-amylase and α-glucosidase inhibitors.","authors":"Mohammed El Behery, Hagar Ahmed Elsayed, Ali H Abu Almaaty, Ruwaida I El-Namaky, Ibrahim S Kamel","doi":"10.1080/17568919.2026.2688852","DOIUrl":"10.1080/17568919.2026.2688852","url":null,"abstract":"<p><strong>Aim: </strong>Postprandial hyperglycemia is an important therapeutic target in type 2 diabetes mellitus. This study aimed to evaluate previously reported pyrazolo[3,4-d]thiazole derivatives as dual inhibitors of α-amylase and α-glucosidase.</p><p><strong>Materials and methods: </strong>Compounds 5a-b, 6a-b and 7 were assessed using <i>in vitro</i> α-amylase and α-glucosidase inhibitory assays, with acarbose as the reference inhibitor. The most active compounds were further evaluated for cytotoxicity against WI-38 normal human fibroblasts. Molecular docking was performed to explore binding modes within the active sites of the target enzymes.</p><p><strong>Results: </strong>All tested compounds inhibited both enzymes in a dose-dependent manner. Compound 6b showed the strongest dual inhibitory activity, with IC₅₀ values of 0.24 μM against α-amylase and 1.34 μM against α-glucosidase, outperforming acarbose. Docking analysis supported these findings, showing favorable binding interactions of 6b within both enzyme active sites. Cytotoxicity testing indicated that the effective enzyme-inhibitory concentrations were markedly lower than the cytotoxic concentration in WI-38 cells.</p><p><strong>Conclusion: </strong>Compound 6b represents a promising lead scaffold for further development of dual α-amylase/α-glucosidase inhibitors targeting postprandial hyperglycemia.</p>","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"1979-1987"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13432810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301484","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":"Metric analysis of molecular graphs of selected anticancer drugs.","authors":"Sandeep Kumar, Vijay Kumar Bhat","doi":"10.1080/17568919.2026.2688858","DOIUrl":"10.1080/17568919.2026.2688858","url":null,"abstract":"<p><strong>Aims: </strong>This study aims to analyze the molecular structures of anticancer drugs using graph-theoretic parameters and to investigate their structural properties through metric-based descriptors.</p><p><strong>Materials and methods: </strong>The chemical structures of vorinostat and tucidinostat are modeled as molecular graphs. Graph theoretical concepts such as metric dimension (MD), edge metric dimension (EMD), and fault-tolerant metric dimension (FTMD) are applied to study these drug molecules.</p><p><strong>Results: </strong>The computed invariants provide quantitative information about structural uniqueness, bond distinguishability, and robustness of the molecular graphs. The results show differences in structural complexity and stability between the two drugs based on MD, EMD, and FTMD values.</p><p><strong>Conclusions: </strong>The study demonstrates that these graph-theoretic parameters effectively capture important structural features of anticancer drugs. They may be useful in mathematical chemistry, molecular modeling, and drug structure analysis for future research.</p>","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"1989-1997"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13557584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148250389","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":"Exploring thiazole conjugates as cholinesterase inhibitors for Alzheimer's disease treatment.","authors":"Anchal Dabas, Parul Yadav, Ram Singh","doi":"10.1080/17568919.2026.2699679","DOIUrl":"10.1080/17568919.2026.2699679","url":null,"abstract":"<p><p>Alzheimer's Disease (AD), a major global health concern, is marked by memory loss and cognitive decline, especially in the elderly. Cholinergic hypothesis is one of the leading hypotheses toward the treatment of AD, prompting the development of cholinesterase (ChE) inhibitors. Acetylcholinesterase (AChE) remains a vital therapeutic target due to its role in enhancing acetylcholine levels and neural function. The natural products, synthetic analogs, and hybrid molecules have been evaluated as inhibitors of ChEs. Recent studies highlight thiazole-fused heterocyclic scaffolds and their derivatives as promising ChE inhibitors with neuroprotective potential. This article covers the synthesis of conjugates of thiazole with piperazine, benzimidazole, pyrazole, and other heterocyclic compounds, along with their potential as ChE inhibitors. This article will be useful to medicinal chemists and pharmaceutical industries to design and synthesize library of thiazole conjugates.</p>","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"2187-2201"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13557598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148420087","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":"Bridging the green skills gap: a framework to align the pharmaceutical workforce with sustainable drug discovery.","authors":"Osama I Alwassil","doi":"10.1080/17568919.2026.2699691","DOIUrl":"10.1080/17568919.2026.2699691","url":null,"abstract":"<p><strong>Background: </strong>The pharmaceutical industry's R&D model faces unsustainable costs and environmental impact, yet educational pipelines lag in integrating AI and green chemistry skills essential for modern drug discovery.</p><p><strong>Methods: </strong>We conducted cheminformatics analysis of 50,000 bioactive compounds from ChEMBL v35 to quantify AI-driven discovery advantages. Natural language processing with BioBERT embeddings systematically analyzed international accreditation standards (ACPE, EAFP).</p><p><strong>Results: </strong>AI-driven approaches achieved 99.998% reduction in experimental burden and 32% lower endocrine disruption potential versus traditional high-throughput screening. Accreditation analysis revealed a critical deficit: mean Sustainability Integration Score of only 18.3% (range: 9.5-27.1%; SD = 6.2). The observed reductions in endocrine disruption potential and predicted E-factors for AI-designed compounds should be interpreted as signals of favorable computational toxicology profiles within the dimensions assessed, rather than comprehensively validated environmental safety.</p><p><strong>Conclusions: </strong>We introduce the Accreditation-Aligned Sustainable Education (AASE) framework and GreenMedSim computational sandbox - an experiential platform virtualizing wet-lab activities for iterative molecular design. GreenMedSim is presented as a theoretically grounded and computationally specified educational prototype; empirical user trials and learning outcome data are planned for Phase 1 implementation (2026-2027).This work provides an actionable strategy aligning pharmaceutical workforce training with sustainable drug development, directly supporting UN Sustainable Development Goals 4.7, 9, and 12.</p>","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"2161-2169"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13557576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148420032","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":"Indole-based kinase modulators for NSCLC: recent advances in synthetic route, SAR and molecular docking studies.","authors":"Shivam Nag, Divyanshi Thakur, Kalicharan Sharma","doi":"10.1080/17568919.2026.2688859","DOIUrl":"10.1080/17568919.2026.2688859","url":null,"abstract":"<p><strong>Aim: </strong>The indole scaffold has gained increasing importance due to its structural versatility and ability to interact with multiple cancerous receptors relevant to non-small cell lung cancer (NSCLC). So, the aim of this review is \"Indole-Based Kinase Modulators for NSCLC: Recent Advances in Synthetic Route, Structure activity relationship (SAR) and Molecular Docking Studies for the betterment of future.\"</p><p><strong>Objective: </strong>Compilation of recently food and drug administration (FDA) approved indole-based drugs and molecular docking validation. In previously reported review they individually focused on the targets such as EGFR and the other targets.</p><p><strong>Material & methods: </strong>A systemic literature survey from 2020 to 2025 was done on the basis of indole as a main scaffold against different NSCLC targets. Data analysed from the given literature data.</p><p><strong>Results: </strong>This review tells the key structural features of indole derivatives that will increase the kinase selectivity and potency against the EGFR, ALK, ROS1 and VEGFR targets.</p><p><strong>Conclusion: </strong>This review highlights indole scaffold as a core pharmacophore for multitargets against the NSCLC like EGFR, ALK/ROS1 and VEGFR. This review helps the medicinal chemist and other researchers to develop more indole-based molecules for muti kinase targets.</p>","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"2069-2085"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13432873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257839","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":"Recent advances in 1,3,5-triazine-based PI3K inhibitors for cancer therapy: a comprehensive review.","authors":"Utkarsha Kulkarni, Adarsh Yadav, Princy Desai, Clement Thangtinkhum, Drashti Shah, Afzal Nagani, Ashish Shah, Mehul Patel, Umang Shah, Swayamprakash Patel, Nilay Solanki, Ashish D Patel","doi":"10.1080/17568919.2026.2699675","DOIUrl":"10.1080/17568919.2026.2699675","url":null,"abstract":"<p><p>Dysregulation of the phosphatidylinositol-3-kinase (PI3K) - AKT/mTOR signaling axis is a major molecular driver of tumor initiation, progression, and therapeutic resistance across diverse cancers, underscoring the need for improved targeted therapies amid a rising global and Indian cancer burden. This comprehensive review critically summarizes advances from 2021-2025 in the design of selective PI3K inhibitors based on the 1,3,5-triazine (<i>s</i>-triazine) scaffold, emphasizing how its symmetric 2/4/6 substitution vectors, electron-deficient hinge-binding profile, and modular cyanuric chloride - enabled SNAr synthesis accelerate structure - activity relationship (SAR) optimization. Medicinal chemistry and biological evidence across multiple triazine chemotypes (benzoyl-hydrazide, thiophene/thiophenyl-arylurea, aminopyrimidine, dimorpholinyl, benzimidazole, phenylamino, and pyrazolyl derivatives) reveal convergent design rules: heteroaryl/aminopyrimidine hinge binders, pocket-filling hydrophobic arms, and solvent-exposed polar groups (notably morpholine/dimorpholine or sulfonyl piperazine) collectively improve potency, isoform selectivity, and cellular efficacy. Mechanistically, representative compounds induce G0/G1 arrest and apoptosis with suppression of p-PI3K/p-AKT and downstream markers, supported by docking/MD interactions frequently involving Val851 (hinge), Asp810, Lys802, and Gln859. Despite substantial progress, pharmacokinetic liabilities, resistance pathways, and isoform-associated adverse effects remain key barriers to translation. Future development should prioritize rational isoform targeting, hybrid/multitarget designs, systematic ADME refinement, and AI-driven SAR modeling to advance <i>s</i>-triazine PI3K inhibitors toward clinically feasible cancer therapeutics.</p>","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"2171-2185"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13557561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387557","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}