Bioorg. Med. Chem. Lett. [JOURNAL]
Sun
200 papers
Solid-phase synthesis and antimicrobial activities of lipid-neomycin conjugates.
Story S, Bhaduri S, Arya DP
Bioorg Med Chem Lett · 2026 Jul · PMID 42398679 · Publisher ↗
Lipid linked aminosugars have been shown to have significant antimicrobial properties. We report here a solid phase strategy for the rapid synthesis of lipid-aminoglycoside compounds, linked with amino acids. Subsequent...
Lipid linked aminosugars have been shown to have significant antimicrobial properties. We report here a solid phase strategy for the rapid synthesis of lipid-aminoglycoside compounds, linked with amino acids. Subsequent screening of the compounds against pathogens known to cause clinical fungal infections is also reported herein. We have screened the library for antifungal activity in eight species of Candida. The lipid-neomycin conjugates show antifungal minimal inhibitory concentrations in the 1.56-3.13 μM range across a broad spectrum of Candida. Generally, conjugates with long chain lipids were much more effective antifungals than those with short chain lipids or lipids with multiple double bonds, and this work therefore targets the synthesis and screening of such long chain saturated compounds. The methods presented here are equally suitable for synthesis of any lipid aminoglycoside combination, efficiently combining lipids and carbohydrates via peptides using solid phase synthesis. The strategy also allows easy manipulation of the linker lengths and hydrophobicities for linkers that combine the lipid to the sugar.
Discovery of a potent sGC stimulator with once-daily dosing potential for the treatment of hypertension.
Raghavan S, Brockunier L, Guo J … +15 more , Rosauer K, Smith C, Yang Q, Shepherd C, Yang L, Pai LY, Metzger J, Pereira A, Salituro G, Xu SS, Johnson T, Maloney K, Mortko C, Roy S, Parmee E
Bioorg Med Chem Lett · 2026 Jun · PMID 42379529 · Publisher ↗
Endothelial dysfunction and impaired NO-sGC - cGMP signaling in hypertension drive the need for next-generation soluble guanylate cyclase (sGC) stimulators with improved pharmacokinetics and once-daily dosing potential....
Endothelial dysfunction and impaired NO-sGC - cGMP signaling in hypertension drive the need for next-generation soluble guanylate cyclase (sGC) stimulators with improved pharmacokinetics and once-daily dosing potential. Metabolism-guided optimization of MK-2947, which showed robust preclinical blood pressure lowering but exhibited compound-specific toxicity and a projected human half-life of ∼12 h, led to the identification of compound 20, a potent sGC stimulator (EC₅₀ = 44 nM) with improved pharmacokinetics and sustained blood pressure lowering in preclinical models (≥24 h). Preclinical PK/PD data support compound 20 as a structurally differentiated sGC stimulator with a profile consistent with once-daily dosing potential, reflecting an improved balance of pharmacokinetic and pharmacodynamic properties, pending further safety evaluation.
OracleScreen-LILRB4 (HTS-Oracle v3): machine learning-guided discovery of myeloid immune checkpoint binders validated in patient-derived cells.
Abdel-Rahman SA, Gabr MT
Bioorg Med Chem Lett · 2026 Jun · PMID 42372925 · Publisher ↗
The identification of small molecule modulators of immune checkpoint proteins remains a significant challenge in drug discovery due to the flat, featureless nature of protein-protein interaction interfaces and the charac...
The identification of small molecule modulators of immune checkpoint proteins remains a significant challenge in drug discovery due to the flat, featureless nature of protein-protein interaction interfaces and the characteristically low hit rates observed in conventional high-throughput screening campaigns. Here we report OracleScreen-LILRB4 (HTS-Oracle v3), an ensemble machine learning framework trained on quantitative biophysical screening data from two structurally diverse compound libraries (19,800 compounds total) screened against the myeloid immune checkpoint leukocyte immunoglobulin-like receptor B4 (LILRB4/ILT3). By formulating binding prediction as a regression task targeting continuous ΔF values rather than binary hit classifications, OracleScreen-LILRB4 achieved a mean Spearman R of 0.61 and ROC-AUC of 0.86 under scaffold-aware cross-validation. Prospective virtual screening of a 45,760-member compound library and experimental validation of the top 200 predictions yielded a 28.5% hit rate, representing a 15.0-fold enrichment over baseline, with 16 compounds demonstrating nanomolar-affinity LILRB4 (ILT3) engagement. Lead compounds ORS-22 and ORS-14 restored anti-tumor immune activity across patient-derived colorectal cancer and acute myeloid leukemia co-culture systems, reversing SCG2-mediated immunosuppression and recovering cytotoxic T-cell function. These findings establish OracleScreen-LILRB4 (HTS-Oracle v3) as an effective computational framework for accelerating small molecule discovery against non-enzymatic immune checkpoint targets.
Rational design and N-terminal acylation of a lactam-cyclized 11-residue antimicrobial peptide for improved antibacterial potency.
Zhang J, Liu G, Jiang Z … +2 more , Jiang M, Li R
Bioorg Med Chem Lett · 2026 Jun · PMID 42372924 · Publisher ↗
Linear antimicrobial peptides frequently suffer from low potency and narrow spectrum, restricting their clinical utility. Starting from the natural amphipathic α-helical peptide FAKWAFKWLKK-NH, we rationally introduced a...
Linear antimicrobial peptides frequently suffer from low potency and narrow spectrum, restricting their clinical utility. Starting from the natural amphipathic α-helical peptide FAKWAFKWLKK-NH, we rationally introduced an i, i + 7 side-chain lactam bridge by mutating Ala and Leu to Lys and Glu, respectively, while preserving the predicted α-helical conformation. Cyclized peptide 2 displayed a minimum inhibitory concentration (MIC) of 4 μg/mL against Pseudomonas aeruginosa ATCC27853 (>32-fold improvement over the linear peptide, MIC >128 μg/mL) and 2 μg/mL against Staphylococcus aureus ATCC25923 (8-fold improvement; linear peptide MIC 16 μg/mL). Peptide 2 also showed potent activity against Acinetobacter baumannii BNCC337173 (MIC = 8 μg/mL), S. aureus ST9 (MIC = 32 μg/mL), and Listeria monocytogenes ATCC13932 (MIC = 32 μg/mL), indicating activity against both Gram-negative and Gram-positive pathogens. N-terminal C10 acylation further improved potency, lowering the MIC against P. aeruginosa and A. baumannii to 2 μg/mL, and against S. aureus ST9 and L. monocytogenes to 4 and 8 μg/mL, respectively. Hemolysis assays showed that peptide 2 had an HC >100 μg/mL, yielding a therapeutic index (HC/MIC) >25 against P. aeruginosa and a favorable safety margin. These findings support a focused stepwise rational design strategy for this peptide scaffold, combining natural template selection, lactam cyclization, and N-terminal lipophilic modification.
Rational design, synthesis, and biological evaluation of chalcone hybrids including benzoylpiperazin (phenylacetylpiperazin)-thiophene as anti- Alzheimer's agents.
Lin Z, Hu L, Liu Y … +4 more , Ning W, Wang S, Fu ZY, Guan L
Bioorg Med Chem Lett · 2026 Jun · PMID 42372923 · Publisher ↗
A series of chalcone hybrids including benzoylpiperazin (phenylacetylpiperazin)-thiophene were designed, synthesized and evaluated their inhibitory activities against cholinesterase (ChE). All compounds displayed good in...
A series of chalcone hybrids including benzoylpiperazin (phenylacetylpiperazin)-thiophene were designed, synthesized and evaluated their inhibitory activities against cholinesterase (ChE). All compounds displayed good inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, compound 2e displayed the most inhibitory activity against AChE, BChE and β-amyloid (Aβ) with IC values 7.01, 5.39 and 4.47 μM, respectively. Meanwhile, 2e was found anti-Alzheimer's disease (AD) effect by significantly alleviating lipopolysaccharide (LPS)/Aβ-induced neurotoxicity, reducing the levels of reactive oxygen species (ROS), pro-inflammatory cytokines, and exert anti-inflammatory effects by regulating the NF-κB (Nuclear factor kappa-light-chain-enhancer of activated B cells) pathway. Furthermore, the molecular modeling studies showed that 2e target both catalytic active site as well as peripheral anionic site of AChE, BChE and Aβ, and possess strong bind affinity. In addition, in silico ADMET and toxicity predictions demonstrated favorable oral absorption and potential blood-brain barrier (BBB) permeability for 2e. The rationale remains partly overstated. The novelty claim should more precisely distinguish this scaffold from previously reported chalcone, piperazine, thiophene, and multitarget ChE/Aβ inhibitors. The phrase "anti-Alzheimer's agents" should be softened, because the data are limited to enzyme assays, Aβ assays, BV-2 cellular models, docking, and computational predictions.
New aminopiperidine-azoles as antifungal agents against Candida albicans with mechanistic insights into the cAMP-PKA pathway.
Guo R, Wei Y, Yao T … +3 more , Wang R, Li Q, Hu C
Bioorg Med Chem Lett · 2026 Oct · PMID 42341851 · Publisher ↗
Candida albicans infections are becoming increasingly prevalent, making the development of new drugs an urgent priority. In this study, a series of new aminopiperidine-azole derivatives were designed, synthesized, and ev...
Candida albicans infections are becoming increasingly prevalent, making the development of new drugs an urgent priority. In this study, a series of new aminopiperidine-azole derivatives were designed, synthesized, and evaluated for their in vitro antifungal activity against both FLC-sensitive and -resistant strains of C. albicans. Several compounds exhibited good antifungal activity, with compound 5p demonstrating the most promising efficacy against the sensitive strain SC5314 (MIC = 0.28 μM). Mechanism studies revealed that 5p significantly inhibited biofilm formation and hyphal growth by downregulating key genes of the cAMP-PKA signaling pathway, including RAS1, EFG1, BCR1, ECE1, and HWP1. Furthermore, 5p showed low cytotoxicity against human bronchial epithelial cells (16HBE) at effective concentrations. These findings suggest that 5p is a promising lead compound for the development of new antifungal drugs.
Novel 1H-pyrrole-2,5-dione derivatives as potential anti-diabetic agents: design, synthesis, in vitro, in ovo, and molecular docking studies.
Gezer D, Ozyıldız Z, Gokmen Z … +7 more , Dagsuyu E, Sacan O, Akar RO, Yıldırım EG, Ulukaya E, Adacan K, Kutlu A
Bioorg Med Chem Lett · 2026 Oct · PMID 42288313 · Publisher ↗
Diabetes mellitus (DM) is the most common metabolism-related health problem across the world and new therapeutics are still emerging into the market. One of the treatments is the inhibition of α-glucosidase, which is a v...
Diabetes mellitus (DM) is the most common metabolism-related health problem across the world and new therapeutics are still emerging into the market. One of the treatments is the inhibition of α-glucosidase, which is a validated therapeutic strategy for mitigating postprandial hyperglycemia in Type 2 DM. However, the clinical utility of current inhibitors, such as Acarbose, is often limited by gastrointestinal side effects and suboptimal pharmacokinetics linked to their surface-binding modes. In this study, we reported the design, synthesis, and biological evaluation of a novel series of 1H-Pyrrole-2,5-dione derivatives, targeting the deep catalytic cleft of human acid α-glucosidase (rhGAA). In vitro studies revealed that all the new compounds showed higher enzyme inhibitory activity than Acarbose (IC = 54.14 ± 6.43 mM) except 3e, 3f, and 5d. In in ovo model, compound 3d worked best to reduce blood glucose levels (around 48 mg/mL) and maintained this effect within 3 h. Molecular docking calculations covering the whole protein surface confirmed the catalytic pocket as the primary binding site, followed by focused docking, which identified 3g as the top in silico hit (-9.35 kcal/mol). In vitro kinetic experiments revealed that 5c possessed the highest inhibitory potential (IC = 0.21 mM) and performed significantly better than Acarbose, while structural dynamics analysis of 5c highlighted its conformational instability. Consequently, compound 3d (IC = 0.64 mM) was selected as the lead candidate to effectively inhibit rhGAA. Structural fingerprinting elucidated a unique "Anchor Mechanism" for 3d, characterized by a critical hydrogen bond with ARG281.
Design, synthesis and biological evaluation of novel CDK8/BRD4 dual inhibitors.
Liang G, Zhang X, Zhu J … +2 more , Wang X, Huang J
Bioorg Med Chem Lett · 2026 Oct · PMID 42285310 · Publisher ↗
CDK8 is recognized as an important therapeutic target in colorectal cancer. Recently, a study has demonstrated that inhibition of CDK8 alone can activate a compensatory BRD4 signaling pathway, which may account for the m...
CDK8 is recognized as an important therapeutic target in colorectal cancer. Recently, a study has demonstrated that inhibition of CDK8 alone can activate a compensatory BRD4 signaling pathway, which may account for the modest in vivo efficacy of CDK8 small-molecule inhibitors and limits their clinical application in colorectal cancer treatment. Simultaneously inhibition of CDK8 and BRD4 has been shown to effectively suppress the growth of colorectal cancer cells, with confirmed safety and efficacy. Nevertheless, to date, no dual-target inhibitors of CDK8/BRD4 have been reported. In this study, a series of 12 novel small-molecule CDK8/BRD4 dual inhibitors were designed and synthesized using a fragment merging strategy. Among these, compound 8d exhibited good inhibitory activity against both CDK8 (IC₅₀ = 5.44 ± 0.10 μM) and BRD4 (IC₅₀ = 4.03 ± 0.95 μM), along with promising anti-proliferative activity in colorectal cancer cells (HCT116, IC₅₀ = 12.41 ± 0.96 μM). Furthermore, molecular docking analysis elucidated the binding mode of compound 8d with the target proteins, providing valuable insights for the future development of novel CDK8/BRD4 dual inhibitors.
Identification of a novel aβ-overlapping binding site on the TREM2 Ectodomain engaged by the small-molecule agonist VG-3927.
Cho S, Gabr MT
Bioorg Med Chem Lett · 2026 Oct · PMID 42276260 · Publisher ↗
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immune receptor genetically and functionally linked to Alzheimer's disease (AD). VG-3927, the first small-molecule TREM2 agonist to enter clinical...
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immune receptor genetically and functionally linked to Alzheimer's disease (AD). VG-3927, the first small-molecule TREM2 agonist to enter clinical development, has been proposed to act as a transmembrane molecular glue and positive allosteric modulator (PAM), but whether it also engages the TREM2 ectodomain has not been systematically explored. Here, we used DiffDock-L, a deep learning-based blind docking algorithm, to map potential VG-3927 binding sites across the TREM2 structure and identified a binding site within the ectodomain hydrophobic groove, a ligand-recognition surface previously implicated in Aβ and apoE binding. Microscale thermophoresis (MST) confirmed VG-3927 interaction with TREM2 under optimized polyethylene glycol 400 (PEG-400) buffer conditions and showed that Aβ binds directly to TREM2. In the presence of Aβ, the VG-3927 MST signal was reduced, supporting interference at an overlapping ectodomain binding surface. Consistently, Aβ induced a rightward shift in the VG-3927 dose-response curve in a Jurkat TREM2-DAP12 Nuclear Factor of Activated T Cells (NFAT) reporter assay and attenuated VG-3927-induced phospho-spleen tyrosine kinase (p-SYK) signaling. Together, these findings support the presence of a previously unrecognized ectodomain interaction mode for VG-3927 and suggest that amyloid-associated ligand occupancy may modulate TREM2 agonist activity in the AD microenvironment.
Synthesis of two indole cyanine scaffolds and evaluation of their nucleic acid-associated near-infrared imaging performance.
Su W, Sun D, Wei Y … +2 more , Fan Y, Wang L
Bioorg Med Chem Lett · 2026 Oct · PMID 42264157 · Publisher ↗
To compare the performance of asymmetric pentamethine cyanines and squaraine-based indole cyanines in nucleic acid imaging, six indole cyanine derivatives were designed, synthesized, and evaluated. T3 which possesses a b...
To compare the performance of asymmetric pentamethine cyanines and squaraine-based indole cyanines in nucleic acid imaging, six indole cyanine derivatives were designed, synthesized, and evaluated. T3 which possesses a benz[e]indole terminal unit, showed the strongest spectral responses to both DNA and RNA, the highest emission intensity under near-neutral conditions, and good anti-interference capability. Cellular imaging showed that T3 had favorable cellular uptake and low background fluorescence. Its intracellular fluorescence was mainly distributed in the cytoplasm and perinuclear regions and was associated with nucleic acids. MTT assays showed that T3 had relatively low cytotoxicity toward both LM3 and Huh-7 cells. T3 can form relatively stable complexes with nucleic acids, and its recognition is dominated by groove binding, with stronger binding affinity toward RNA. These results indicate that the asymmetric pentamethine scaffold favors strong response signals and high imaging intensity, whereas the squaraine scaffold provides better structural stability. T3 therefore represents a promising candidate for near-infrared nucleic acid imaging.
NO-donating Bergenin derivatives with enhanced anti-inflammatory activity.
Yuan E, Deng Q, Li N … +1 more , Chen L
Bioorg Med Chem Lett · 2026 Oct · PMID 42248368 · Publisher ↗
Ten new nitric oxide (NO)-donating Bergenin derivatives were designed, synthesized, and evaluated for their anti-inflammatory activity. Distinguished by its superior safety profile, a single furoxan moiety conjugated hyb...
Ten new nitric oxide (NO)-donating Bergenin derivatives were designed, synthesized, and evaluated for their anti-inflammatory activity. Distinguished by its superior safety profile, a single furoxan moiety conjugated hybrid I was selected for mechanistic studies. The results revealed that the anti-inflammatory effects of I is probably related to the negative feedback inhibition of iNOS expression by promoting NO release, as well as the inhibition of the pro-inflammatory cytokines (TNF-α, IL-6) levels. These findings provide direct evidence supporting the hypothesis that BG-NO hybrids exert enhanced anti-inflammatory effects via NO signaling, identifying I as a promising lead compound for further development.
A facile one-pot synthesis to access unique benzopyranonyl cyanopyrimidinols with multitargeting potential against resistant bacteria.
Duan PP, Wang L, Li ZZ … +1 more , Zhou CH
Bioorg Med Chem Lett · 2026 Oct · PMID 42248367 · Publisher ↗
To combat rising antimicrobial resistance, a class of novel cyanopyrimidinols (CPOs) were designed and synthesized via a three-component one-pot reaction strategy. Several prepared CPOs exhibited strong antibacterial act...
To combat rising antimicrobial resistance, a class of novel cyanopyrimidinols (CPOs) were designed and synthesized via a three-component one-pot reaction strategy. Several prepared CPOs exhibited strong antibacterial activity against the tested bacteria. Especially, benzopyranonyl CPO 4 demonstrated potent activity against Enterococcus faecalis p1-2007226001 (MIC = 0.001 mM), displaying 6- and 64-fold lower MIC values than norfloxacin (MIC = 0.006 mM) and sulfadiazine (MIC = 0.064 mM). CPO 4 showed negligible hemolysis and lower resistance propensity than norfloxacin. In silico ADME analysis revealed favorable drug-likeness and pharmacokinetics of compound 4. Moreover, the highly active molecule CPO 4 displayed superior in vivo antibacterial activity to norfloxacin in Galleria mellonella infection model. Further investigation suggested that CPO 4 could intercalate into DNA to form a CPO 4 - DNA complex, thereby blocking DNA replication, while also disrupting bacterial metabolism and inducing intracellular protein leakage. These findings highlighted cyanopyrimidinols as novel scaffolds for developing multitargeting antibacterial agents.
Design, synthesis, and biological evaluation of BODIPY-based photoactivatable Crizotinib prodrugs for precision cancer therapy.
Xu C, Lu P, Qin M … +2 more , Ji M, Xu H
Bioorg Med Chem Lett · 2026 Oct · PMID 42235861 · Publisher ↗
Crizotinib is an established first-line therapy for patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). However, long-term treatment is often associated with systemic toxi...
Crizotinib is an established first-line therapy for patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). However, long-term treatment is often associated with systemic toxicity, leading to various adverse effects that compromise patient outcomes. Herein, we report the design of novel BODIPY-based photoactivatable Crizotinib prodrugs to achieve precise spatiotemporal control over drug activity. The boron-dipyrromethene (BODIPY) chromophore was selected as the photolabile protecting group due to its excellent photophysical properties, including tunable absorption within the tissue-penetrating near-infrared (NIR) window, high photostability, and synthetic versatility, offering significant advantages over conventional UV-cleavable groups. Upon light irradiation, the caged compound undergoes efficient uncaging to release active Crizotinib, restoring its potent kinase inhibitory and antiproliferative activities. This work establishes BODIPY-caged Crizotinib as a promising photoactivatable agent for precision cancer therapy.
A rapid and scalable microwave-assisted strategy for the synthesis of neocryptolepine and its analogues: Comprehensive bioactivity profiling.
Salgaonkar S, Rebello M, Barretto DA … +2 more , Tilvi S, Mandrekar V
Bioorg Med Chem Lett · 2026 Oct · PMID 42235860 · Publisher ↗
A rapid synthesis of neocryptolepine and its analogues have been developed using 2-Bromo-1H-indole-3-carbaldehydes and N-methylanilines as starting materials under microwave irradiation. A total of 14 different 5-methyl-...
A rapid synthesis of neocryptolepine and its analogues have been developed using 2-Bromo-1H-indole-3-carbaldehydes and N-methylanilines as starting materials under microwave irradiation. A total of 14 different 5-methyl-5H-indolo[2,3-b]quinoline derivatives containing 7 novel analogues of neocryptolepine have been synthesized. The method has also been used for gram-scale (1.03 g) synthesis of neocryptolepine starting from 1.02 g of Bromoindolecarbaldehyde. The synthesized compounds were evaluated in vitro for their antidiabetic, anti-inflammatory, antioxidant, and antibacterial activities. The obtained results suggest that the compound 1ad exhibits comparable antidiabetic activity, inhibiting α-amylase and α-glycosidase. The natural product neocryptolepine revealed the best anti-inflammatory and antioxidant activity, compared to the standards diclofenac and ascorbic acid, respectively. Among all the derivatives evaluated for antibacterial activity in vitro against Gram-positive bacteria (S. aureus and S. pyogenes) and Gram-negative bacteria (S. typhi and P. aeruginosa), neocryptolepine exhibits the maximum antibacterial potency, with MIC values ranging from 0.25 to 0.5 μg/mL against all four strains. These MIC values were slightly lower than those observed for streptomycin (0.5-2 μg/mL), and comparable to Ciprofloxacin (0.125-2 μg/mL), with slightly enhanced antibacterial efficacy for gram-positive bacteria compared to gram-negative bacteria.
Cannabidiol-thiosemicarbazone exhibits dual tyrosinase inhibition and antioxidant activity in human skin-derived cells.
Shabat-Simon M, Cohen O, Yaval L … +4 more , Hujeirat S, Pitashny PA, Jackson K, Musa S
Bioorg Med Chem Lett · 2026 Oct · PMID 42235859 · Publisher ↗
The search for modulators of melanogenesis with improved biological compatibility remains an active area of investigation, as existing tyrosinase (TYR) inhibitors are often limited by low potency, instability, or cytotox...
The search for modulators of melanogenesis with improved biological compatibility remains an active area of investigation, as existing tyrosinase (TYR) inhibitors are often limited by low potency, instability, or cytotoxicity. Here, we investigated CBD-TSC, a cannabidiol-based thiosemicarbazone derivative, as a TYR-targeting scaffold. Structural characterization confirmed a single, stable E-isomer, and pKa profiling together with kinetic analyses indicated reversible mixed-type inhibition of human TYR, involving interactions with both free enzyme and enzyme-substrate complexes. CBD-TSC exhibited higher inhibitory activity than CBD and kojic acid under the tested conditions while maintaining low cytotoxicity in G361 melanoma and HaCaT keratinocyte cell lines. In addition, CBD-TSC reduced intracellular oxidative stress at low micromolar concentrations. In zebrafish larvae, treatment with CBD-TSC resulted in a dose-dependent reduction in melanin content, comparable to that of kojic acid under identical experimental conditions, supporting an association between thiosemicarbazone modification and the observed biological activity. Overall, CBD-TSC demonstrated consistent activity across biochemical, cellular, and zebrafish-based assays under the tested conditions. Although the mechanistic relationship between TYR inhibition, redox modulation, and melanogenesis regulation remains to be fully clarified, the present findings support further investigation of cannabidiol-based thiosemicarbazone derivatives as modulators of TYR-related pathways.
Small molecule inhibition of CPSF3 may impact R-loop distribution and abundance.
Hofman CR, Tse V, Hu J … +1 more , Corey DR
Bioorg Med Chem Lett · 2026 Oct · PMID 42214474 · Publisher ↗
R-loops are three-stranded nucleic acid structures consisting of an RNA/DNA hybrid and a displaced strand of DNA. These structures have been implicated in a variety of regulatory cellular processes. Their untimed or exce...
R-loops are three-stranded nucleic acid structures consisting of an RNA/DNA hybrid and a displaced strand of DNA. These structures have been implicated in a variety of regulatory cellular processes. Their untimed or excess accumulation, however, can cause genomic instability and induce DNA damage. Most R-loops form co-transcriptionally when the nascent transcript reanneals to unwound DNA duplex. Changes in transcription rates have the potential to impact R-loop formation, and compounds that modulate R-loop formation would be useful molecular tools and therapeutic leads. Cleavage and Polyadenylation Specific Factor 3 (CPSF3) recognizes the pre-mRNA 3' cleavage site, cleaves the transcript prior to polyadenylation, and has been linked to R-loop formation. Inhibition of CPSF3 has been found to induce transcriptional readthrough and cell proliferation defects. A previous report suggested that inhibition of CPSF3 with a small molecule causes a global increase in R-loop formation. Here, we test the impact of YT-II-100, a novel inhibitor of CPSF3. We find that addition of YT-II-100 increases global R-loop formation but does not change R-loop formation at specific genes that are normally used as positive controls for R-loop formation. We performed parallel assays using a previously reported compound, JTE-607, and observed similar results. Our data emphasize the need for cautious interpretation of experiments using JTE-607 and YT-II-100. There may be different mechanisms of R-loop formation depending on gene loci, where the control of R-loop formation by agonists at certain genes may differ from the trends observed for impacts on global R-loop formation.
Disulfide bond formation between Cys22 and Cys44 in SARS-CoV-2 main protease.
Blankenship LR, Yang K, Cho CD … +3 more , Chen YP, Sankaran B, Liu WR
Bioorg Med Chem Lett · 2026 Oct · PMID 42190838 · Publisher ↗
SARS-CoV-2 main protease (M) is a cysteine enzyme essential for viral replication and pathogenesis. It contains multiple cysteines that are susceptible to covalent modifications. Reported modifications include inhibitor-...
SARS-CoV-2 main protease (M) is a cysteine enzyme essential for viral replication and pathogenesis. It contains multiple cysteines that are susceptible to covalent modifications. Reported modifications include inhibitor-derived modifications at the catalytic Cys145, Cys145-Cys117 disulfide, an S-O-N (SON) crosslink between Cys22 and Lys61, and S-O-N-O-S (SONOS) crosslink spanning Cys22-Lys61-Cys44, Cys300 S-glutathionylation, and inhibitor-derived adducts on Cys156 and Cys300. Reanalysis of M crystal structures obtained from samples exposed to air identified nine structures containing the SON crosslink and thirty-one containing the SONOS crosslink. Among five newly determined structures, one unexpectedly showed a Cys22-Cys44 disulfide. Cys44 lies in a segment that contributes to the active site architecture but is flexible to adopt alternative conformations. Redox transformations at this position by formation of either SONOS crosslink or disulfide suggest potential redox regulation of M activity in host cells experiencing virus-induced oxidative stress. A C22S mutant enzyme displays much higher activity than wild type enzyme supporting potential redox regulation mechanisms involving Cys22 and Cys44.
Chlorophenylpyrazolone derivatives as novel PD-L1-targeted inhibitors of the PD-1/PD-L1 immune checkpoint.
Klupsch F, Le Biannic R, El Bouazzati H … +10 more , Magnez R, Rivoal M, Thiroux B, Tardy M, Vergoten G, Bailly C, Quesnel B, Thuru X, Leleu-Chavain N, Millet R
Bioorg Med Chem Lett · 2026 Oct · PMID 42190837 · Publisher ↗
Immune checkpoint inhibitors have emerged as one of the most promising approaches for cancer immunotherapy. Several injectable monoclonal antibodies targeting the programmed cell death-1/programmed cell death-ligand 1 (P...
Immune checkpoint inhibitors have emerged as one of the most promising approaches for cancer immunotherapy. Several injectable monoclonal antibodies targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway are used to treat solid tumors. The development of orally active small molecules remains a challenge. In this context, we describe new pyrazolone derivatives bearing a chlorophenyl moiety aimed at targeting PD-L1 dimers. Ten new compounds with nanomolar affinities for PD-L1 were identified and among them, six were able to reactivate proliferation of CTLL-2 cytotoxic T-cells. The best compounds were further characterized for their capacity to modulate PD-L1 dimerization and their interaction with PD-L1 dimers, by microscale thermophoresis and molecular docking, respectively. Novel symmetric bis-pyrazolones with a high affinity for PD-L1 protein were also obtained. The 2,4-dichlorophenylpyrazolone scaffold offers novel perspectives to design PD-L1-targeting agents for the treatment of cancer.
A simple solid-phase approach for the synthesis of DOTA-conjugated α-ketoamide-based fibroblast activation protein-targeted ligands.
Jozi S, Ng P, Merkens H … +3 more , Cookson F, Bénard F, Lin KS
Bioorg Med Chem Lett · 2026 Sep · PMID 42176782 · Publisher ↗
Several studies have shown that fibroblast activation protein (FAP)-targeted radioligands with an α-ketoamide as the warhead can lead to high affinity for FAP and prolonged tumor retention. However, the preparation of re...
Several studies have shown that fibroblast activation protein (FAP)-targeted radioligands with an α-ketoamide as the warhead can lead to high affinity for FAP and prolonged tumor retention. However, the preparation of reported FAP-targeted ligands requires multiple solution-phase synthesis and purification steps. Herein, we report a simple solid-phase approach for synthesizing DOTA-conjugated α-ketoamide-based FAP-targeted ligands. The new ligand, FAPI-CRC, was constructed on Rink Amide MBHA resin by sequentially coupling Fmoc-protected amino acids and DOTA-tris(tert-butyl ester), oxidation of α-hydroxyamide to α-ketoamide by 2-iodoxybenzoic acid in dimethyl sulfoxide, and final cleavage/deprotection with trifluoroacetic acid, followed by HPLC purification. FAPI-CRC was labeled with Ga/Ga to investigate its ability to target FAP in vitro and in vivo, respectively. Ga-FAPI-CRC was obtained in 50% yield and [Ga]Ga-FAPI-CRC was obtained in 27% decay-corrected radiochemical yield with >99% radiochemical purity and a molar activity of 30.8 GBq/μmol. FAPI-CRC and Ga-FAPI-CRC exhibited high affinity for FAP with IC values of 0.33 ± 0.09 and 0.42 ± 0.27 nM, respectively. Positron emission tomography (PET) imaging and ex vivo biodistribution studies in mice showed that [Ga]Ga-FAPI-CRC was specifically taken up by HEK293T:hFAP tumor xenografts with good tumor-to-background contrast at 1 h post-injection. Therefore, our simple solid-phase approach is promising for the synthesis of potent α-ketoamide-based FAP-targeted ligands and can be used to greatly facilitate the development of radiopharmaceuticals for the management of FAP-expressing cancer.
Design, synthesis and antibacterial evaluation of novel unsaturated butenolide-fatty amine hybrids against multidrug-resistant pathogens.
Tang SY, Wang YP, Qin DM … +6 more , Zhang XM, Liu XJ, Zi XQ, Zhu SY, Pu H, Zhao Q
Bioorg Med Chem Lett · 2026 Sep · PMID 42167554 · Publisher ↗
To address the growing public health challenge of multidrug-resistant bacterial infections, 26 new butenolide amides bearing fatty chains of different lengths (CH, n = 4-16) were designed and synthesized and evaluated fo...
To address the growing public health challenge of multidrug-resistant bacterial infections, 26 new butenolide amides bearing fatty chains of different lengths (CH, n = 4-16) were designed and synthesized and evaluated for their antibacterial activity. The antibacterial activities of the derivatives were evaluted against four clinically common pathogens, Acinetobacter baumannii ATCC 19606(A. baumannii), Klebsiella pneumoniae ATCC 13883(K. pneumoniae), Pseudomonas aeruginosa ATCC 15442(P. aeruginosa) and methicillin-resistant Staphylococcus aureus ATCC 43300(MRSA 43300). The results indicated that derivative 17j, with a 13‑carbon fatty chain, exhibited prominent antibacterial activity, with MIC values of 0.25 μg/mL against A. baumannii and K. pneumoniae, 0.125 μg/mL against P. aeruginosa, and 1 μg/mL against MRSA 43300. The antibacterial activity of 17j against A. baumannii, K. pneumoniae and P. aeruginosa was approximately 64-fold higher than of that of kanamycin, while its activity against MRSA 43300 was close to that of vancomycin. Structure-activity relationship analysis revealed that the length of the fatty chain is a crucial determinant that impacts antibacterial activity. Cytotoxicity and hemolysis assays revealed that 17j exhibited very low toxicity toward mammalian cells (Beas-2B, SMMC-7721, MCF7) and red blood cells. The in vivo antibacterial activity of compound 17j was evaluated using the Galleria mellonella larval infection model, in which 17j showed better antibacterial activity than kanamycin. Scanning electron microscopy (SEM) analysis revealed that the likely mechanism of action involves the disruption of bacterial membrane integrity, leading to cell lysis and death. This research provides promising lead compounds for the development of antibacterial drugs targeting drug-resistant bacteria.
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