Molecular Diversity最新文献

{"title":"Design, synthesis, and antibacterial efficacy of new methylene disalicylic acid/1,3,4-oxadiazole hybrids as dual inhibitors of DNA gyrase and topoisomerase IV.","authors":"Fatma A M Mohamed, Hamad H Alanazi, Abdelbaset Mohamed Elasbali, Awadh Alanazi, Emad Manni, Hesham A M Gomaa, Saleha Y M Alakilli, Abdullah Yahya Abdullah Alzahrani, Bandar A Alyami, Shimaa A Othman, Bahaa G M Youssif, Safwat M Rabea","doi":"10.1007/s11030-026-11490-w","DOIUrl":"10.1007/s11030-026-11490-w","url":null,"abstract":"<p><p>DNA gyrase and topoisomerase IV enzymes are promising candidates for dual targeting with novel antibacterial agents, lowering the risk of bacterial resistance development. A new series of methylene disalicylic acid/1,3,4-oxadiazole hybrids (5a-l) was developed as dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity. The structures of the novel compounds were validated using ¹H NMR, ¹³C NMR, and elemental microanalysis. Compounds 5a-l were tested for their inhibitory effect against E. coli DNA gyrase. Compounds 5g, 5h, 5j, and 5l exhibited the highest inhibitory activity against E. coli DNA gyrase, with IC₅₀ values ranging from 164 to 179 nM. Compound 5h has the highest potency as an E. coli DNA gyrase inhibitor with an IC₅₀ value of 164 nM, representing an enhanced potency compared to reference novobiocin. Compounds 5g, 5h, 5j, and 5l were tested against S. aureus DNA gyrase, E. coli, and S. aureus topoisomerase IV. The findings indicated that 5g, 5h, 5j, and 5l activities on DNA gyrase from S. aureus were predominantly less effective than those on E. coli gyrase, with IC₅₀ values ranging from 44 to 56 nM. Compound 5h was the most efficient inhibitor of E. coli and S. aureus topoisomerase IV. Compound 5h showed significant antibacterial effectiveness against the multi-drug resistant (MDR) VRE-12201 and MRSA (EMRSA-15) strains, outperforming the reference drugs vancomycin and amoxicillin. This study used molecular docking to analyze compound 5h with E. coli DNA gyrase B. ADME analysis highlighted enhanced lipophilicity, making it a promising candidate for further optimization as a Gyrase B inhibitor.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"6023-6037"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First structural Elucidation of Bcl-2 functional conversion induced by validated modulators using microsecond-scale molecular dynamics simulations and density functional theory.","authors":"N D Yash, Monika Jain, Amit Kumar Singh, Jayaraman Muthukumaran","doi":"10.1007/s11030-026-11479-5","DOIUrl":"10.1007/s11030-026-11479-5","url":null,"abstract":"<p><p>Cancer remains a leading cause of mortality worldwide, largely driven by uncontrolled cell proliferation and the evasion of apoptosis, a tightly regulated process essential for cellular homeostasis. The Bcl-2 family of proteins plays a central role in regulating the intrinsic apoptotic pathway, with anti-apoptotic Bcl-2 promoting cell survival by sequestering pro-apoptotic Bax. Although Bcl-2 functional converters (BFCs) have been experimentally validated to reprogram Bcl-2 toward a pro-apoptotic function, the molecular-level structural and dynamic mechanisms underlying this functional conversion remain poorly understood. In particular, direct atomistic evidence explaining how targeting the intrinsically flexible loop domain drives conformational switching in Bcl-2 is still lacking. To address this critical gap, the present study provides the first structural and dynamic insights into FLD-mediated functional conversion of Bcl-2 using representative synthetic, experimentally validated BFCs (BFC1103 & BFC1108). Molecular docking followed by atomistic microsecond-scale MD simulations was employed to delineate binding stability and conformational changes. Extensive docking analyses revealed strong binding affinity and persistent non-covalent interactions with key FLD residues. Long-timescale atomistic MD simulations demonstrated that FLD engagement induces pronounced conformational changes in Bcl-2, resulting in BH3 domain exposure and a Bax-like, pro-apoptotic structural state. Collectively, this work establishes a first-of-its-kind structural frame work that links FLD targeting to Bcl-2 functional conversion, thereby bridging experimental observations with atomistic simulations and providing a rational basis for the design of next-generation apoptosis-restoring anticancer therapeutics.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"5971-5987"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cu-catalyzed deaminative thiocyanation of anilines via nitrate reduction.","authors":"Yong-Sheng Zhou, Yan Yang, Jing-Yao Zhou, Li-Jun Xu, Yi-Xie Tan, Xin-Chun Zhang, Liang Wang","doi":"10.1007/s11030-026-11513-6","DOIUrl":"10.1007/s11030-026-11513-6","url":null,"abstract":"<p><p>An efficient protocol for the synthesis of aryl thiocyanates from anilines and KSCN by merging nitrate reduction with copper-catalysis has been developed. The combination of inexpensive Fe(NO₃)₃·9H₂O and Na₂S₂O₃·5H₂O enabled a safe and green diazotization of anilines. The fleeting diazonium salts reacted with KSCN rapidly to afford the aryl thiocyanates in good to excellent yields using Cu(OTf)₂ as the catalyst. The operational simplicity and safety, good substrate scope and scalability highlight the synthetic significance of this protocol.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"6167-6175"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated computational and experimental approaches for drug repurposing targeting key Mycobacterium tuberculosis proteins.","authors":"Hongfu Li, Likun Zhao, Zixin Liu, Zhenzhen Du, Jianhong Xie, Mingxing Huang, Huitao Huang, Hongtou Chan, Yijie Zhao, Henry H Y Tong, Xiaojun Yao, Huanxiang Liu, Qianqian Zhang","doi":"10.1007/s11030-026-11534-1","DOIUrl":"10.1007/s11030-026-11534-1","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"6323-6338"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploration of a Novel Imidazo[4,5-b]pyridine-dihydropyrimidinone hybrids as aurora kinase a inhibitors: integrated pharmacophore modelling, docking and simulation approaches.","authors":"Bhuvaneswari Sivaraman, Lalmohan Maji, Bharath Kumar Chagaleti, Kathiravan Muthukumaradoss","doi":"10.1007/s11030-026-11537-y","DOIUrl":"10.1007/s11030-026-11537-y","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"6367-6388"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluopyram analogues containing a five-membered heterocyclic ring moiety: synthesis, nematicidal activity and molecular docking study.","authors":"Zhitian Huang, Shenghong Jing, Qianyu Huang, Jie Chu, Hao Ling, Jiayi Wang, Gonghua Song","doi":"10.1007/s11030-026-11492-8","DOIUrl":"10.1007/s11030-026-11492-8","url":null,"abstract":"<p><p>Plant-parasitic nematode (PPNs) infections threaten global crop protection and result in substantial annual losses to agriculture worldwide. However, only a limited number of nematicides are currently available, and drug resistance is becoming a more significant concern. Therefore, there is an urgent need to develop new, highly effective, and environmentally friendly nematicides. This study designed and synthesized forty-two novel fluopyram analogues containing five-membered heterocyclic molecules via a \"Ring Replacement\" strategy. Results from the nematicidal activity testing showed that all the target compounds showed certain activity against Caenorhabditis elegans. Notably, compound 21r demonstrated an LC₅₀ value of 1.83 mg/L, which is significantly lower than that of the commercial nematicide, tioxazafen, but slightly higher than that of the SDHI nematicide, fluopyram. Enzymatic assays and molecular docking studies identified nematode SDH as the probable molecular target. An ecological and environmental risk assessment was also conducted on the target compound 21r. However, the long-term toxic effects of these compounds on aquatic life remain to be further explored. The study indicates that the thiophene moiety, a five-membered heterocyclic ring system, holds significant potential for developing novel SDHI nematicides. The results provide critical mechanistic insights and lay the groundwork for the development of novel nematicides, which will contribute to improving crop protection strategies in agriculture.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"6011-6022"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network pharmacology, molecular docking, and In Vitro evaluation of morin against gastric cancer.","authors":"Nilesh Naskar, Sunil Kumar, Deepanshu Mamgai, Harish Chandra Vishwakarma, Santosh Kumar Guru, Bijo Mathew, Naseer Maliyakkal, Uday R Kumar, Shweta Shrivastava, Manish Kumar Jeengar","doi":"10.1007/s11030-026-11535-0","DOIUrl":"10.1007/s11030-026-11535-0","url":null,"abstract":"<p><p>Gastric cancer (GC) remains one of the most prevalent and lethal malignancies worldwide. Natural flavonoids are increasingly recognized for their therapeutic potential due to their multi-target actions and favourable safety profiles. Morin, a dietary flavonol found in several plants of the Rosaceae, Moraceae, and Fagaceae families, has not been well explored in GC. In this study, network pharmacology analysis identified ten major morin-associated hub genes (PIK3R3, PIK3CA, PIK3CB, PIK3CD, PIK3R2, PLCG1, JAK2, IGF1R, ZAP70, and ERBB4), several of which are key regulators of the PI3K-Akt signalling axis. Molecular docking showed strong binding affinities of morin toward PIK3CD (-11.01 kcal/mol), ZAP70 (-10.72 kcal/mol), JAK2 (-10.53 kcal/mol), IGF1R (-9.99 kcal/mol), PIK3CA (-9.79 kcal/mol), and ERBB4 (-8.83 kcal/mol). Molecular dynamics simulations of 500 ns, along with PCA, DCCM, FEL, and MM-GBSA analyses further confirmed stable interaction of morin with PIK3CA. In vitro, morin demonstrated selective cytotoxicity, with low IC₅₀ values in AGS (15.16 ± 0.02 μM) and NCI-N87 (15.85 ± 0.8 μM) GC cells, compared to a significantly higher IC₅₀ in normal MCF10A cells (101.97 ± 2.61 μM). Wound-healing assays showed that morin inhibits AGS cell migration in a dose- and time-dependent manner. Integrating in silico and in vitro evidence, we propose that morin primarily targets PIK3CA leading to modulation of the PI3K-Akt pathway, thereby contributing to reduced proliferation and migration of GC cells. Together, these findings highlight morin as a promising natural molecule with therapeutic potential against gastric cancer.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"6339-6366"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and antifungal and antitumor activities of acridine-containing tetrahydronaphthalene spiroisoxazoline derivatives.","authors":"Tianhao Pang, Yanhui Zhao, Yuanhao Li, Jianling Gao, Xueqing Zhang, Ayzukram Yasen, Buer Song","doi":"10.1007/s11030-026-11524-3","DOIUrl":"10.1007/s11030-026-11524-3","url":null,"abstract":"<p><p>To develop novel functional molecules with both antifungal and antitumor activities, this study rationally designed and synthesized 11 acridine-containing tetrahydronaphthalene spiroisoxazoline derivatives based on the bioactive fragment characteristics of isoxazoline, acridine, tetrahydronaphthalene, and spirocycle moieties. Using o-aminoacetophenone and other reagents as starting materials, the target compounds were prepared via a multi-step synthetic route involving copper-catalyzed Ullmann coupling, Wittig reaction, and Huisgen cycloaddition. The results of biological activity assays demonstrated that these compounds exerted definite antifungal effects against a variety of fungi, especially Ampelomyces humuli. Among them, compound 10a displayed the half-maximal effective concentration value of 0.9768 µg/mL against Ampelomyces humuli, which was superior to that of the positive controls Chlorothalonil (1.767 µg/mL), Famoxadone (13.87 µg/mL), and Carbendazim (27.02 µg/mL). The mycelial growth rate method indicated that its inhibitory effect on the mycelial growth of Ampelomyces humuli was concentration-dependent. Fluorescence staining experiments revealed that this compound could induce damage to fungal cell membranes and inhibit fungal spore secretion. In vitro experiments confirmed that it possessed certain protective and curative effects on corn leaves infected by Ampelomyces humuli. In addition, cytotoxicity studies showed that these compounds exhibited relatively high toxicity against normal cells while exerting significant antiproliferative activity against human colorectal cancer cells; notably, compound 10e had the half-maximal inhibitory concentration value of 2.53 µM, which was higher than that of the positive controls Cisplatin (36.00 µM) and Doxorubicin (10.43 µM). These findings suggest that the novel acridine-containing tetrahydronaphthalene spiroisoxazoline derivatives with multiple active fragments hold promise as candidates for the development of new antifungal agents and antitumor drugs.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"6205-6219"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validated virtual screening models for identifying allosteric inhibitors of ATP-citrate lyase: the role of docking scores and protein-ligand interaction similarity in hit selection.","authors":"Tan Thanh Mai, Nghia Vo-Trong Lai, Thua-Phong Lam, Lam Nguyen-Ngoc Truong, My Ngoc Nguyen, Nghi Van-Tuong Nguyen, Minh-Hoang Phan, Lam-Truong Tuong, Khac-Minh Thai","doi":"10.1007/s11030-026-11519-0","DOIUrl":"10.1007/s11030-026-11519-0","url":null,"abstract":"<p><p>ATP-citrate lyase (ACLY) is an upstream enzyme involved in fatty acid synthesis, cholesterol metabolism, and histone acetylation. Therefore, selective inhibition of ACLY represents a promising strategy for the treatment of dyslipidemia and various cancers. Recently, the cryo-EM structure of the ACLY complex with the allosteric inhibitor NDI-091143 has been reported, providing an opportunity to discover new potent inhibitors of this emerging target. In this in silico study, we report structure-based models that were rigorously developed and evaluated using reported allosteric inhibitors of ACLY. The pharmacophore model (ROC-AUC = 0.85, GH = 0.78, and EF_1% = 49.18) and the molecular docking model (RMSD_redock = 0.884 Å and ROC-AUC = 0.95) were applied to virtual screening of the ZINC15 library. During hit selection for further evaluation by molecular dynamics simulations, post-docking analysis was performed based on docking scores (ΔG_dock) alone and in combination with the Tanimoto similarity coefficient of protein-ligand interaction fingerprints (Tc_IFP). The combined ΔG_dock and Tc_IFP approach enabled the identification of four out of five selected top hits with binding free energies more favorable than that of the reference compound NDI-091143, supporting their potential as allosteric ACLY inhibitors. These compounds may be subjected to further experimental evaluation to confirm their biological activity. In addition, the workflow developed in the present study may provide a basis for future discovery and optimization of allosteric ACLY inhibitors.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"6177-6192"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of new sulfonamides from sulfamethizole: in vitro antitubercular and antimicrobial activities supported by molecular docking, molecular dynamics, and ADME studies.","authors":"Sevda Türk, Burak Kırılmaz, Elif Çiftçi, İsmail Çelik, Sevgi Karakuş, Dilek Şatana","doi":"10.1007/s11030-026-11544-z","DOIUrl":"10.1007/s11030-026-11544-z","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"6389-6402"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147662110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}