Bioorg Med Chem Lett
· 2026 Feb · PMID 41213481
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Lung cancer remains the leading cause of cancer-related deaths worldwide, emphasizing the need for effective targeted therapeutics. Telomerase, which is aberrantly activated in most lung tumors, is an attractive molecula...Lung cancer remains the leading cause of cancer-related deaths worldwide, emphasizing the need for effective targeted therapeutics. Telomerase, which is aberrantly activated in most lung tumors, is an attractive molecular target; however, the clinical translation of its inhibitors has been limited. In this study, we employed a rational design approach that integrated pharmacophore modeling, virtual screening, QSAR, and molecular docking to develop acridine-thiadiazole hybrids as potential telomerase inhibitors. Guided by pharmacophore-based virtual screening and 3D-QSAR studies, 32 derivatives were synthesized through an optimized route for synthesis and evaluated for anticancer activity. Several compounds displayed potent sub-micromolar cytotoxicity against A549 lung cancer cells with minimal toxicity toward Vero cells. Among them, compound 28 emerged as the most potent, exhibiting nanomolar activity and strong telomerase inhibition, while compounds 21, 29, and 39 also demonstrated significant efficacy. Mechanistic studies confirmed apoptosis induction, inhibition of clonogenic survival, and telomerase suppression. In vivo evaluation in a benzo[a]pyrene-induced lung cancer model further validated the therapeutic potential of these hybrids, showing reduced tumor burden, restoration of antioxidant balance, and preservation of lung architecture. Collectively, these findings highlight acridine-thiadiazole hybrids, particularly compound 28, as promising, selective telomerase inhibitors for lung cancer therapy.
Seo K, Jeon M, Han JE
… +8 more, Hong J, Kim DH, Choi JH, Jung SY, Kim KM, Kim DH, Ryu JH, Lee JY
Bioorg Med Chem Lett
· 2026 Feb · PMID 41205766
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Despite the widespread use of monoaminergic antidepressants, their clinical efficacy is often limited by delayed onset and adverse effects. Targeting the α adrenoceptor (AR) has emerged as a promising strategy to overcom...Despite the widespread use of monoaminergic antidepressants, their clinical efficacy is often limited by delayed onset and adverse effects. Targeting the α adrenoceptor (AR) has emerged as a promising strategy to overcome these limitations. Here, a series of benzoxazole and oxalamide derivatives were designed, synthesized, and biologically evaluated as potential antidepressants targeting α AR. Among them, 11e (KMCA-0011), 21b (KMCA-0002), and 21e (KMCA-0028) exhibited the highest binding affinity. Molecular docking studies provided a rationale for the differences in their binding affinities. These compounds demonstrated antagonistic activity by inhibiting ERK phosphorylation without agonistic effects. In a maternal separation (MS) mouse model, all three compounds significantly alleviated depressive-like behaviors, with 11e (KMCA-0011) and 21e (KMCA-0028) showing the most consistent efficacy. Mechanistically, 11e (KMCA-0011) increased hippocampal brain-derived neurotrophic factor (BDNF) levels and restored corticosterone-induced impairments in long-term potentiation (LTP), indicating modulation of synaptic plasticity. Additionally, 11e (KMCA-0011) and 21e (KMCA-0028) displayed favorable ADME profiles, including high plasma stability and minimal CYP inhibition. Given the predicted limited blood-brain barrier (BBB) permeability of 21e (KMCA-0028), these results collectively identify 11e (KMCA-0011) as a promising lead compound that demonstrates robust antidepressant-like activity, likely mediated through α AR antagonism and BDNF-dependent neuroplastic mechanisms.
Jeong GH, Song HY, Lee H
… +3 more, Chung BY, Lee KB, Bai HW
Bioorg Med Chem Lett
· 2026 Feb · PMID 41202901
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Facile structural modification of naringin (1) induced by γ-irradiation produced five novel hydroxymethylated flavan-4-ols, namely, narinflavans A (2), B (3), C (4), D (5), and E (6). The structures of the newly synthesi...Facile structural modification of naringin (1) induced by γ-irradiation produced five novel hydroxymethylated flavan-4-ols, namely, narinflavans A (2), B (3), C (4), D (5), and E (6). The structures of the newly synthesized flavan derivatives were determined through comprehensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) analyses, whereas their absolute configurations were confirmed by electronic circular dichroism (ECD) spectroscopy. The new unusual flavan derivatives 4 and 5 containing a hydroxymethyl, instead of a ketone moiety, exhibited significantly modulated inhibitory effects on cytokine production than the parent compound. These results highlight γ-irradiation as an efficient one-step approach to generate structurally novel flavan-4-ols with biological functions.
Bioorg Med Chem Lett
· 2026 Feb · PMID 41202900
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The nontuberculous mycobacterial (NTM) pathogen, Mycobacteroides abscessus, can cause severe pulmonary infections. Emerging multidrug resistance to current antibiotics poses significant challenges for treatment of M. abs...The nontuberculous mycobacterial (NTM) pathogen, Mycobacteroides abscessus, can cause severe pulmonary infections. Emerging multidrug resistance to current antibiotics poses significant challenges for treatment of M. abscessus infections. Thus, new antibiotics are needed, preferably ones that target new microbial pathways. Earlier, we examined the in vitro inhibitory activities of several gallium compounds, Ga(NO), GaCl, gallium meso-tetraphenylporphyrin (GaTP) and gallium nanoparticles (GaNP), against intra- and extracellular M. abscessus. We have previously shown that these gallium compounds function by disrupting microbial iron/heme acquisition and utilization. Here, we explored an alternative therapeutic approach using gallium hematoporphyrin (GaHP), a toxic heme analogue. GaHP inhibited growth of clinical M. abscessus isolates, with MICs in range of 0.5 and 1 μg/ml. GaHP was more active than rifampin against M. abscessus, showed synergism with clarithromycin, and induced ROS formation in M. abscessus. GaHP also inhibited biofilm formation of both smooth and rough M. abscessus colony morphotypes. GaHP also disrupted preformed biofilms by both M. abscessus morphotypes. Hence, GaHP could be a potential lead compound for development of anti-NTM agents that targets heme-metabolism of M. abscessus.
Peddakotla SVK, Lingala S, Perumal O
… +2 more, Amaravathi M, Chandramoulia GVP
Bioorg Med Chem Lett
· 2026 Feb · PMID 41202899
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A novel series of AB and A type porphyrin derivatives bearing pyrazole moieties was efficiently synthesized and structurally characterized. These pyrazolyl-porphyrins were evaluated for their α-glucosidase inhibitory act...A novel series of AB and A type porphyrin derivatives bearing pyrazole moieties was efficiently synthesized and structurally characterized. These pyrazolyl-porphyrins were evaluated for their α-glucosidase inhibitory activity using Saccharomyces cerevisiae α-glucosidase as the target enzyme. In vitro enzyme assays and kinetic studies revealed that compounds 6c, 7b, and 6d exhibited inhibitory effects comparable to the standard drug Acarbose. Notably, compound 6c demonstrated the highest potency, with an IC₅₀ value of (31.36 μM), closely matching that of Acarbose (31.69 μM) under identical experimental conditions. In silico molecular docking studies further supported the biological data, showing that compound 6c interacts with key residues within the enzyme's active site in a binding mode similar to Acarbose. These findings suggest that pyrazolyl-porphyrin hybrids, particularly compound 6c, hold promise as potential α-glucosidase inhibitors for the development of antidiabetic agents.
Vikram VN, Ranawat M, Singh A
… +6 more, Kumar S, Sharma A, Yadav S, Kumar V, Kshatri AS, Narender T
Bioorg Med Chem Lett
· 2026 Feb · PMID 41197882
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Millions of people are being affected by chronic pain, and it is insufficiently addressed by the current classes of analgesics. Nav1.7 channels have emerged as promising targets in this pain context since their systemic...Millions of people are being affected by chronic pain, and it is insufficiently addressed by the current classes of analgesics. Nav1.7 channels have emerged as promising targets in this pain context since their systemic inhibition can cancel pain perception altogether. In this work, we report a novel, O-alkylated piperine derivative 3ag as an inhibitor of Nav1.7 channels with an IC of 3.10 μM. Furthermore, this molecule displayed an oral analgesic efficacy in a CFA inflammatory pain model at 10 mg/kg. Based on our findings, this molecule could be used as a starting point for the development of new Nav1.7-specific blockers for anti-nociception.
Banales-Mejia F, Dieter EM, Radmall KJ
… +3 more, Foight GW, Fowler DM, Maly DJ
Bioorg Med Chem Lett
· 2026 Feb · PMID 41197881
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Chemically-controlled genetic tools are useful for studying biological systems due to their ability to dose-dependently and temporally modulate intracellular function. Chemically-disrupted proximity (CDP) systems, which...Chemically-controlled genetic tools are useful for studying biological systems due to their ability to dose-dependently and temporally modulate intracellular function. Chemically-disrupted proximity (CDP) systems, which involve the pre-localization of two interacting protein components that can be disrupted with a small molecule, are complementary to more commonly used chemically-inducible dimerization (CID) systems. However, fewer CDP systems have been developed, and the genetically-encoded protein components have not been as optimized for intracellular applications. Here, we describe a transcriptional activation reporter assay for screening the intracellular interaction between the 21-amino acid peptide ANR and HCVp NS3a, which are the genetically-encoded components of a CDP system that utilizes clinically-approved antiviral drugs. We used this assay to screen a library of single amino acid substitution ANR variants and identified several that increase the intracellular interaction between ANR and NS3a. By combining affinity-optimized single substitutions, we achieved improved transcriptional activation and engineered an autoinhibited signaling switch with low basal activity. Together, our study describes a functional assay for screening genetically-encoded CDP components and a more optimized version of ANR for intracellular applications.
Bioorg Med Chem Lett
· 2026 Feb · PMID 41192685
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Chitinase-3-like 1 (CHI3L1) is a secreted glycoprotein implicated in carcinogenesis and tumor immune evasion. Elevated CHI3L1 expression is frequently detected in cancer patients, highlighting it as a promising therapeut...Chitinase-3-like 1 (CHI3L1) is a secreted glycoprotein implicated in carcinogenesis and tumor immune evasion. Elevated CHI3L1 expression is frequently detected in cancer patients, highlighting it as a promising therapeutic target. To overcome the limited availability of small molecule CHI3L1 inhibitors, we established a surface plasmon resonance (SPR)-based high-throughput screening platform and applied it to a focused chemical library of small molecules. Primary screening identified seven hits, with compounds 1-4 and 1-7 validated as CHI3L1 binders (Kd = 10.4 ± 1.0 μM and 7.40 ± 0.78 μM, respectively). Both compounds disrupted the CHI3L1-galectin-3 interaction in AlphaLISA assays and engaged the CHI3L1 binding pocket in docking and molecular dynamics (MD) simulations. Importantly, functional evaluation in a multicellular 3D glioblastoma (GBM) spheroid model demonstrated that compound 1-7 potently reduced spheroid viability and inhibited STAT3 phosphorylation, outperforming both compound 1-4 and the known CHI3L1-STAT3 disruptor hygromycin B (HB). These findings validate SPR as a robust primary screening platform for CHI3L1 and demonstrate that the identified small molecule binders exert functional activity in a physiologically relevant multicellular GBM spheroid model.
Bioorg Med Chem Lett
· 2026 Feb · PMID 41183623
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The Ba/F3 cell line is a widely used model in kinase drug development. Such cells are transformed to depend on a certain kinase for proliferation, and the use of an inhibitor of the kinase thus prevents their growth. We...The Ba/F3 cell line is a widely used model in kinase drug development. Such cells are transformed to depend on a certain kinase for proliferation, and the use of an inhibitor of the kinase thus prevents their growth. We used Ba/F3 cells that expressed mutated FLT3 (FLT3-ITD), a known drug target in acute myeloid leukaemia (AML), to study drug resistance against two potent and selective inhibitors (gilteritinib and FF-10101). The cells could be made resistant to the drugs in concentrations that are similar to those in the plasma of patients, but this often required multiple secondary mutations. Several novel inhibitors, designed to be active against FLT3 mutants were tested but could not inhibit the growth of the resistant Ba/F3 cells. Several hitherto unidentified mutations in FLT3 were discovered that lead to drug resistance. These mutations were further studied using computational tools in order to understand how they lead to drug resistance. The discovery of novel mutations is significant since few patients were tested upon relapse due to lack of therapeutic options. Finally, we discuss the pros and cons of the Ba/F3 cell lines in the context of AML where patients express FLT3-ITD mutations in comparison with other cell lines, when the aim is development of drugs that overcome resistance.
Yang DM, Kang YW, Kim K
… +6 more, Lee SH, Oh T, Shin KJ, Kim MJ, Heo TH, Kim I
Bioorg Med Chem Lett
· 2026 Feb · PMID 41183622
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The immune system plays a critical role in cancer control, but tumor cells often evade immune responses by exploiting inhibitory molecules like PD-1/PD-L1. Monoclonal antibodies targeting PD-1/PD-L1 interaction blockade...The immune system plays a critical role in cancer control, but tumor cells often evade immune responses by exploiting inhibitory molecules like PD-1/PD-L1. Monoclonal antibodies targeting PD-1/PD-L1 interaction blockade have shown remarkable success in reactivating T-cell function in various advanced cancers, but they face limitations such as long half-life and immune-related adverse events (irAEs). In this study, we identified a new class of indoline-based scaffold through molecular docking analysis and synthesized derivatives, identifying compound 31 with an IC of 0.89 nM in FRET assay. Compound 31 showed less than 50 % inhibition against CYP and hERG, and demonstrated moderate liver microsomal stability in mice. These results suggest that indoline derivatives may serve as potential PD-L1 inhibitors and warrant further investigation.
Wandrey N, Boley J, Gómez-Galicia D
… +7 more, Hill M, Bach M, Gawrych S, Hagemeister M, Cole PA, Moxley MA, Thomas AA
Bioorg Med Chem Lett
· 2026 Feb · PMID 41176235
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Arylalkylamine N-acetyltransferase (AANAT) is a key enzyme in melatonin biosynthesis and a regulator of circadian rhythm, with potential relevance to mood disorders such as seasonal affective disorder (SAD). We report a...Arylalkylamine N-acetyltransferase (AANAT) is a key enzyme in melatonin biosynthesis and a regulator of circadian rhythm, with potential relevance to mood disorders such as seasonal affective disorder (SAD). We report a series of hydantoin indolinone-based AANAT inhibitors, developed as more stable alternatives to a previously reported rhodanine scaffold. Guided by docking studies and prior structure-activity data, we modified four regions of the molecule to improve potency. Substitution at the 5-position of the indolinone ring led to marked increases in activity, with compound 5g (bearing a CHCOCH- substituent) resulting in an IC₅₀ of 1.1 μM-representing a 19-fold improvement over the parent compound. Kinetic mechanism studies were also conducted with respect to acetyl-CoA and serotonin to explore inhibitor binding. These findings establish a promising starting point for the development of more potent AANAT inhibitors as chemical probes for studying melatonin's function.
Bolt HL, Kaiser M, Luo Y
… +5 more, Lundy FT, Moon L, Zuckermann RN, Denny PW, Cobb SL
Bioorg Med Chem Lett
· 2026 Feb · PMID 41176234
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Protozoan parasites represent a severe threat to global human health as they are responsible for infection in Malaria, and a range of Neglected Tropical Diseases (NTDs) including Chagas disease, leishmaniasis and African...Protozoan parasites represent a severe threat to global human health as they are responsible for infection in Malaria, and a range of Neglected Tropical Diseases (NTDs) including Chagas disease, leishmaniasis and African sleeping sickness. Often treatments for protozan parasites are limited in their efficacy and drug resistance is an emerging problem. The current efforts to develop new treatments for the aforementioned diseases have been met with limited success and as such novel compound classes for development are being actively sought. Peptoids are peptidomimetics that have showed promise as antimicrobial agents but their application in the field of vector-borne parasitic diseases is highly underdeveloped. Herein, a library of over 50 peptoids containing a wide variety of chemical functionalities has been prepared and biologically evaluated against a range of protozoan parasitic targets. Selected members of the peptoid library were found to have potent anti-parasitic activity and good selectivity indices (SI). For example, peptoid 29 [NamyNspeNspe)(NhArgNspeNspe)] had an IC of 0.05 μM against Plasmodium falciparum and a SI > 100.
Wang Y, Que Y, Gu Y
… +5 more, Xia J, Dong Y, Tang L, Mou S, Chen G
Bioorg Med Chem Lett
· 2026 Feb · PMID 41135668
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Cycloastragenol (CAG), a bioactive compound from Huangqi, exhibits anti-inflammatory properties but has poor water solubility. This study enhanced CAG's solubility via C3-position modifications, synthesizing phosphorylat...Cycloastragenol (CAG), a bioactive compound from Huangqi, exhibits anti-inflammatory properties but has poor water solubility. This study enhanced CAG's solubility via C3-position modifications, synthesizing phosphorylated, sulfonated, and glycosylated derivatives with improved solubility. The phosphorylated derivative (11a) excelled in suppressing nitric oxide (NO) production in LPS-induced RAW264.7 macrophages. Further investigation revealed that both CAG and 11a effectively reduced levels of pro-inflammatory cytokines IL-6 and TNF-α, suggesting their anti-inflammatory effects are mediated through these pathways. Our findings indicate that chemical modifications can successfully enhance the solubility of CAG without compromising its bioactivity, with derivative 11a emerging as a particularly promising candidate for further development.
Hu X, Yu X, Zhang Y
… +5 more, Zhou B, Li C, Li D, Li S, Huang X
Bioorg Med Chem Lett
· 2026 Feb · PMID 41130328
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Natural β-carboline alkaloids are currently under extensive scrutiny for their antitumor properties. To improve the antitumor efficacy of β-carboline, a range of β-carboline-ACS81 hybrids were created through molecular h...Natural β-carboline alkaloids are currently under extensive scrutiny for their antitumor properties. To improve the antitumor efficacy of β-carboline, a range of β-carboline-ACS81 hybrids were created through molecular hybridization with diallyl disulfide derivatives, and preliminary structure-activity relationships (SAR) were established. Furthermore, the newly synthesized hybrids (12a-c, 13a-d, 14a-d, and 15a-d) were evaluated for in vitro cytotoxicity against a panel of six human cancer cell lines (HL-60, U937, HepG2, HCT-116, A375, and A549), as well as one normal human hepatic cell line (L-02). Among them, hybrid 12c exhibited the strongest inhibitory activity against the HL-60 cell line, with an IC value of 1.52 μM, surpassing the efficacy of the positive control drug 5-FU. Moreover, this compound displayed minimal cytotoxicity against L-02 cells (IC > 30 μM), indicating a favorable selectivity profile between tumor cells and normal cells. Comprehensive investigations revealed that 12c induced apoptosis by arresting the cell cycle at the G2/M phase. This effect was achieved by inducing alterations in nuclear morphology and the collapse of mitochondrial membrane potential. These findings suggested that 12c exerted an antiproliferative impact by triggering apoptosis through the mitochondrial pathway. Given these observations, 12c may represent a promising anti-leukemia agent and warrants further investigation.
Bioorg Med Chem Lett
· 2026 Feb · PMID 41130327
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Due to the relentless advance of bacterial resistance mechanisms, there exists an urgent need to develop novel surface disinfectants that eradicate a wide range of pathogenic bacteria. Our efforts in this arena have focu...Due to the relentless advance of bacterial resistance mechanisms, there exists an urgent need to develop novel surface disinfectants that eradicate a wide range of pathogenic bacteria. Our efforts in this arena have focused on optimization of potency, resistance-to-resistance, and safety. Herein, we report the efficient and modular construction of a series of triscationic quaternary ammonium compounds with a bolaamphiphilic architecture, based on a versatile phloroglucinol core where the cationic residues are either quaternized nitrogen atoms or imidazolium residues. A broad subset of the 28 prepared structures boast single-digit micromolar activity against a panel of eight bacteria that represent Gram-positive, Gram-negative, and resistant strains. Importantly, we have identified structure-activity relationships that highlight a set of four compounds (PHL-6,8, PHL-8,6, PHL-4-imid-8, and PHL-6-imid-6) that have MIC values generally ≤2 μM, as well as therapeutic indices (using red blood cell lysis as a proxy) of 32-250. Interestingly, a series of compounds with a single additional carbon per side chain shows marginally better potency (average MIC = 1 μM) but a significant jump in eukaryotic toxicity, dropping TI levels significantly. These observations reinforce the importance of amphiphilic balance in the development of disinfectant structures.
Onajole OK, Lun S, Kishore DR
… +9 more, Savić A, Morales A, Guzman A, Schmidt E, Lazzara A, Fajardo G, Jamieson DP, Ayitou AJ, Bishai WR
Bioorg Med Chem Lett
· 2026 Feb · PMID 41130326
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Tuberculosis (TB) is an insidious disease that has been around for many centuries. The advent of multidrug-resistant strains of TB has caused a significant setback in eradicating this disease; most importantly, there are...Tuberculosis (TB) is an insidious disease that has been around for many centuries. The advent of multidrug-resistant strains of TB has caused a significant setback in eradicating this disease; most importantly, there are limited safe therapeutics available to combat multidrug- and extensively drug-resistant (MDR and XDR, respectively) strains of TB, hence the race to find highly effective antitubercular drug candidates with little to no side effects. Herein, we report on the design, synthesis, and biological evaluation of 33 novel heterobicyclic (imidazothiazole- and imidazopyrimidine-containing) carboxamide derivatives for their antitubercular properties. These compounds were designed based on reported anti-TB properties of indole-2-carboxamides, imidazo[1,2-a]pyridine-3-carboxamides, and imidazo[2,1-b]pyrimidine-5-carboxamides derivatives. This effort led to the discovery of compounds 21 (imidazothiazole-based) and 37 (imidazopyrimidine-based), which showed excellent anti-TB activity against susceptible, MDR, and XDR-TB strains (MIC: 0.2-6.36 μM). Compound 21 also displayed excellent drug-like properties based on its pharmacokinetic profiles and is void of cytotoxicity to Vero cells at the highest tested concentration. Importantly, compounds 21 and 37 were found to be inactive against selected non-TB forming mycobacteria (MIC: >40 μM) and bacteria (both gram-negative and gram-positive microorganisms), indicating their selectivity for Mycobacterium tuberculosis.
Zhu EJ, Bu XS, Yue Y
… +7 more, Hou YS, Liu JR, Gatera T, Ni SY, Chai T, Wang XR, Yang JL
Bioorg Med Chem Lett
· 2026 Feb · PMID 41130325
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Cervical cancer is the fourth most common and deadly cancer globally. Hypoxia-inducible factor-1α (HIF-1α) plays a key promoter of tumor progression and treatment resistance, making it an important anticancer target. Her...Cervical cancer is the fourth most common and deadly cancer globally. Hypoxia-inducible factor-1α (HIF-1α) plays a key promoter of tumor progression and treatment resistance, making it an important anticancer target. Here, we designed and synthesized a series of novel HIF-1α-targeting PROTAC degraders based on LW-6 and its derivative W-1. Among them, Z12 showed the strongest anti-proliferative and HIF1α degradation activities in HeLa cells. Z12 promoted HIF-1α degradation via the ubiquitin-proteasome pathway by facilitating the formation of a HIF-1α/VHL ternary complex. Furthermore, Z12 inhibited HeLa cell proliferation, migration, and colony formation, induced apoptosis, and reduced p-MEK and p-AKT expression in the MAPK and PI3K/AKT pathways. This work offers a promising strategy for developing HIF1α-PROTAC degraders and treating cervical cancer.
Hoshikawa S, Kimura K, Hanada C
… +6 more, Karuo Y, Tarui A, Sato K, Omote M, Kataoka M, Kawai K
Bioorg Med Chem Lett
· 2026 Feb · PMID 41120007
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This study describes the development of novel dibenzyl ether derivatives that selectively inhibit intestinal CYP3A4 and are expected to function as pharmacokinetic boosters. Based on previously reported phenylazole deriv...This study describes the development of novel dibenzyl ether derivatives that selectively inhibit intestinal CYP3A4 and are expected to function as pharmacokinetic boosters. Based on previously reported phenylazole derivatives, new compounds were synthesized by systematically modifying the azole moiety, linker structure, and ester functionality to explore structure-activity relationships. The selected dibenzyl ether derivatives exhibited potent CYP3A4 inhibitory activity and remained stable in the presence of intestinal S9 fractions, whereas they were rapidly metabolized in liver S9 fractions to form less active metabolites. The ability to undergo rapid hepatic metabolism is considered advantageous for reducing the risk of drug-drug interactions. These findings suggest that the dibenzyl ether derivatives represent a promising lead for the development of intestine-selective pharmacokinetic booster candidates.
Li D, Zhen Y, Tang R
… +4 more, Wang B, Zhong H, Jiang X, Yeung YY
Bioorg Med Chem Lett
· 2026 Feb · PMID 41120006
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The cytotoxicity of α-exo-methylene-lactones has been extensively studied. However, further study of the α-exo-methylene-lactones for anticancer application was hampered primarily by its poor selectivity and solubility....The cytotoxicity of α-exo-methylene-lactones has been extensively studied. However, further study of the α-exo-methylene-lactones for anticancer application was hampered primarily by its poor selectivity and solubility. In the present work, a series of α-exo-methylene-selenolactone derivatives bearing amine substituent, selenium functionality and quaternary carbon center were synthesized and evaluated for their anticancer activities. The most potent compound, 2d, was about 9-fold more selective for cancer cells than normal cells. Moreover, 2d significantly inhibited tumor growth in mouse xenograft model and had no observable toxic effect.
Arya CG, Thomas NM, Chandrakanth M
… +5 more, Kallingal A, Amrutha PG, Sivapriya MS, Gondru R, Banothu J
Bioorg Med Chem Lett
· 2026 Feb · PMID 41115536
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A series of coumarin-benzimidazole conjugates (6a-p) was designed and synthesized via a polyphosphoric acid (PPA)-mediated condensation of o-phenylenediamine derivatives with coumarin-3-carboxylic acids. The in vitro ant...A series of coumarin-benzimidazole conjugates (6a-p) was designed and synthesized via a polyphosphoric acid (PPA)-mediated condensation of o-phenylenediamine derivatives with coumarin-3-carboxylic acids. The in vitro anticancer activity of all conjugates was evaluated against lung (A549) and breast (MCF7) cancer cell lines. Except for hybrids 6l (A549) and 6c (MCF7), all compounds exhibited notable cytotoxicity toward both cell lines, with IC values ranging from 0.85 ± 0.07 to 48.01 ± 0.45 μM. Among them, the unsubstituted derivative 6b emerged as the most potent compound, showing IC₅₀ values of 0.85 ± 0.07 μM (A549) and 1.90 ± 0.08 μM (MCF7). Compounds 6a, 6c, and 6g also demonstrated strong activity against A549 cells, with IC values of 1.86 ± 0.19 μM, 1.05 ± 0.09 μM, and 2.23 ± 0.13 μM, respectively. Furthermore, the potent conjugates 6b and 6g were found to be non-toxic toward Vero cells (LD > 100 μM), indicating selective cytotoxicity toward cancer cells. In silico molecular docking studies suggested that the activity of compound 6b against both cell lines may result from inhibition of sphingosine kinase 1 (SK1), whereas the potency of 6g against A549 cells could be attributed to cyclin-dependent kinase 2 (CDK2) inhibition. These computational predictions warrant further validation through target-specific biological assays. ADMET analysis further revealed that conjugate 6b possesses favorable pharmacokinetic properties, supporting its potential as a promising lead for future anticancer drug development.