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":"https://doi.org/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":""},"PeriodicalIF":3.8,"publicationDate":"2026-02-24","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":"Molecular insights into anti-cancer cyclotides and their interaction with breast cancer targets: an in silico study.","authors":"Ankita Grover, Sawraj Singh, Lovekesh Mehta, Sanjay Kumar","doi":"10.1007/s11030-026-11480-y","DOIUrl":"https://doi.org/10.1007/s11030-026-11480-y","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225099","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":"https://doi.org/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":""},"PeriodicalIF":3.8,"publicationDate":"2026-02-19","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":"Pan-cancer multi-omics characterization of CDK12 and virtual screening of Vietnamese natural products for novel inhibitors.","authors":"Thanh Dat Pham, Le Bao Xuyen Nguyen, Trung Duc Luu, Minh Tuan Nguyen, Nhung Thi Hong Le, Thach Phan Van","doi":"10.1007/s11030-026-11477-7","DOIUrl":"https://doi.org/10.1007/s11030-026-11477-7","url":null,"abstract":"<p><p>Cyclin-dependent kinase 12 (CDK12), a key regulator of cell-cycle-linked transcriptional programs, has gained increasing attention as a driver of tumorigenesis and a promising therapeutic vulnerability across diverse malignancies. In this study, we combined pan-cancer multi-omics profiling with a computational screen of a Vietnamese medicinal herbs compound library to identify candidate inhibitors targeting both wild-type CDK12 and its drug-resistant C1039F variant. Transcriptomic and proteomic analyses of TCGA and GTEx datasets revealed significant CDK12 overexpression in 14 tumor types compared with matched normal tissues. Overall survival comparisons further indicated that elevated CDK12 expression predicts markedly poorer outcomes in different renal cancer types and glioma, whereas genomic profiling identified ovarian cancer as the malignancy with the highest frequency of CDK12 alterations. Immune deconvolution analyses showed strong associations between CDK12 expression and infiltration by endothelial cells and natural killer T cells, suggesting a link between CDK12 dysregulation and tumor immune evasion. Complementing the multi-omics investigation, molecular docking, molecular dynamics simulations, and MM/PBSA free-energy calculations were conducted to evaluate the binding profiles of natural compounds derived from Vietnamese medicinal plants against both CDK12 variants. Several phytochemicals including 2,3-Diepicastasterone from Phaseolus vulgaris (- 131.038 ± 23.572 kcal/mol), as well as compounds from Eurycoma longifolia and Oryza sativa-exhibited highly favorable binding affinities and stable interaction dynamics, highlighting them as promising scaffolds for CDK12 inhibitor development. Collectively, our findings establish CDK12 as a robust biomarker for cancer diagnosis, prognosis, and immune modulation, while highlighting natural-product-based scaffolds as promising leads for next-generation CDK12 inhibitors targeting both wild-type and resistant variants, potentially synergizing with emerging immuno-oncology strategies.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218286","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":"Discovery of 5-fluoro-aminopyrimidine derivatives as dual BTK/FLT3 inhibitors for the treatment of rheumatoid arthritis.","authors":"Fansheng Ran, Yifan Ma, Tiantian Sun, Liujie Ji, Qinyan Cai, Yanan Zhang, Yong Ling, Chunlin Zhuang","doi":"10.1007/s11030-026-11484-8","DOIUrl":"https://doi.org/10.1007/s11030-026-11484-8","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is a severe autoimmune disease characterized by dysregulated functions of multiple immune cells such as phagocytes, lymphocytes, and dendritic cells. Bruton's tyrosine kinase (BTK) and FMS-like tyrosine kinase 3 (FLT3) play critical roles in RA pathogenesis, regulating B-cell survival, myeloid cell differentiation, and dendritic cell activation. Starting from the lead compound CC-292, a series of novel 5-fluoro-aminopyrimidine derivatives were designed and synthesized as dual BTK/FLT3 inhibitors for potential RA therapy. Our in vitro screening revealed that compounds 7a, 7b, and 7c are potent dual inhibitors, demonstrating potent activity with IC₅₀ values in the low nanomolar range. Among them, 7b demonstrated particularly strong dual-target activity (BTK IC₅₀ = 18 nM; FLT3 IC₅₀ = 10 nM), along with high plasma stability and hepatic microsomal metabolic stability. In collagen-induced arthritis model, 7b administration produced dose-dependent reductions in joint swelling and significantly mitigated cartilage degradation and bone erosion, as confirmed by histopathological evaluation. Acute toxicity tests revealed no obvious adverse effects at a dose of 1000 mg/kg, indicating a promising safety profile. This work presents not only a promising lead compound but also a strategic framework for developing next-generation RA therapies.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218225","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":"A multifunctional 5-fluorouracil prodrug: synthesis, biological evaluation, and antitumor mechanism investigation.","authors":"Ran Zhang, Liqing Tang, Jianglong He, Guanyu Jiang, Yingfei Su, Xueping Jiang, Ping Wu, Dongyang Zhang, Sitong Chen, Hao Li, Zhongzheng Gui","doi":"10.1007/s11030-025-11445-7","DOIUrl":"https://doi.org/10.1007/s11030-025-11445-7","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218249","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":"Recent advances in Xanthone-based molecular hybrids: emerging therapeutic strategies for multifactorial diseases.","authors":"Nilanjana Medhi, Lingkan Kalita, Jessica Kalita, Nilotpal Choudhury, Deijy Choudhury, Babita Deka, Pooja Patowary, Debaprotim Dasgupta, Bhargab Jyoti Sahariah, Bitu Gogoi, Muslek Uddin Mazumder","doi":"10.1007/s11030-026-11472-y","DOIUrl":"https://doi.org/10.1007/s11030-026-11472-y","url":null,"abstract":"<p><p>Multifactorial diseases such as cancer, diabetes, neurodegenerative and inflammatory disorders remain major global health challenges due to their complex pathophysiology and limited therapeutic options. Xanthones (9 H-xanthen-9-ones), a class of oxygenated heterocycles with a dibenzo-γ-pyrone scaffold, have emerged as privileged structures in drug discovery owing to their exceptional structural diversity and broad spectrum of biological activities. This review highlights recent advances in the design and development of xanthone-based molecular hybrids, which integrate multiple bioactive pharmacophores to achieve multitarget or synergistic therapeutic effects. Structure-activity relationship (SAR) and quantitative structure-activity relationship (QSAR) studies have elucidated key functional modifications such as hydroxylation, prenylation, and hybridization with heterocyclic or amino alkyl groups-that significantly enhance potency, selectivity, and safety. Natural and synthetic xanthone derivatives have demonstrated promising antibacterial, anticancer, anti-inflammatory, antioxidant, antidiabetic, and neuroprotective properties, with molecular targets ranging from COX-2 and α-glucosidase to topoisomerase II and cholinesterase. Triazole-, thiazole-, chalcone-, and alkyl benzylamine-linked xanthone hybrids exhibit multitarget activity suitable for treating complex diseases. Collectively, these findings position xanthone-based hybrids as versatile scaffolds with high translational potential, warranting further preclinical and clinical evaluation to optimize pharmacokinetics, efficacy, and safety for next-generation therapeutics.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146217958","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":"https://doi.org/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":""},"PeriodicalIF":3.8,"publicationDate":"2026-02-18","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":"Integrating computational and biological approaches for the discovery of putative MmpL3 inhibitors against Mycobacterium tuberculosis.","authors":"Likun Zhao, Hongfu Li, Xiuling Ma, Jiahao Sun, Henry H Y Tong, Huitao Huang, Hongtou Chan, Xiaojun Yao, Huanxiang Liu, Qianqian Zhang","doi":"10.1007/s11030-026-11478-6","DOIUrl":"https://doi.org/10.1007/s11030-026-11478-6","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146163440","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":"Plant-derived coumarins: emerging natural scaffolds for antidiabetic drug discovery.","authors":"Sakshi Attri, Sanjeev Kumar Sahu, Paranjeet Kaur","doi":"10.1007/s11030-026-11474-w","DOIUrl":"https://doi.org/10.1007/s11030-026-11474-w","url":null,"abstract":"<p><p>Diabetes mellitus is a leading global health problem, with type 2 diabetes being the main type and already very inefficient treatments posing a challenge. Plant-based compounds, especially those that are naturally occurring have become very popular lately and are regarded as major sources of new antidiabetic drugs owing to the diversity of their structures and the fact that they act on multiple targets at the same time. One of these groups of compounds is coumarins, which have proved to be an important class of bioactive substances with considerable antidiabetic properties. The review that we are presenting gives an inclusive report on the occurrence of natural coumarins and their derivatives with antidiabetic activity being reported, along with the discussion of their mechanisms of action that include among others the inhibition of the enzymes that digest carbohydrates, increase of the insulin sensitivity, regulation of the glucose uptake, protection of the pancreatic β-cells and regulation of oxidative stress and inflammation. Also, the structure-activity relationships of coumarin derivatives are discussed to bring out the important functional features that are responsible for the biological activity. Moreover, the latest developments in drug design, molecular docking studies and the therapeutic prospects of coumarin-based antidiabetic agents have been reviewed. Overall, this review has pointed out the plant-based coumarins as being very versatile scaffolds in the development of antidiabetic therapeutics that are both safe and effective with fewer side effects.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146163443","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}