Philippsen GS, Nozaki LY, da Silva MJV
… +4 more, Nakamura J, Kioshima ES, Rosa FA, Seixas FAV
Bioorg Med Chem Lett
· 2026 Aug · PMID 42002052
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The pandemic caused by the SARS-CoV-2 virus established the urgency in the development of vaccines and specific antivirals. Currently, vaccines and one specific medicine (Paxlovid) are available. Despite this, the resear...The pandemic caused by the SARS-CoV-2 virus established the urgency in the development of vaccines and specific antivirals. Currently, vaccines and one specific medicine (Paxlovid) are available. Despite this, the research for therapeutic resources is still active to expand the possibilities for COVID-19 treatment. In this work, the libraries of natural compounds from Sigma-Aldrich and Molport were computationally screened, aiming to identify potential inhibitors against the SARS-CoV-2 main protease. The compounds SID336241534, SID264573190, and SID336181660 were identified as potential ligands and had their inhibitory activity against SARS-CoV-2 main protease confirmed by the in vitro proteolytic activity assays, suggesting their use as leads for the optimization of more efficient inhibitors. The in vivo and clinical tests are still needed to explore the applicability of the prospected compounds for the COVID-19 treatment.
Palli KK, Lee T, Cheng X
… +2 more, Piermarini PM, Rakotondraibe HL
Bioorg Med Chem Lett
· 2026 Aug · PMID 41999994
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Aedes aegypti mosquitoes are vectors of deadly arboviruses such as dengue, yellow fever, chikungunya, and Zika which kill millions worldwide. Prior research by our group discovered a drimane-type sesquiterpene cinnamodia...Aedes aegypti mosquitoes are vectors of deadly arboviruses such as dengue, yellow fever, chikungunya, and Zika which kill millions worldwide. Prior research by our group discovered a drimane-type sesquiterpene cinnamodial (CDIAL, 1), which was isolated from endemic and medicinal Malagasy plants, that showed promising mosquitocidal activities against A. aegypti. Subsequent synthetic medicinal chemistry efforts to develop more stable and potent mosquitocides derived from CDIAL led to the discovery of novel active compounds with drimane or quinone chemotypes. Here we use medicinal chemistry to further explore the toxicity of these chemotypes against mosquitoes. A dihomodrimene 23b and two quinone derivatives 24a & 24b each displayed superior adulticidal potency compared to 1. A preliminary structure-adulticidal activity relationship (SAR) study showed that lipophilic compounds produced by alkylation of the conjugated ketone at C-12 position together with the presence of an aldehyde at C-11 enhance insecticidal activity. For the larvicidal activity of the quinone derivatives, analogs 22a, 24a and 24b were superior in potency compared to CDIAL, with 24a appearing to be the most potent among the active samples.
Li T, Alkhatib M, Ramdhan PA
… +8 more, Bourn L, Rainwater JK, Nguyen N, Farrington CP, Lewis B, Li C, Keck TM, Boateng CA
Bioorg Med Chem Lett
· 2026 Aug · PMID 41997545
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Preclinical studies indicate that selective targeting of DR may improve behavioral and cognitive outcomes in animal models relevant to cognitive disorders, like ADHD and Alzheimer's disease, and substance use disorders (...Preclinical studies indicate that selective targeting of DR may improve behavioral and cognitive outcomes in animal models relevant to cognitive disorders, like ADHD and Alzheimer's disease, and substance use disorders (SUDs). In this study, we extend upon prior development of analogs of A-412997, a DR-selective partial agonist, by exploring ligand interactions within the secondary binding pocket. We modified the alkyl chain on the phenylacetamide's benzyl ring by extending and cyclizing the alkyl chain. A series of compounds were synthesized and tested using competition radioligand binding assays on DR, DR, and DR, using [H]N-methylspiperone as the competing radioligand. Herein, we report that while increasing the chain length beyond two carbons reduced DR affinity and selectivity, cyclizing the alkyl chain enhanced DR affinity and maintained selectivity over DR and DR by 120-fold or more. Molecular modeling results suggest that the cyclized rings engage in more favorable interactions within the DR binding pocket.
Bioorg Med Chem Lett
· 2026 Sep · PMID 41997544
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Ophioceric acid (1) is a representative member of africane-type sesquiterpenoids featured with a 5/7/3 tricyclic skeleton. Guided by retrobiosynthesis, we mined the biosynthetic gene cluster of 1 from the fungus Trichode...Ophioceric acid (1) is a representative member of africane-type sesquiterpenoids featured with a 5/7/3 tricyclic skeleton. Guided by retrobiosynthesis, we mined the biosynthetic gene cluster of 1 from the fungus Trichoderma harzianum. Based on the results from both in vivo and in vitro studies, the biosynthesis of 1 was elucidated. A class I sesquiterpenoid cyclase OphA catalyzes the formation of africanol (2) from farnesyl-diphosphate. And the conversion of 2 to 1 is catalyzed by two cytochrome P450s, via a P450 mediated enone formation and a P450 catalyzed functionalization of a methyl group to a carboxylic acid.
Ohira S, Doi I, Nakabayashi J
… +6 more, Tanaka H, Sonoda Y, Ammar YB, Kochi M, Tanaka T, Tsumura K
Bioorg Med Chem Lett
· 2026 Aug · PMID 41980672
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We present a novel strategy for the conversion of macrocyclic peptides into small molecules to identify potent and membrane-permeable protein-protein interaction (PPI) inhibitors. Our approach utilizes amino acid mapping...We present a novel strategy for the conversion of macrocyclic peptides into small molecules to identify potent and membrane-permeable protein-protein interaction (PPI) inhibitors. Our approach utilizes amino acid mapping (AAM) descriptors in conjunction with a generative artificial intelligence (AI) structure generator, enabling the design of small molecules that capture essential interaction profiles without relying on the original peptide scaffold. Using this method, we successfully transformed the known PD-L1 inhibitor Peptide-71 (K = 0.004 μM) into novel small-molecule inhibitors. Notably, compound 1, derived from the key interaction sites of Peptide-71, retained critical binding features and achieved a two-fold increase in a measure of activity per molecular weight, i.e., binding efficiency index (BEI: 9.2 vs. 4.7), despite a ∼ 10,000-fold decrease in absolute K (39 μM vs. 0.004 μM). Furthermore, structure-based optimization utilizing protein structural information led to the discovery of compound 2c, which exhibited a significant increase in potency (K = 5.7 μM), representing a more than six-fold increase over 1. These results demonstrate the potential of the combined AI-AAM and structure-based optimization strategy to efficiently convert peptides into small-molecule PPI inhibitors and accelerate the discovery of novel therapeutics.
Wang H, Liu X, Zheng W
… +5 more, Xu J, Liu S, Zhang S, Wang L, Peng T
Bioorg Med Chem Lett
· 2026 Aug · PMID 41974286
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Toll-like receptors (TLRs), a family of pattern recognition receptors of the innate immune system, have been shown to exert radioprotective effects by activating the NF-κB signaling pathway. In this context, we designed...Toll-like receptors (TLRs), a family of pattern recognition receptors of the innate immune system, have been shown to exert radioprotective effects by activating the NF-κB signaling pathway. In this context, we designed and synthesized a series of novel TLR2/1 small molecule agonists, 1H-1,2,3-triazole derivatives, to evaluate their radioprotective activity, with compound H9 exhibiting the most potent radiation-protective effect.H9 showed significant radioprotective effects in mice irradiated with 8.5 Gy of 60Co γ rays. The survival rates of the 80 mg/kg and 60 mg/kg H9-treated groups were both 100%. Furthermore, H9 can accelerate the recovery of peripheral blood cells in irradiated mice. The ELISA experiment showed that the levels of the antiradiation cytokine biomarker G-CSF were significantly increased in the serum of irradiated mice after treatment with H9. In human TLR2 and TLR1 transiently cotransfected HEK 293 T cells., H9 exhibits significant TLR2/1 agonist activity. Immunoprecipitation and cellular thermal shift assays (CETSA) confirmed that H9 targets the TLR2/1 rather than TLR2/6 heterodimeric complex. Summary: We demonstrated that H9 is a novel TLR2/1 agonist with significant efficacy in acute radiation protection, indicating that TLR2/1 small molecule agonists hold broad promise for applications in acute radioprotection.
Long Z, Li Y, Liu R
… +4 more, Tang X, Zhang H, Xie S, Xie W
Bioorg Med Chem Lett
· 2026 Aug · PMID 41967614
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A series of novel 5,6-disubstituted pyridone derivatives containing 1,3,4-thiadiazol (3a-3p) were synthesized starting from 2,3-dihydroxypyridine via oxidation-Michael additions, condensations and cyclizations. The antic...A series of novel 5,6-disubstituted pyridone derivatives containing 1,3,4-thiadiazol (3a-3p) were synthesized starting from 2,3-dihydroxypyridine via oxidation-Michael additions, condensations and cyclizations. The anticancer activity of the newly synthesized compounds were evaluated against Gastric cancer (MGC-803), hepatocellular cancer (HepG2) and Pulmonary cancer (PC-9) cell lines using the MTT assay. Most compounds exhibited antiproliferative activity against various cancer cells in vitro. Compared with the standard drug 5-fluorouracil, compounds 3a, 3 g and 3 h showed better activity against MGC-803, HepG2 and PC-9 cell lines, respectively. Compound 3 h demonstrated the most potent antitumor activity with IC values of 2.43 μM, 1.73 μM and 4.03 μM against MGC-803, HepG2 and PC-9 cell lines, respectively, which was 1.7-4.5 folds more potent than 5-Fluorouracil (IC = 10.92 μM 7.15 μM and 6.88 μM against MGC-803, HepG2 and PC-9 cell lines respectively). These findings suggest that compound 3 h shows promise as a lead compound for the development of novel small-molecule anticancer agents.
Abdel-Rahman SA, Delaunay M, Ha-Duong T
… +1 more, Gabr M
Bioorg Med Chem Lett
· 2026 Aug · PMID 41966493
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The SLIT2/ROBO1 signaling axis regulates cellular migration and angiogenesis but also contributes to tumor progression and immune evasion in glioblastoma. Targeting this pathway with small molecules or antibodies remains...The SLIT2/ROBO1 signaling axis regulates cellular migration and angiogenesis but also contributes to tumor progression and immune evasion in glioblastoma. Targeting this pathway with small molecules or antibodies remains challenging due to the shallow and extended nature of the SLIT2/ROBO1 interface. Here, we report the first computational design and experimental validation of macrocyclic peptides that inhibit SLIT2/ROBO1 binding. Twenty peptides were generated through a structure-guided interface mapping approach (Des3PI 2.0) and ranked using a contact-based scoring function. The top candidates were synthesized and evaluated using time-resolved fluorescence resonance energy transfer (TR-FRET) and biolayer interferometry (BLI) assays. Among the SLIT2-targeting peptides, SP4 and SP3 showed the most pronounced inhibition in TR-FRET (62% and 46%, respectively), with dose-dependent IC₅₀ values of 41 ± 5.2 μM and 68 ± 7.5 μM by BLI, confirming direct binding to the SLIT2/ROBO1 interface. The lead peptide SP4 also demonstrated favorable in vitro pharmacokinetic properties, including strong stability in simulated intestinal fluid (t₁/₂ = 7.6 h), high plasma integrity (89% at 1 h), and moderate metabolic stability in rat liver microsomes (t₁/₂ = 4.7 h). Collectively, this work provides a foundation for developing next-generation SLIT2/ROBO1 modulators for cancer and neuroimmune disorders.
Moukha-Chafiq O, Yatchang MF, Houghtling K
… +11 more, Cantor D, Tillotson JP, Sarngadharan SC, Al Abir F, Chen JY, Zhang S, Zhai L, Vinson P, Agarwal A, Athar M, Augelli-Szafran CE
Bioorg Med Chem Lett
· 2026 Aug · PMID 41966492
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Arsenicals and other vesicant chemical weapons are highly reactive, toxic substances capable of causing severe and painful blistering and inflammation following topical exposure. These effects can also lead to a wide ran...Arsenicals and other vesicant chemical weapons are highly reactive, toxic substances capable of causing severe and painful blistering and inflammation following topical exposure. These effects can also lead to a wide range of systemic organ damage resulting in significant morbidity and death. Two major proteins, Bromodomain 4 (BRD4) and receptor-interacting protein kinase-3 (RIPK3), are associated with the arsenicals-mediated inflammatory and tissue wounding responses in the skin and in other organs. The downstream pathway of these two proteins also leads to induction of various cytokines and chemokines, including interleukin-6 (IL-6). Our medicinal chemistry efforts were focused on the identification and lead optimization of potent small-molecule dual inhibitors of BRD4 and RIPK3with consequent dampening of the activation of IL-6. The initial hit compound, 5a was identified from a high-throughput screening (HTS) campaign of 4 K compounds which inhibited all three proteins, BRD4 (IC = 22.40 μM), RIPK3 (IC = 0.56 μM), and IL6 (IC = 12.60 μM), and had moderate metabolic stability (MLM t = 23.7 min, HLM t = 14.6 min), but was insoluble at pH 7.4 (solubility <1 μM). A structure-activity relationship (SAR) campaign led to the discovery of a new potent inhibitor, 12 m, 6-[[4-(2-fluoro-N-methyl-anilino)pyrimidin-2-yl]amino]-3-methyl-1,4-dihydroquinazolin-2-one, which had improved potency against BRD4 (IC = 5.91 μM), RIPK3 (IC = 1.32 μM), and IL6 (IC = 0.22 μM), and similar metabolic stability (MLM t = 11.0 min, HLM t = 33.2 min). Herein, we report a hit-to‑lead optimization study that led to the discovery of novel BRD4 and RIPK3 dual inhibitors.
Zhou Y, Lang Z, Lin H
… +6 more, Wang J, Zhang B, Asan K, Wang X, Sun L, Ji J
Bioorg Med Chem Lett
· 2026 Aug · PMID 41956429
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In this study, we designed and synthesized a series of compounds derived from the histone deacetylase inhibitor (HDACi) Chidamide and the BET bromodomain inhibitor (+)-JQ-1. All target compounds were structurally charact...In this study, we designed and synthesized a series of compounds derived from the histone deacetylase inhibitor (HDACi) Chidamide and the BET bromodomain inhibitor (+)-JQ-1. All target compounds were structurally characterized by H NMR, C NMR, and high-resolution mass spectrometry (HRMS). Antiproliferative activity was assessed by an MTT assay in MDA-MB-231 (breast cancer), HeLa (cervical cancer), and HCT116 (colon cancer) cells, with chidamide and (+)-JQ-1 as reference compounds; cytotoxicity in 293 T cells was further evaluated to estimate selectivity. Results indicated that most derivatives exhibited superior activity to Chidamide, with compound 6e demonstrating the strongest inhibitory effect against MDA-MB-231 cells. The IC values of 6e were 0.10 ± 0.02 μM (MDA-MB-231), 0.90 ± 0.17 μM (HeLa), 19.60 ± 0.90 μM (HCT116), and 70.13 ± 5.19 μM (293 T). Further assays showed that 6e inhibited colony formation, migration, adhesion, and invasion of MDA-MB-231 cells in a concentration-dependent manner. Annexin V-FITC/PI flow cytometry indicated apoptosis induction. In the chicken embryo chorioallantoic membrane (CAM) model, 6e inhibited tumor growth and angiogenesis more effectively than chidamide. In summary, 6e demonstrates promising optimization potential as a lead compound for breast cancer therapy.
Zhang X, Shi X, Song Y
… +9 more, Chen X, Yang Y, Ding L, Tu H, Bai F, Sun Y, Yang D, Xu X, Xie Y
Bioorg Med Chem Lett
· 2026 Aug · PMID 41956428
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It is well-established that clofibrate (CF)-induced hepatotoxicity involves oxidative stress and inflammatory responses. To address this issue, we employed a molecular hybridization strategy to optimize the CF structure,...It is well-established that clofibrate (CF)-induced hepatotoxicity involves oxidative stress and inflammatory responses. To address this issue, we employed a molecular hybridization strategy to optimize the CF structure, aiming to develop compounds with improved lipid-lowering efficacy, antioxidant capacity, and anti-inflammatory properties while minimizing hepatotoxicity risk. The designed hybrid molecule, eugenol-clofibrate (CF-Eugenol), was synthesized by replacing the ethoxy group of CF with eugenol. In vitro and in vivo evaluations demonstrated that CF-Eugenol exhibits high binding affinity for PPAR-α and effectively reduces serum triglyceride (TG) and total cholesterol (TC) levels in hyperlipidemic mice. Notably, CF-Eugenol significantly mitigates liver injury, as evidenced by reduced liver coefficient, decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and improved liver tissue pathology (e.g., reduced cell degeneration, necrosis, and swelling). Mechanistically, CF-Eugenol suppresses inflammatory responses by downregulating pro-inflammatory cytokines (TNF-α and IL-6) and alleviates oxidative stress through enhanced superoxide dismutase (SOD) activity and glutathione (GSH) levels, accompanied by reduced malondialdehyde (MDA) accumulation. Further analysis revealed that these effects are mediated via the activation of the Nrf2/HO-1 pathway. Collectively, CF-Eugenol demonstrates superior lipid-lowering activity with reduced hepatotoxicity, potentially through its dual anti-inflammatory and antioxidant mechanisms driven by Nrf2/HO-1 pathway activation. This hybrid strategy offers a promising approach for designing safer lipid-modulating agents.
Wang YX, Zhou XW, Du WR
… +3 more, Qin SH, Zhang CY, Ma ZY
Bioorg Med Chem Lett
· 2026 Aug · PMID 41936874
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In this study, a series of 2-amino-5-formamidopyrimidine derivatives were designed and synthesized. Their potential as cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD) were evaluated by the...In this study, a series of 2-amino-5-formamidopyrimidine derivatives were designed and synthesized. Their potential as cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD) were evaluated by the Ellman method. Meanwhile, the antioxidant activity of these compounds were assessed by the DPPH (2,2-diphen-yl-1-picrylhydrazyl) free radical scavenging assay. The cholinesterase (ChE) inhibition test showed that most compounds exhibited excellent to moderate inhibitory effects on acetylcholinesterase (AChE), while most of them did not show significant inhibitory effects on butyrylcholinesterase (BuChE), demonstrating significant selectivity. Among them, compound 9 s (AChE: IC = 1.60 μM) whose AChE inhibitory activity is superior to the positive control galantamine (AChE: IC = 5.10 μM) is the most promising representative compound. Meanwhile, compound 9 s has high selectivity with a SI (IC ratio of BuChE to AChE) value of 29.85. The results of enzyme kinetics study determined that compound 9 s was a mixed-type inhibitor. Additionally, the molecular docking studies results indicated that compound 9 s could simultaneously interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, which was consistent with the results of the enzyme kinetics experiments. Molecular dynamics (MD) simulation study further verified the stability of the 9 s-AChE complex. In addition, the DPPH radical scavenging assay indicated that these compounds also possessed relatively weak antioxidant activities. Among them, compound 9p exhibited the best antioxidant activity with an IC value of 113.93 μM, which was lower than that of the positive control ascorbic acid (IC = 41.17 μM). Overall, these experimental results suggested that compound 9 s as AChE inhibitor had potential value for further research.
Braconi L, Perrin E, Conti AC
… +7 more, Marotta G, Mattolini L, Bartolucci G, Manetti D, Romanelli MN, Teodori E, Crocetti L
Bioorg Med Chem Lett
· 2026 Aug · PMID 41935546
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Antimicrobial resistance (AMR) represents a serious problem for human health and arises through several mechanisms. Bacteria can further enhance their intrinsic resistance by forming biofilms, defensive barriers that pro...Antimicrobial resistance (AMR) represents a serious problem for human health and arises through several mechanisms. Bacteria can further enhance their intrinsic resistance by forming biofilms, defensive barriers that protect bacterial cells from antibiotics and the host immune system. Moreover, sub-inhibitory concentrations of antibiotics, such as chloramphenicol (CHL), stimulate biofilm development. A valid strategy to counteract biofilm-associated resistance is the use of biofilm formation inhibitors. For this purpose, a series of benzyldiazepane derivatives was synthesized as new anti-biofilm agents. First, their minimum inhibitory concentration (MIC) values and their effect with CHL on bacterial growth inhibition were evaluated. Then, each molecule was studied alone and in combination with sub-inhibitory concentrations of CHL to assess its ability to inhibit biofilm formation in the Escherichia coli K-12 strain. Four compounds showed intrinsic anti-biofilm activity and, interestingly, a combinatorial effect with CHL was observed for almost all derivatives. Overall, the results highlight benzyldiazepane as a promising scaffold for the development of anti-biofilm agents, since the tested compounds were able to decrease biofilm formation. In particular, the nitrobenzyl derivative 2 significantly reduced biofilm formation both alone and in combination with CHL.
Bioorg Med Chem Lett
· 2026 Aug · PMID 41935545
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A series of 2,4-diaylpyridine analogues 8(1-9) was synthesised and evaluated for antiproliferative activity against a panel of human tumour and non-tumour breast cell lines that was characterised for CYP1 A1, A2 and B1 i...A series of 2,4-diaylpyridine analogues 8(1-9) was synthesised and evaluated for antiproliferative activity against a panel of human tumour and non-tumour breast cell lines that was characterised for CYP1 A1, A2 and B1 isoforms expression. Diarylpyridine 8 (6) was the most potent analogue with high cytotoxicity towards MDA-MB-468 cells (IC = 0.08 μM) and no toxicity towards MCF-10 A cells (IC = 100 μM). In vitro enzyme inhibition studies revealed that CYP1 isozymes were responsible for the metabolism and consequent bioactivation of 8 (6). CYP1-catalysed metabolism experiments using 8 (6) revealed the formation of four main metabolites (M1-4) that were characterised by LC-MS analysis. It was found that the primary metabolisation route for 8 (6) consisted in the dealkylation of its 3,4-methylenedioxy A-ring functionality to generate the toxic catechol metabolite M2. The latter was synthesised (9), co-eluted with samples spiked with original CYP1-generated metabolites and evaluated for antiproliferative activity. Our studies confirmed that 9 was the CYP1-generated metabolite (M2) exhibiting cytotoxic activities at low micromolar level against all cell lines in the panel regardless of their expression of CYP1 enzymes. In summary, we demonstrated the pro-drug mode of action of the tumour-selective 8 (6), which upon CYP1-mediated conversion to toxic metabolites, was capable of exerting antiproliferative activity in breast cancer cells.
Fan Z, Huang J, Shahriar MF
… +3 more, Lin Z, Wang H, Kong Y
Bioorg Med Chem Lett
· 2026 Aug · PMID 41921827
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Antimicrobial peptides (AMPs) are regarded as the most promising candidates for next-generation antimicrobial agents, with amphipathicity serving as a critical factor in de novo design or systematic optimization. Previou...Antimicrobial peptides (AMPs) are regarded as the most promising candidates for next-generation antimicrobial agents, with amphipathicity serving as a critical factor in de novo design or systematic optimization. Previous studies rarely investigated into imperfect amphipathicity scenarios. Therefore, we developed a series of peptides exhibiting diverse imperfect amphipathicity derived from the hybrid peptide P18 to explore the effect of different imperfect amphipathicity on peptides by evaluating their antimicrobial activity and toxicity. We found that imperfectly amphipathic peptides exhibited stronger antimicrobial activity than their perfect counterparts, among them, peptides with incompletely hydrophobic surfaces and completely hydrophilic surfaces showed higher activity than those with incompletely hydrophilic surfaces and completely hydrophobic surfaces. Moreover, imperfect amphipathicity did not lead to an increase in hemolytic activity and incompletely hydrophilic surface did not lead to an increase in cytotoxicity. Notably, APH143 (LWKKFKLKKKFLWLWKKF-NH), a completely imperfect amphipathic peptide, exhibited stronger antimicrobial activity (MIC values of 2-4 μg/mL) against common clinical pathogenic bacteria (K.pneumoniae, P.aeruginosa, A.baumannii, S.aureus) and low hemolytic activity (HC > 256 μg/mL), compared to other designed peptides. Subsequent experiment indicated that APH143 possessed good stability in mouse plasma, bronchoalveolar lavage fluid and different pH, temperature, salt conditions, it was also safe in mice sub-acute toxicity assay. APH143 may be a promising candidate for antimicrobial therapy. Our research deepens the understanding of designing antimicrobial peptides based on imperfect amphiphilicity and provides a novel perspective of changing degree of imperfect amphiphilicity for the design of antimicrobial peptides to overcome multi-drug resistant infection.
Mu Q, Zhou H, Li Q
… +5 more, Chen Y, Zhu Y, Liu R, Tian L, Gu S
Bioorg Med Chem Lett
· 2026 Aug · PMID 41921826
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Based on the structure of NTM-006, a selective adenosine A receptor (AAR) agonist developed by Janssen Pharmaceutica NV, a series of novel analgesics was designed and synthesized. Their analgesic activity was evaluated u...Based on the structure of NTM-006, a selective adenosine A receptor (AAR) agonist developed by Janssen Pharmaceutica NV, a series of novel analgesics was designed and synthesized. Their analgesic activity was evaluated using the acetic acid-induced writhing model in mice. Among the 46 target compounds, 15 of them exhibited significant inhibition of writhing responses at 100 mg/kg (inhibition rate ≥ 32.89%), with analgesic efficacy comparable to that of the positive controls (NTM-006 and acetaminophen), indicating their potential for further development as analgesic agents. Dose-response studies revealed that compounds 37 and 40 inhibited writhing in a dose-dependent manner within the range of 30-300 mg/kg. Molecular docking further elucidated their potential binding modes with AAR, and molecular dynamics (MD) simulations revealed that compound 37 exhibited superior binding affinity and stability toward AAR compared to the lead compound NTM-006. The studies of preliminary structure-activity relationships and potential mechanisms of action provided insights for the design and development of novel analgesics targeting AAR.
Zhang B, Xu Z, Zhang M
… +4 more, Ma G, Chang Y, Tian D, Tang J
Bioorg Med Chem Lett
· 2026 Aug · PMID 41921825
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Sorbicillinoids, a class of fungal metabolites, have shown promising anti-inflammatory activity. Considering the importance of the biphenyl pharmacophore in anti-inflammatory agents and the favorable role of halogenation...Sorbicillinoids, a class of fungal metabolites, have shown promising anti-inflammatory activity. Considering the importance of the biphenyl pharmacophore in anti-inflammatory agents and the favorable role of halogenation in optimizing drug-like properties, we designed and synthesized a series of novel sorbicillinoid derivatives. This study reports the first preparation of 12 sorbicillinoid-based bibenzyl analogues and two brominated sorbicillinoid analogues. Their anti-inflammatory effects were assessed in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages by measuring nitric oxide (NO) production and the expression of key inflammation-related proteins. Most analogues inhibited NO release and downregulated the expression of these proteins to varying degrees. Notably, the bibenzyl analogue 1i exhibited dose-dependent suppression of NO production, with potency comparable to the lead compound JNUTS013 (12a). Furthermore, 1i exerted superior activity in suppressing the expression of iNOS, COX-2, and NLRP3, and showed a strong binding affinity with NLRP3 (-6.76 kcal/mol). These findings highlight 1i as a promising anti-inflammatory lead compound and its underlying mechanism may involve the interaction with NLRP3.
Dos Santos JRN, Martinez AKA, Mendes Abe SH
… +6 more, Palmeira-Mello MV, Dos Santos JPA, Rodrigues CR, de Souza AMT, Batista AA, Corrêa AG
Bioorg Med Chem Lett
· 2026 Aug · PMID 41921824
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The coumarin scaffold is widely recognized for its broad range of biological activities, including antibacterial, anti-HIV, and anticancer properties. In parallel, molecular hybridization has emerged as an effective stra...The coumarin scaffold is widely recognized for its broad range of biological activities, including antibacterial, anti-HIV, and anticancer properties. In parallel, molecular hybridization has emerged as an effective strategy to enhance biological activity and expand chemical diversity within drug discovery libraries. In this study, a series of coumarin-dihydropyrimidinone (DHPM) hybrids were synthesized via a Biginelli multicomponent reaction. The in vitro cytotoxic activity of these compounds was evaluated against a panel of cancer cell lines. A structure-activity relationship (SAR) analysis was carried out to elucidate the influence of different substituents and physicochemical properties on anticancer activity. Among the synthesized compounds, LSPN925 emerged as a good anticancer candidate and was further investigated for its effects on cell morphology and colony formation. In addition, in silico pharmacokinetic and toxicological evaluations were performed for the most active compounds to predict their drug-likeness and safety profiles. The preliminary SAR analysis revealed that lipophilicity and molecular volume of the compounds play a critical role in modulating their cytotoxic activity, highlighting these parameters as key considerations in the rational design of new coumarin-based anticancer agents. Overall, these findings support the potential of coumarin-DHPM hybrids as promising scaffolds for further anticancer drug development.
Bioorg Med Chem Lett
· 2026 Aug · PMID 41912099
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A series of novel twenty benzothiazole-fused iminothiazoline derivatives (7aa-7df) were synthesized and evaluated for their invitro anticancer activity and their antimicrobial studies. The structures of the final compoun...A series of novel twenty benzothiazole-fused iminothiazoline derivatives (7aa-7df) were synthesized and evaluated for their invitro anticancer activity and their antimicrobial studies. The structures of the final compounds were confirmed through H NMR,C NMR and LC-MS spectroscopic techniques. The anticancer evaluation revealed that compounds 7ce and 7dc exhibited excellent activity with an IC value of 1.40 and 1.716 μM, respectively, against MCF-7 cells and notable potency was observed against MDA-MB-231 cancer cells with IC values of 5.03 and 8.42 μM. It was observed that compounds possessing a nitro, chloro and bromo substitution at 4th position enhanced the anticancer activity. While, antimicrobial screening revealed that compounds 7dc and 7bf were exhibited moderate anti-bacterial activity significantly less potent than standard drug against E. coli and S. aureus, with MICs of 32 μg/mL and 64 μg/mL, respectively. Furthermore, molecular docking studies supported the biological potential of the synthesized compounds by establishing key interactions with the target proteins. In addition, ADMET analysis was performed to elucidate the pharmacokinetic and toxicological properties, which validates the drug-likeness of the compounds.
Williams MJ, Ronayne CT, Schumacher TJ
… +5 more, Johnson KM, Wittmer MD, Johnson JL, Anderson GW, Mereddy VR
Bioorg Med Chem Lett
· 2026 Aug · PMID 41912098
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Reprogrammed cancer cell proliferation requires high levels of protein synthesis and concomitant folding and processing. N-terminal methionine amino peptidases (MetAP) are a class of enzymes that cleave the initiator met...Reprogrammed cancer cell proliferation requires high levels of protein synthesis and concomitant folding and processing. N-terminal methionine amino peptidases (MetAP) are a class of enzymes that cleave the initiator methionine amino acids to allow for peptide maturation and co-translational processing. The protein MetAP2 is upregulated in cancer cells and has been explored as a potential anticancer target. Cellular perturbations that impinge on protein synthesis activate cellular stress pathways, including the integrated stress response and mTORC1. Nitroxoline, a MetAP2 inhibitor has been explored as an anticancer agent but is hampered by poor pharmacokinetic properties. Here, we synthesized O-substituted silyl and nonsilyl nitroxoline analogs to diversify the nitroxoline template. In vitro MetAP2 and cancer cell proliferation inhibition assays demonstrated that synthesized analogs retain potency when compared to the parent nitroxoline. Mechanistically, we showed that the lead compound 3 and nitroxoline activate ATF4 mediated stress responses through non-canonical mTORC1. These results further implicate MetAP2 protein processing in mTORC1 nutrient sensing pathways and provide novel synthetic analogs of nitroxoline.