Bioorganic & Medicinal Chemistry最新文献

{"title":"Tackling microbial resistance with 4H-chromen-4-one derivatives as a novel class of penicillin binding protein 2a inhibitors","authors":"Menna-Allah W. Shalaby ,&nbsp;Nader S. Abutaleb ,&nbsp;Eman M.E. Dokla ,&nbsp;Yehia Elgammal ,&nbsp;Hsin-Wen Liang ,&nbsp;Rabah A.T. Serya ,&nbsp;Inas A. Abdallah ,&nbsp;Jennifer Fishovitz ,&nbsp;Mohamed N. Seleem ,&nbsp;Khaled A.M. Abouzid","doi":"10.1016/j.bmc.2025.118376","DOIUrl":"10.1016/j.bmc.2025.118376","url":null,"abstract":"<div><div>With the continued upsurge of antibiotic resistance and reduced susceptibility to almost all frontline antibiotics, there is a pressing need for the development of new, effective, and safe alternatives. In this study, a scaffold-hopping strategy was utilized to develop a novel class of penicillin-binding protein 2a (PBP2a) inhibitors, centered around a 4<em>H</em>-chromen-4-one core structure. These newly designed compounds demonstrated strong antibacterial efficacy against methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) and other drug-resistant gram-positive pathogens. Notably, compounds <strong>16</strong> and <strong>18</strong>–<strong>20</strong> exhibited significant potency against the tested Staphylococcal strains, with minimum inhibitory concentrations (MICs) ranging from 0.008 to 1 μg/mL, outperforming standard treatments such as vancomycin and linezolid, as well as the reference compound <strong>III</strong>. These derivatives also retained their activity against a range of clinically relevant multidrug-resistant gram-positive bacteria and showed no detectable cytotoxicity in human cell assays. Additionally, compounds <strong>19</strong> and <strong>20</strong> displayed synergistic effects when co-administered with β-lactam antibiotics against two MRSA strains. Finally, these derivatives exhibited excellent binding affinities to the allosteric site of PBP2a, with dissociation constants ranging from 13 to 23 μM, indicating that this novel class inhibits PBP2a as the primary target by binding non-covalently to its allosteric site, hence impairing cell-wall crosslinking, and resulting in cell death. Accordingly, the reported 4<em>H</em>-chromen-4-one-based class of inhibitors merit further investigation as potential therapeutic options for treatment of staphylococcal infections.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118376"},"PeriodicalIF":3.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145004135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the bioactive constituents from spices targeting N-methyl-d-aspartate receptors: An in silico and in vitro approach to identify druggable leads against neurological disability","authors":"Nemat Ali ,&nbsp;Salim S. Al-Rejaie ,&nbsp;M. Arockia Babu ,&nbsp;Prashant Nayak ,&nbsp;VenuPrasad KD ,&nbsp;Mohamed Mohany ,&nbsp;Thakur Gurjeet Singh ,&nbsp;Mohammad Suhail Akhter ,&nbsp;Mohammad Fareed ,&nbsp;Yogita Tyagi ,&nbsp;Nisha Bansal ,&nbsp;Sarthak Puri","doi":"10.1016/j.bmc.2025.118378","DOIUrl":"10.1016/j.bmc.2025.118378","url":null,"abstract":"<div><div><em>N</em>-methyl-<span>d</span>-aspartate (NMDA) receptors are validated druggable targets for the treatment of Alzheimer's and other associated neurological conditions, particularly in individuals with disabilities. Considering the excitotoxicity associated with NMDA receptors, which leads to neuronal damage, cognitive impairment, and limitations of current therapeutic regimens, better therapeutic candidates are required. One of the validated drug discovery approaches is computer-assisted drug discovery, supplemented by molecular docking, mechanics, and dynamics. To this end, we curated 134 bioactive constituents derived from spices. These were subjected to high-throughput virtual screening (HTVS) considering the pharmacophoric features of the NMDA receptor. Molecular docking, followed by molecular mechanics and dynamics, indicated that curcumin and quercetin could plausibly bind to the NMDA receptor in comparison to memantine. In vitro ELISA-based analysis revealed that curcumin may inhibit the NMDA receptor with an IC50 of 2.36 μM compared to memantine's 736.48 nM, employed as a positive control. However, targeting the neuronal receptor NMDA requires that the ligand efficiently cross the blood-brain barrier (BBB). To overcome this challenge, we performed a rational bioisosteric replacement strategy to potentially optimize the pharmacokinetic features of curcumin without affecting its NMDA binding. We generated 150 bioisosteres of curcumin, and through extensive computational analyses, the top 5 scoring molecules were further validated via a molecular dynamics approach. However advantageous, in the present work, curcumin or its proposed derivatives have not been corroborated by extensive biological investigation. It is a prototype study to identify the druggable leads from the spices that have the potency to interact and inhibit NMDA. Owing to this, the mechanism of action is not fully elucidated. Further, the work upon validation (biologically) may serve as a useful pharmacophore (tool molecule) using which NMDA may be downregulated. The designed derivatives thus open avenues to synthesize and biologically test them against NMDA inhibition, plausibly establishing their roles in Alzheimer's and related disabilities.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118378"},"PeriodicalIF":3.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin derivatives as ferroptosis inducers: design, synthesis and anti breast cancer activity evaluation","authors":"Nan Wu ,&nbsp;Yue Zhang ,&nbsp;Xiongjie Yin ,&nbsp;Peng Du ,&nbsp;Yan Piao ,&nbsp;Jiuzhen Zhao ,&nbsp;Jing Zhu ,&nbsp;Zheshan Quan ,&nbsp;Cheng-Zhu Wu ,&nbsp;Lili Jin ,&nbsp;Changhao Zhang","doi":"10.1016/j.bmc.2025.118374","DOIUrl":"10.1016/j.bmc.2025.118374","url":null,"abstract":"<div><div>Curcumin (CUR) is a natural product isolated from <em>Curcuma longa</em> L., which has become a research hotspot due to its significant anti-tumor activity by inducing tumor cell apoptosis and inhibiting proliferation. This study designed and synthesized <strong>20</strong> CUR derivatives containing 1,2,3-triazoles and heterocycles by modifying the methylene group between two carboxyl groups of CUR and hybridizing with aldehyde containing fragments. Among them, compound <strong>A4</strong> showed significant in vitro anti proliferative activity against 4T1 and MDA-MB-231, and could dose dependently induce early and late apoptosis in 4T1 cells. Further research has found that <strong>A4</strong> induces ferroptosis in 4T1 cells by regulating the levels of reactive oxygen species (ROS), ferrous ions (Fe²⁺), lipid peroxidation (LPO), and glutathione (GSH), as well as disrupting the integrity and homeostasis of mitochondrial membranes. In addition, <strong>A4</strong> significantly inhibits the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), while promoting the expression of p53 protein. Gene knockout test confirmed that <strong>A4</strong> may induce cell ferroptosis through p53/SLC7A11/GPX4 signaling pathway and play an anti breast cancer role. These findings indicate that CUR derivative <strong>A4</strong> is a new type of ferroptosis inducer. It can induce apoptosis of cells by regulating multiple targets in cells to achieve the purpose of anti breast cancer, which is helpful for cancer treatment and overcoming the further development of drug resistance.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118374"},"PeriodicalIF":3.0,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 activity of novel para-substituted phenylamino and phenyl derivatives of northebaine as selective delta opioid receptor agonists","authors":"Denggao Zhang ,&nbsp;Jiangwen Gui ,&nbsp;Linghui Kong ,&nbsp;Chuyuan Hu ,&nbsp;Xinmeng Kou ,&nbsp;Biying Wang ,&nbsp;Shaoliang Duan ,&nbsp;Min Liu ,&nbsp;Zixiang Li ,&nbsp;Jiawen Luo ,&nbsp;Siyuan Tang ,&nbsp;Hui Xiao ,&nbsp;Zeyi Du ,&nbsp;Qiong Xie ,&nbsp;Jinggen Liu ,&nbsp;Liming Shao ,&nbsp;Wei Fu ,&nbsp;Yujun Wang ,&nbsp;Wei Li","doi":"10.1016/j.bmc.2025.118373","DOIUrl":"10.1016/j.bmc.2025.118373","url":null,"abstract":"<div><div>The delta opioid receptor (DOR) is a promising target for developing analgesics with fewer side effects compared to mu opioid receptor (MOR) agonists. However, non-peptidyl DOR-selective agonists remain limited. Using the “message-address” concept in opioid ligand design, we designed and synthesized a series of <em>para</em>-substituted <em>N</em>-cyclopropylmethyl-7α-phenyl-6,14-<em>endo</em>etheno-tetrahydronorthebaines to explore their binding affinity and selectivity for DOR over MOR and kappa opioid receptor (KOR). Key findings revealed that <em>para</em>-substituted phenylamino derivatives exhibited high DOR affinity and subtype selectivity. Functional assays confirmed their agonistic activity at DOR, with compounds <strong>4a</strong> and <strong>4e</strong> showing IC₅₀ values of 580.9 <em>n</em>M and 4807 <em>n</em>M, respectively. Molecular modeling studies revealed that DOR selectivity might be mediated by specific interactions with residue L300^7.35 in the TM7 domain, where structural rearrangement of the address component facilitates its transition from KOR- to DOR-selective binding modes. These findings highlight the critical role of “address” component optimization in achieving receptor subtype specificity, providing a structure-based strategy for developing new opioid therapeutics with tailored pharmacological profiles.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118373"},"PeriodicalIF":3.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances of HDAC dual inhibitors in breast cancer treatment","authors":"Chuanjiang Wu ,&nbsp;Jiyong Wu ,&nbsp;Linlin Ni ,&nbsp;Minyan Liang ,&nbsp;Rui Feng ,&nbsp;Xiaoni Kong ,&nbsp;Honglei Zhou ,&nbsp;Jing Nie","doi":"10.1016/j.bmc.2025.118372","DOIUrl":"10.1016/j.bmc.2025.118372","url":null,"abstract":"<div><div>Breast cancer remains the most common prevalent malignancy among women globally, constituting the primary cause of cancer-associated mortality. While therapeutic advancements have been achieved, persistent challenges in treatment resistance, disease recurrence, and distant metastasis continue to undermine clinical outcomes. Histone deacetylases (HDACs), a conserved family of epigenetic regulators, catalyze the removal of acetyl groups from histone substrates, thereby orchestrating chromatin remodeling and transcriptional regulation. Beyond their canonical epigenetic functions, these enzymes critically modulate diverse oncogenic progresses, including cell proliferation, differentiation, and metastasis, positioning them as promising therapeutic targets in oncology. Recent studies have demonstrated the therapeutic prospects of dual-target inhibitors. Current evidence suggests such combinatorial approaches not only enhance anti-neoplastic efficacy through multi-modal mechanisms but also circumvent the drug resistance frequently observed in single-target therapy. This therapeutic paradigm shift underscores the clinical potential of HDAC-based dual inhibitors for breast cancer management. In this review, we systematically analyze recent advancements in dual-target HDAC inhibitors (HDACis), integrating mechanistic insights, preclinical evidences, and translational implications to establish a foundational framework for future therapeutic development and clinical implementation.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118372"},"PeriodicalIF":3.0,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144917633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of a cryptic ligand binding site on Plasmodium falciparum Hsp90","authors":"Christopher R. Mansfield ,&nbsp;Elizabeth L. Taggart ,&nbsp;Michael E. Chirgwin ,&nbsp;Emily R. Derbyshire","doi":"10.1016/j.bmc.2025.118371","DOIUrl":"10.1016/j.bmc.2025.118371","url":null,"abstract":"<div><div>The molecular chaperone heat shock protein 90 (Hsp90) has an important role in maintaining proteostasis in <em>Plasmodium</em> parasites, the causative agents of malaria, and is of interest as a potential antimalarial drug target. Inhibitors targeting its well-characterized N-terminal ATP-binding site are lethal, but the development of high-affinity binders with selectivity for the <em>Plasmodium</em> over the human homolog has been challenging given the high conservation of this domain. A binding site in the less conserved Hsp90 C-terminus has been reported to interact with nucleotides and inhibitors in other eukaryotic systems, which could offer an alternative route for antimalarial design. Herein, we characterize the potential ligandability of the C-terminus in the <em>Plasmodium falciparum</em> chaperone PfHsp90 with in silico and in vitro methods. We conducted affinity experiments with both a lysine-reactive nucleotide analog and an ATP resin that support a specific interaction between ATP and a C-terminal truncation of PfHsp90. We further explored the nucleotide structural requirements for this interaction with limited proteolysis experiments, which suggest association with ATP, dATP, and ADP, but not AMP or GTP. Lastly, we employed computational analyses and mutagenesis studies to interrogate the molecular basis for the interaction. Our findings provide the foundation for future studies to assess and develop C-terminal Hsp90 inhibitors against <em>Plasmodium</em> parasites.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118371"},"PeriodicalIF":3.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hybrid molecules of ibuprofen and piperidone: a rational approach toward anti-cancer drug development","authors":"Siva S. Panda ,&nbsp;Walid Fayad ,&nbsp;Ahmed A.F. Soliman ,&nbsp;Pablo S. Chagas ,&nbsp;Sahar Emami Naeini ,&nbsp;Mohamed A. Morsy ,&nbsp;FaithAnn A. Ferguson ,&nbsp;Kunj Bihari Gupta ,&nbsp;Guido F. Verbeck ,&nbsp;Babak Baban ,&nbsp;Muthusamy Thangaraju ,&nbsp;Bal L. Lokeshwar ,&nbsp;Adel S. Girgis","doi":"10.1016/j.bmc.2025.118370","DOIUrl":"10.1016/j.bmc.2025.118370","url":null,"abstract":"<div><div>The persistent challenge of cancer treatment, exacerbated by multidrug resistance and the limited effectiveness of monotherapies, underscores the need for innovative therapeutic strategies. This study details the design, synthesis, and biological evaluation of a novel series of twelve hybrid conjugates (<strong>7a–l</strong>) that combine a curcumin-mimic scaffold (3,5-diarylidene-4-piperidinone), ibuprofen, and amino acid linkers. By employing a molecular hybridization approach, the synthesized compounds were thoroughly characterized and assessed for their antiproliferative activity against diverse cancer cell lines, including A431 (skin), HCT116 (colon), and MCF7 (breast). Flow cytometry results suggest that these potent hybrids induce G1-phase cell cycle arrest and apoptosis. Among them, compound <strong>7b</strong> emerged as the most effective candidate. Both in vitro and in vivo studies demonstrated that <strong>7b</strong> exhibited superior efficacy compared to cisplatin in melanoma models, significantly reducing tumor growth and improving survival rates. Mechanistic investigations indicate that MDM2 inhibition and p53 activation may be key mechanisms of action, supported by enzymatic assays, molecular docking analyses, and dynamic simulations. Quantitative Structure-Activity Relationship (QSAR) modeling further elucidated the critical structural descriptors influencing bioactivity. These findings underscore the therapeutic potential of curcumin-inspired hybrid conjugates as multi-target anticancer agents and establish a solid foundation for future preclinical development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118370"},"PeriodicalIF":3.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144913464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and synthesis of novel thrombopoietin mimetic peptides via dual-mechanistic modification","authors":"Jun Xu ,&nbsp;Jiahui Xu ,&nbsp;Jianguang Lu ,&nbsp;Yuanzhen Dong ,&nbsp;Xue Feng ,&nbsp;Yapeng Wang ,&nbsp;Hongxiang Zhu ,&nbsp;Chengcheng Wang ,&nbsp;Jun Feng","doi":"10.1016/j.bmc.2025.118365","DOIUrl":"10.1016/j.bmc.2025.118365","url":null,"abstract":"<div><div>Thrombopoietin (TPO) mimetic peptides activate c-Mpl receptor-mediated signaling to stimulate platelet production, possessing similar bioactivity to endogenous TPO. However, their clinical application is limited by rapid clearance <em>in vivo</em> (t₁_/₂ ≈ 1 h). To address this limitation, various long-acting modification strategies, such as PEGylation and Fc fusion, have been extensively developed. In this study, we designed a new molecule by integrating two long-acting technologies with complementary mechanisms: (1) fatty acid conjugation to enhance albumin binding, and (2) XTENylation to increase hydrodynamic radius. The novel TPO mimetic peptide demonstrated comparable <em>in vitro</em> activity (0.12 ± 0.076 nM <em>vs.</em> romiplostim 0.10 ± 0.026 nM) and comparable <em>in vivo</em> platelets elevating efficacy in normal mice to romiplostim while exhibiting superior pharmacokinetic properties: prolonged elimination half-life (10.86 ± 0.36 h <em>vs.</em> 2.93 ± 0.05 h in controls) and elevated maximum plasma concentration (184.57 ± 64.00 ng/mL <em>vs.</em> 93.22 ± 60.99 ng/mL in controls). These findings validate the synergistic efficacy of dual-mechanistic modifications and provide a novel strategy for developing next-generation TPO therapeutics with tunable pharmacokinetic profiles.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118365"},"PeriodicalIF":3.0,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Alzheimer's pathology: Tetralone- and thiochromanone-based benzyl pyridinium derivatives as promising multi-target-directed ligands","authors":"Anjali Sobha ,&nbsp;Lekshmy Krishnan ,&nbsp;Shareef Shaik ,&nbsp;Aravinda Pai ,&nbsp;Jayamurthy Purushothaman ,&nbsp;Kumaran Alaganandam ,&nbsp;Sasidhar B. Somappa","doi":"10.1016/j.bmc.2025.118369","DOIUrl":"10.1016/j.bmc.2025.118369","url":null,"abstract":"<div><div>The lack of therapeutics that can fully halt the progression of Alzheimer's disease (AD) has prompted us to design and synthesize a series of tetralone/thiochromanone-based benzyl pyridinium salts <strong>(4a-4</strong><strong>s)</strong> aimed at modulating multiple pathological targets associated with AD. Preliminary screening for cholinesterase and monoamine oxidase inhibition identified compounds <strong>4e</strong> and <strong>4</strong><strong>g</strong> as the most potent inhibitors (AChE IC₅₀: 2.17 ± 0.13 μM and 2.29 ± 0.15 μM; MAO-B IC₅₀: 0.89 ± 0.07 μM and 0.92 ± 0.16 μM, respectively). Both compounds also demonstrated anti-neuroinflammatory activity by reducing pro-inflammatory cytokines (TNF-α and IL-6) and downregulating COX-2 and NF-κB signalling pathways. Additionally, <strong>4e</strong> exhibited significant ROS scavenging ability by mitigating oxidative stress and conferred neuroprotection in SH-SY5Y cells by attenuating Aβ₁₋₄₂-induced mitochondrial dysfunction and apoptosis. Collectively, these findings position compound <strong>4e</strong> as a promising multi-target-directed ligand (MTDL) for the treatment of AD.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118369"},"PeriodicalIF":3.0,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144913462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of novel Piperazine based bisubstrate inhibitors of human nicotinamide N-methyltransferase (hNNMT) with potential anticancer activities","authors":"A.S. Harikrishna ,&nbsp;Venkitasamy Kesavan","doi":"10.1016/j.bmc.2025.118368","DOIUrl":"10.1016/j.bmc.2025.118368","url":null,"abstract":"<div><div>Overexpression of human Nicotinamide <em>N</em>-methyltransferase (hNNMT), nictotinamide metabolizing enzyme, is associated with numerous diseases including metabolic disorders and several cancers. Hence, development of novel inhibitors against hNNMT activity would result in New Chemical Entities (NCEs). Further, identification of novel bisubstrate inhibitors which bind to substrate and co-factor binding pockets of hNNMT is more challenging and warranted. In this present study, we methodically investigated piperazine derivatives as novel bisubstrate inhibitors of hNNMT with potential anticancer activities. Initially, studies on the piperazine derivatives were undertaken to determine their binding affinities with hNNMT <em>in silico</em>. The molecules, which displayed potent binding affinity <em>in silico</em>, were synthesized and further subjected to biochemical, biophysical and computational studies. Thus, we have identified a novel bisusbtrate inhibitor of hNNMT with nanomolar IC₅₀. Computational studies demonstrated that incorporation of quinolone pharmacophore enables the binding in the pocket of cofactor “SAM” and pyridine moiety at the substrate “nicotinamide”. The MOA studies suggest that compound 7b functions as a bisubstrate competitive inhibitor of hNNMT, exhibiting competitive inhibition with respect to both SAM and quinoline, without altering V_max. These observations indicate the identification of novel bisubstrate inhibitors which can be further diversified to improve their DMPK properties. Furthermore, cellular assays showed that compounds 7b, 7c, and 7d selectively suppressed the proliferation of U87 and PANC-1 cancer cells, and low cytotoxicity in HEK293 normal cell lines. Notably, compound 7b exhibited the strongest antiproliferative activity, underscoring the therapeutic potential of this scaffold in targeting NNMT-associated cancers.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118368"},"PeriodicalIF":3.0,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}