BIOORGANIC & MEDICINAL CHEMISTRY生物有机化学与药物化学
BIOORGANIC & MEDICINAL CHEMISTRY(英文缩写 BIOORGAN MED CHEM),ISSN 0968-0896,eISSN 1464-3391,中文译名:生物有机化学与药物化学 是一本学术期刊。本页汇总该期刊的最新影响因子、分区信息以及最新收录于 PubMed 的文献,帮助您快速了解期刊全貌。
发文量统计区间：2025-09-27 至 2026-09-27，按本站收录文献的发表日期统计。
期刊介绍
历年影响因子趋势
| JCR 数据年份 | 影响因子 | JCR 分区 |
|---|---|---|
| 2021 | 3.461 | Q2 |
| 2022 | 3.500 | Q1 |
| 2023 | 3.300 | Q1 |
| 2024 | 3.000 | Q1 |
| 2025 | 3.500 | Q1 |
BIOORGANIC & MEDICINAL CHEMISTRY 最新收录文献
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1. Novel hydrazone-linked pyridin-1-ium salts as multi-targeted agents for Alzheimer's disease: design, synthesis, in vitro and in silico studies.
1. 新型腙键联吡啶-1-鎓盐作为阿尔茨海默病多靶点药物：设计、合成、体外与计算机模拟研究PMID:日期:2026-11-01Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder requiring multi-target-directed ligands (MTDLs) to simultaneously modulate cholinergic dysfunction and amyloid-β pathology. In this study, a series of hydrazone-linked pyridin-1-ium salts was rationally designed and synthesized by integrating key pharmacophores of acetylcholinesterase (AChE) and β-secretase 1 (BACE-1) inhibitors into a compact scaffold. Biological evaluation revealed potent AChE inhibitory activity for most compounds, with several derivatives outperforming donepezil. Compound 8b exhibited the highest potency (IC = 0.026 ± 0.005 μM). Structure-activity relationship analysis indicated that small, moderately polar substituents enhanced AChE inhibition, whereas the introduction of bulkier groups into this series led to a relative improvement in BACE-1 inhibitory activity. Kinetic studies on AChE suggested a mixed-type inhibition mechanism. Molecular docking favored key π-π and π-cation interactions within the AChE gorge, while hydrophobic interactions contributed to BACE-1 binding. Complementing the static docking analysis, all-atom MD simulations further supported persistent residence of compound 8b within both AChE and BACE-1 binding sites, with interaction fingerprints refining the docking model by revealing dominant hydrophobic/π-π contacts in AChE and dynamic π-cation/hydrophobic contacts in BACE-1. In silico ADMET analysis demonstrated favorable drug-like properties. These findings highlight hydrazone-linked pyridin-1-ium salts as promising scaffolds for developing compact multi-targeted agents for AD.
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2. Targeting SIRT6: the design and therapeutic implications of activators and inhibitors.
PMID:日期:2026-11-01Sirtuin 6 (SIRT6) is an NAD-dependent deacylase that maintains genomic stability, regulates metabolism, and influences aging, making it an attractive but challenging therapeutic target. Pharmacological modulation of SIRT6 holds promise for cancer and metabolic disorders, yet its context-dependent functions demand precise intervention strategies. Potent, selective, and drug-like chemical probes are therefore essential to dissect SIRT6 biology and to validate its therapeutic potential. This review critically evaluates recent medicinal chemistry advances in SIRT6 modulation. We focus on structure-guided design strategies and structure-activity relationships (SAR) that have transformed initial hits into optimized leads for both activators and inhibitors, highlighting the remaining challenges in achieving isoform selectivity and drug-like properties.
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3. PSMA binding of carbamate-containing peptidomimetics influenced by side chain length and stereocenter configuration in preclinical prostate cancer model.
PMID:日期:2026-11-01To explore how core backbone modifications influence prostate-specific membrane antigen (PSMA) targeting, we synthesized a series of novel peptidomimetics replacing the classic urea linkage of established radiotracers with a carbamate functionality. This panel systematically varied side chain length (aspartic vs. aminoadipic acid), stereocenter configuration (S/S vs. S/R diastereomers), and the radiometal chelator (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA] vs. N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid [HBED-CC]). In vitro binding assays in LNCaP cells revealed that the carbamate backbone severely compromised PSMA affinity (K) for short-chain aspartic acid derivatives, whereas long-chain aminoadipic acid conjugates successfully retained low-nanomolar potencies. Across all variations, S/S configurations displayed superior affinities over S/R counterparts, demonstrating that natural stereochemistry is essential for optimal binding pocket interactions. Although both conjugates showed high in vitro potency, high-temperature radiolabeling of the DOTA derivative with gallium-68 caused thermal degradation via hydrolytic cleavage and intramolecular cyclization of the carbamate backbone. Conversely, the companion HBED-CC conjugate, 37(S/S), was successfully radiolabeled at ambient temperature without structural compromise to yield the intact radiotracer, 40(S/S). In vivo positron emission tomography (PET) imaging and biodistribution studies of 40(S/S) in LNCaP tumor-bearing mice demonstrated high tumor uptake (∼12%ID/g) at 1 h post-injection, rapid renal clearance, and excellent tumor-to-background ratios (tumor-to-muscle: ∼23; tumor-to-bone: ∼36). These findings demonstrate that carbamate backbones can successfully mimic urea linkages in PSMA ligands, provided they are paired with precise side chain lengths and mild radiolabeling conditions.
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4. Phenotypic discovery of a pyrimidine derivative with dual anti-prostate cancer and cardioprotective potential via ROS modulation.
PMID:日期:2026-11-01Cardiotoxicity remains a major limitation of current anticancer therapies, highlighting the need for agents that combine antitumor efficacy with intrinsic cardiac safety. Phenotypic screening of a pyrimidine-based compound library identified compound 9v as a potent anti-prostate cancer candidate with dual biological functions. Compound 9v inhibited PC-3 cell proliferation with an IC₅₀ of 3.96 ± 0.18 μM, outperforming 5-fluorouracil, and markedly suppressed colony formation and migration while inducing apoptosis. Mechanistic studies showed that 9v activated the mitochondrial apoptotic pathway by increasing Bax, cleaved caspase-9, and cleaved caspase-3 levels while reducing Bcl-2 expression. Remarkably, 9v exerted bidirectional regulation of ROS homeostasis, promoting ROS accumulation in PC-3 cells but suppressing oxidative stress in H9C2 cardiomyocytes under H₂O₂ challenge. In addition, 9v exhibited weak cytotoxicity toward normal prostate stromal cells, no obvious acute toxicity in mice, and no detectable cardiotoxicity in vitro. Moreover, it exhibited protective effects against oxidative injury in cardiomyocytes, as demonstrated by increased cell viability and decreased LDH and cTnT release. Taken together, these results identify 9v as a promising lead compound with both anti-prostate cancer activity and cardioprotective potential in an in vitro oxidative stress model, providing a basis for the development of multifunctional anticancer agents with improved cardiovascular safety.
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5. Cationic amino acid-engineered radiopeptides for breast cancer targeting.
PMID:日期:2026-11-01G-protein coupled estrogen receptors (GPER) represent clinically important target for detection and treatment of breast cancer owing to their high expression. Present study aimed to incorporate and determine the influence of cationic amino acids on the GPER-targeting tetrapeptide, Pro-Leu-Met-Ile (PLMI). Peptide variants were synthesized on solid phase by introducing nuclear localization sequence (KRSKK) at C and N-terminus of PLMI peptide respectively. The three peptides: DOTA-PLMI, DOTA-PLMIKRSKK and DOTA-KRSKKPLMI were radiolabeled with lutetium-177. [Lu]Lu-DOTA-PLMI, [Lu]Lu-DOTA-PLMIKRSKK and [Lu]Lu-DOTA-KRSKKPLMI could be obtained in high radiolabeling yield (> 97%). Cellular studies in SKOV3 (ER-, PR- and GPER+) cells revealed highest binding affinity (K: 13.24 ± 0.89 nM) for [Lu]Lu-DOTA-PLMIKRSKK along with enhanced nuclear localization and cellular internalization. Amongst the three radiopeptides, [Lu]Lu-DOTA-PLMIKRSKK exhibited significantly reduced cellular uptake (95% inhibition) during blocking studies in SKOV3 cells (ER-, PR- and GPER+) than in MCF7 (ER+, PR+ and GPER+) cells (80%) indicating high GPER-specificity. Cellular internalization was also observed to be higher in SKOV3 cells (89%) in comparison to MCF7 cells (75%). Confocal microscopy confirmed high nuclear localization (∼85%) of dye conjugated peptide (Cf-PLMIKRSKK). Biodistribution studies in healthy mice demonstrated no radioactive accumulation in major organs except kidneys. Present studies thus demonstrate strong influence of cationic amino acids at C-terminal, boosting the biological properties of GPER-targeting PLMI peptide.
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6. Design, synthesis and biological evaluation of triazolo[1,5-a]pyrimidinone derivatives as potent and orally efficacious WRN helicase inhibitors for MSI cancer therapy.
PMID:日期:2026-11-01Microsatellite instability-high (MSI-H) cancers represent an unmet clinical need due to treatment resistance, and WRN helicase is a validated synthetic lethal target for this indication. Herein, we rationally designed, synthesized, and biologically evaluated a novel series of triazolo[1,5-a]pyrimidinone derivatives as potent WRN helicase inhibitors. Systematic structure-activity relationship (SAR) exploration identified optimal pharmacophores: 4-chlorobenzothiophene/2,2-difluoro-4-bromo-1,3-benzodioxole as R, dihydro-2H-pyran as R, and 3-hydroxypyridine/4-methyl-5-hydroxypyrimidines as R. Lead candidate 10r exhibited nanomolar enzymatic inhibition (IC = 0.015 ± 0.004 μM) and sub-micromolar cellular potency (IC = 0.174 ± 0.036 μM) against HCT116-MSI cells, with high oral bioavailability (71.53 ± 17.96%) and favorable pharmacokinetics in mice. In HCT116-MSI cell-derived xenograft models, 10r achieved robust tumor growth inhibition (TGI = 94.7 ± 15.5%) at 100 mg/kg BID, with durable efficacy after treatment cessation, and a well-tolerated safety profile. This study delivers an attractive lead series worthy of further investigation for MSI cancers and provide a structural framework for further development.
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7. Design, synthesis and antiviral activity of ciclopirox (CPX) analogs against orthopoxvirus.
PMID:日期:2026-11-01In search for structurally novel antiviral leads against orthopoxvirus, we have previously identified and characterized ciclopirox (CPX) as a strong antiviral hit inhibiting vaccinia virus (VACV) replication. We report herein the antiviral activity-guided structure-activity relationship (SAR) of CPX, probing three structural zones (R-R) with the synthesis of 29 analogs. Major findings include that the hydroxyl group as R is required for activity, that most R modifications confer cytotoxicity, and that R changes are largely tolerated. In the end, the SAR identified one analog (5h, EC = 0.12 μM) showing substantially improved antiviral activity over CPX (EC = 0.51 μM), and numerous analogs exhibiting strong antiviral activities (EC = 0.71-1.2 μM) comparable to CPX without significant cytotoxicity. These SAR trends and additional potent analogs identified provide a strong foundation for future optimization efforts.
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8. Non-covalent dual HDAC6/proteasome inhibitors with anti-multiple myeloma activity.
PMID:日期:2026-11-01Multiple myeloma (MM) remains an incurable hematological malignancy, even with the clinical success of proteasome inhibitors (PIs). The compensatory upregulation of HDAC6 following proteasome inhibition offers a strong rationale for dual targeting. However, a systematic comparison of different zinc-binding groups (ZBGs) within a non-covalent scaffold has been lacking. Here, we designed a series of non-covalent dual HDAC6/proteasome inhibitors based on a carfilzomib-derived scaffold, incorporating either a hydroxamic acid or an ortho-aminoanilide ZBG with linkers of varying lengths. Our SAR analysis revealed a clear division of labor: the R position dominates proteasome inhibition (IC = 2.6-8.1 nM, comparable to MG-132 at 10.8 nM), whereas HDAC6 activity is highly dependent on the choice of ZBG and cap group. For instance, the ortho-aminoanilide ZBG confers potent HDAC6 inhibition only when paired with a 2-chlorobenzyl cap (IC = 29.8 nM); with a tetralin cap, it is essentially inactive (IC > 5 μM). In contrast, the hydroxamic acid ZBG delivers moderate HDAC6 activity (130-280 nM) across both cap groups. Among the nine compounds, H-07 emerged as the most balanced dual inhibitor, with proteasome IC = 4.2 nM and HDAC6 IC = 29.8 nM. In RPMI-8226 cells, H-07 increased ac-α-tubulin and ac-histone H3 levels and induced PARP cleavage-findings consistent with engagement of both HDAC6 and class I HDACs, in addition to the expected effects from proteasome inhibition. Molecular dynamics simulations provided plausible binding modes for both targets. Despite this promising in vitro profile, a substantial loss of potency was observed in cell-based functional assays: the cellular proteasome IC of H-07 was 6.768 μM, representing a > 1600-fold increase relative to its enzymatic IC (4.2 nM). This marked shift is consistent with the limited membrane permeability frequently associated with polar peptidomimetic scaffolds, and it underscores a key limitation that must be addressed in future optimization efforts. Nevertheless, this work establishes a clear SAR framework and identifies key determinants for the rational optimization of this class of non-covalent dual inhibitors.
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9. Design, synthesis, and biological evaluation of selective estrogen receptor modulators (SERMs) as anticancer agents for ER-positive breast cancer.
PMID:日期:2026-11-01Globally, breast cancer stands as one of the primary causes of cancer related deaths. Among the types of breast cancer, estrogen receptor- positive (ER+) breast cancer accounts for the highest incidence and mortality worldwide. The present study emphasizes the design, synthesis, and biological evaluation of a series of novel triphenylethylene (TPE) based selective estrogen receptor modulators (SERMs) for their antiproliferative activity against ER+ breast cancer. All the synthesized compounds were well characterized using spectroscopic and chromatographic techniques. Favorable druglike properties indicating acceptable permeability through membrane and oral bioavailability were observed in in-silico physicochemical, ADME, and toxicity profiling. Further, biological evaluation of the synthesized compounds against MCF-7 breast cancer cells demonstrated significant antiproliferative nature of the synthesized compounds. Compounds 5g and 5o showed antiproliferative activity comparable to the standard metabolite 4-hydroxytamoxifen (4-OH TAM) and the IC of compounds 5g and 5o were found to be 4.350 ± 0.373 and 3.562 ± 0.466 μM respectively. Subsequently, the cell death pathway was revealed through caspase-3/7 assay and immunoblotting analysis and the compounds were found to cause cell death through activation of apoptosis-related proteins such as cleaved PARP and cleaved caspase-7. The molecular docking studies on the target protein ERα (PDB ID: 3ERT) exhibited favorable docking interactions between the compounds 5g and 5o with key amino acid residues such as Asp351, Thr347, Leu346, and His524. Similar interactions with amino acid residues were observed in the case of 4-OH TAM. Comprehensively, the results of the study highlight the promising anticancer potential of the synthesized compounds 5g and 5o as TPE-based SERM for selective ER+ breast cancer.
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10. Novel furo[2,3-d]pyrimidinones as direct thrombin inhibitors: Design, synthesis and biological evaluation.
PMID:日期:2026-11-01Thrombin, a versatile protease is a promising target in coagulation cascade for thrombosis related conditions. We designed and synthesized thirty novel furo[2,3-d]pyrimidinone analogs and evaluated them for their antithrombotic potential. Initial in vitro screening revealed that most of the compounds displayed good to moderate level of antithrombin properties. Compounds (7b, IC = 0.96 μM and 7g, IC = 1.36 μM) displayed the most potent direct thrombin inhibition activity. The results from the ex vivo anticoagulant activity demonstrated compound (7b) having prolonged PT and aPTT in rats relative to the control. Interestingly, compound (7b, BT = 91 s.) exhibited better safety profile than the standard drug dabigatran (BT = 102 s.) in terms of bleeding risk. Molecular docking and dynamics simulation studies identified and validated the binding interactions of potent derivatives with the target protein thrombin.