Dam TBH, Ngu TN, Truong PCH
… +12 more, Pham HKT, Le Vu TT, Do TL, Vu HN, Nguyen PDN, Le TTL, Do TT, Nguyen PH, Pham MQ, Hoang LM, Nguyen TK, To DC
Bioorg Med Chem Lett
· 2026 May · PMID 41571010
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Ludwigia adscendens (Onagraceae) has been traditionally used for the treatment of inflammatory and metabolic disorders; however, the bioactive constituents responsible for these effects remain insufficiently characterize...Ludwigia adscendens (Onagraceae) has been traditionally used for the treatment of inflammatory and metabolic disorders; however, the bioactive constituents responsible for these effects remain insufficiently characterized. In this study, twelve secondary metabolites (1-12), including triterpenoids, flavonoids, and phenolic acids, were isolated from L. adscendens and evaluated for their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and α-glucosidase activity in vitro. Among the tested compounds, sulfuretin (8) exhibited the most potent NO inhibitory activity (IC = 12.3 ± 0.56 μM), while uvaol (3) and ursolic aldehyde (4) showed strong α-glucosidase inhibition (IC = 5.6 ± 0.7 and 4.2 ± 0.3 μM, respectively), surpassing acarbose. Molecular docking studies against inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-8 (IL-8), and oligo-1,6-glucosidase supported the experimental findings, revealing favorable binding affinities and key interactions consistent with the observed structure-activity relationships. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis predicted acceptable drug-likeness and low acute toxicity for the active compounds. Collectively, these results identify sulfuretin as a promising dual anti-inflammatory and antidiabetic scaffold, while triterpenoid derivatives emerge as potent and selective α-glucosidase inhibitors, providing a rational basis for further medicinal chemistry optimization.
Bu H, Wu QL, Wang CC
… +4 more, Guo Q, Deng S, Li Y, Wang S
Bioorg Med Chem Lett
· 2026 May · PMID 41571009
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To develop novel mosquito control agents, we designed and synthesized a series of derivatives based on the natural alkaloid arecoline as a lead compound, targeting muscarinic acetylcholine receptors (mAChRs). Using compu...To develop novel mosquito control agents, we designed and synthesized a series of derivatives based on the natural alkaloid arecoline as a lead compound, targeting muscarinic acetylcholine receptors (mAChRs). Using computer-aided drug design and docking techniques focused on mAChRs, we designed piperidine derivatives and screened for synthetically accessible candidates. The compounds were synthesized, structurally characterized, and evaluated for activity via a Fluo-4 calcium fluorescence assay using Chinese Hamster Ovary-K1 (CHO-K1) cells expressing the muscarinic acetylcholine receptor M1. Most compounds showed potent mAChRs agonist activity, with Half Maximal Effective Concentration (EC₅₀) values below 10 μM. In subsequent insecticidal activity tests, these piperidine derivatives exhibited strong larvicidal effects against Aedes aegypti. The Median Lethal Concentration (LC₅₀) values for compounds 1a, 2a, 3a, 4a, 13a, 22a, 2b, and 9b were 58.4, 29.6, 11.4, 21.7, 42.0, 61.7, 125.9, and 81.6 mg/L, respectively. Notably, compound 13a maintained high insecticidal activity even against pyrethroid-resistant mosquitoes, indicating a mode of action different from conventional neurotoxic insecticides. These results demonstrate that mAChR-targeting derivatives derived from betel alkaloids represent a promising strategy for developing new mosquito control agents and offer a novel approach to combating insecticide resistance.
Lim HJ, Kim UI, Kim KR
… +7 more, Lee JM, Park KY, Bang HT, Yoon J, Jo E, Kim K, Heo JN
Bioorg Med Chem Lett
· 2026 May · PMID 41565125
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We report the design, synthesis, and characterization of a novel series of triazolopyrimidinone and imidazotriazinone derivatives as potent and selective TNKS1/2 inhibitors. These compounds bind to the nicotinamide pocke...We report the design, synthesis, and characterization of a novel series of triazolopyrimidinone and imidazotriazinone derivatives as potent and selective TNKS1/2 inhibitors. These compounds bind to the nicotinamide pocket of TNKS and exhibit strong enzymatic inhibition and cellular Wnt/β-catenin pathway suppression, with minimal off-target activity against other PARP family members. Among them, 11b (STP1002, Basroparib) demonstrated the most favorable profile, with sub-nanomolar IC values for TNKS1/2, high selectivity, and excellent physicochemical and ADME properties. These findings support the further development of STP1002 as a promising therapeutic candidate for Wnt-driven cancers, with potential applications as both a monotherapy and in combination with other targeted agents.
Chen X, Zhang R, He Z
… +7 more, Qian X, Yao C, Xiong X, Weng F, Xu S, Wu Y, Li Z
Bioorg Med Chem Lett
· 2026 May · PMID 41554381
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In the search for novel anti-atherosclerotic agents, we herein report the design, synthesis, and evaluation of a series of benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives (5a-5n). Cytotoxicity assessment in RAW 264.7...In the search for novel anti-atherosclerotic agents, we herein report the design, synthesis, and evaluation of a series of benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives (5a-5n). Cytotoxicity assessment in RAW 264.7 cells indicated minimal toxicity for most compounds under experimental conditions. Notably, compound 5j exhibited superior anti-inflammatory activity, significantly attenuating intracellular reactive oxygen species (ROS) while maintaining exceptional cytocompatibility (>100% cell viability at 1.25-20 μM) and demonstrating the most potent suppression of lipid accumulation. Mechanistic studies revealed that compound 5j synergistically modulates two key pathways: downregulation of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and restoration of cholesterol homeostasis via upregulation of ABCG1, leading to enhanced cholesterol efflux and 69.9% inhibition of foam cell formation at 3.25 μM (p < 0.001). SwissADME predictions indicated that compound 5j possesses favorable membrane permeability, high gastrointestinal absorption, and potential oral bioavailability. These findings establish compound 5j as a potential lead for developing atherosclerosis therapies through coordinated modulation of inflammation and lipid metabolism.
Fitria A, Kurniawan YS, Sholikhah EN
… +2 more, Pranowo HD, Jumina
Bioorg Med Chem Lett
· 2026 Jun · PMID 41539589
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The present study is intended as an initial exploration of allyl-functionalized calix[4]resorcinarenes (4a-4f) as cytotoxic agents. These derivatives were obtained via the O-allylation of 3-methoxy-4-hydroxybenzaldehyde...The present study is intended as an initial exploration of allyl-functionalized calix[4]resorcinarenes (4a-4f) as cytotoxic agents. These derivatives were obtained via the O-allylation of 3-methoxy-4-hydroxybenzaldehyde (vanillin) and 4-hydroxybenzaldehyde with resorcinol, pyrogallol, or 2-methylresorcinol. All compounds were examined for their in vitro anticancer activity against human breast cancer cell lines (MDA-MB-231 and MCF-7). Among them, analogue 4a exhibited moderate cytotoxicity in breast cancer cell lines, i.e., MCF-7 cells (IC = 8.27 μM), showing notable cytotoxicity in the low micromolar range, comparable to that of cisplatin and within the same order of magnitude as doxorubicin. Accompanied by apoptosis profiling, compound 4a at 1 × and 2 × IC showed a concentration-dependent increase in apoptosis cell death compared to untreated controls. Meanwhile, computational studies were conducted to explore potential interactions with EGFR as a putative target, suggesting that compound 4a may possibly interact with EGFR through hydrogen bonding and hydrophobic contacts.
Guarnieri OH, de Moura Lodi Cruz MGF, de Melo Resende D
… +14 more, Pontes CLM, Roberto IV, D'Agostini LS, Chithambo B, Ehlenz N, Siwe-Noundou X, Krause RWM, Biavatti MW, Lakkakula JR, Wagh NS, Steindel M, Opatz T, Fonseca Murta SM, Sandjo LP
Bioorg Med Chem Lett
· 2026 May · PMID 41539588
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Trypanosoma cruzi and Leishmania spp. are the protozoan parasites responsible for Chagas disease and leishmaniasis. The treatment of these neglected diseases relies on repurposed drugs and faces several challenges includ...Trypanosoma cruzi and Leishmania spp. are the protozoan parasites responsible for Chagas disease and leishmaniasis. The treatment of these neglected diseases relies on repurposed drugs and faces several challenges including high toxicity, and the emergence of resistant strain. Therefore, there is a constant demand for promising antiparasitic agents. The present work aimed to investigate seventeen prepared N,N-bisbenzylbutane-1,4-diamines against recombinant T. cruzi and L. infantum as well as their inhibitory effects against the T. cruzi recombinant trypanothione reductase (TcTR). N,N-bis(4-chlorobenzyl)butane-1,4-diamine showed significant trypanocidal activity with an IC of 6.0 ± 0.9 μM with a selectivity index of 4.3. This compound was more active than the positive control, benznidazole (IC of 14.6). It moderately inhibited TcTR with an IC of 55.6 ± 18.6 μM. N,N-bis(4-chlorobenzyl)butane-1,4-diamine also inhibited L. infantum with an IC of 19.3 ± 1.2 μM (SI of 3.4). N,N-bis((E)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine exhibited potent inhibitory effect against T. cruzi (2.4 ± 0.3 μM); However, it also turned out to be highly cytotoxic to the L929 fibroblast cell line. Its inhibitory effect against TcTR was also significant, with an IC of 3.9 ± 1.9 μM. Alongside the two diamines, nine other synthesized derivatives displayed antitrypanosomal activity with IC ranging from 8 to 150 μM. Concerning the leishmanicidal effects, all tested compounds were moderately active. Moreover, during in silico studies of the active compounds using TcTR (PDB ID 4NEW), N,N-bis((E)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine emerged as the most promising candidate, displaying both strong binding affinity and significant biological activity.
Lee EY, Varlı M, Kim H
… +6 more, Kim S, Kang S, Chin J, An H, Kim H, Nam SJ
Bioorg Med Chem Lett
· 2026 May · PMID 41520845
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Wounds pose significant healthcare challenges, prompting the need for novel therapeutics with pro-regenerative potential. Natural products from marine-derived actinomycetes are a promising source of small bioactive molec...Wounds pose significant healthcare challenges, prompting the need for novel therapeutics with pro-regenerative potential. Natural products from marine-derived actinomycetes are a promising source of small bioactive molecules. The first total syntheses of monaprenylindole A (1) and its analog (2) were accomplished. Here, we report the isolation, structural characterization, synthesis, and pharmacological evaluation of monaprenylindole A (1) and its analog, 6-isoprenylindole-3-carboxylic acid (2), for their wound healing potential. Compounds 1 and 2 were isolated from a marine-derived Streptomyces sp. and structurally characterized using mass spectrometry (MS), ultraviolet (UV), and nuclear magnetic resonance (NMR) analyses. Firstly, we analyzed the predicted favorable pharmacokinetics and safety of the compounds for their underlying translational potential. Furthermore, pharmacological network analysis identified multiple wound healing-related gene targets that were modulated by these molecules, suggesting a multi-target mechanism. In vitro assays showed that all compounds enhanced keratinocyte invasion, with compound 1 demonstrating the strongest effects by upregulating genes involved in cell motility. Furthermore, compound 1 promoted the upregulation of key motility-related genes, suggesting that this compound promotes wound healing through activating transcriptional programs involved in adhesion, cytoskeletal remodeling, growth factors, and spheroid formation, indicating a shift toward regenerative epithelial behavior. Finally, topical treatment with 1 significantly accelerated wound closure in a murine model. These results highlight the potential of monaprenylindole A as promising multi-target therapeutics for skin repair.
Huang XY, Liu XH, Xu N
… +6 more, Peng T, Hu XY, Su M, Luo ZY, Liu SY, Ma DY
Bioorg Med Chem Lett
· 2026 May · PMID 41519209
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Spinosad, a natural-origin pesticide, is extensively employed in agriculture and public health. Its primary component, Spinosyn A, has also attracted considerable interest due to its antiproliferative activity against va...Spinosad, a natural-origin pesticide, is extensively employed in agriculture and public health. Its primary component, Spinosyn A, has also attracted considerable interest due to its antiproliferative activity against various cancer cell lines. While ASS1 has emerged as a promising target for anticancer therapy, the development of ASS1 activators remains a largely unexplored research area. Previous work by our group identified Spinosyn A as the first-in-class ASS1 activator. In this study, to further elucidate the structure-activity relationship (SAR) of Spinosyn A as both an ASS1 activator and a tumor inhibitor, we introduced structural modifications at the nitrogen atom, yielding 25 novel derivatives. Biological evaluation revealed a strong correlation between the antitumor effects of these compounds and their ability to activate ASS1. For optimal activity, the introduction of a suitable aminoalkyl side chain at the nitrogen atom of dimethyl-Spinosyn A proved to be essential.
Chen Y, Li R, Chen Y
… +10 more, Li C, Pan M, Chen P, Jiang Y, Chen J, Huang Z, Feng Y, Wang Y, Li H, Xu S
Bioorg Med Chem Lett
· 2026 Apr · PMID 41519208
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This study investigated the ethnomedicine Celastrus rosthornianus Lose. for its chemical constituents and anti-nonalcoholic fatty liver disease (NAFLD) potential. Phytochemical analysis led to the isolation of six diterp...This study investigated the ethnomedicine Celastrus rosthornianus Lose. for its chemical constituents and anti-nonalcoholic fatty liver disease (NAFLD) potential. Phytochemical analysis led to the isolation of six diterpenoids (1-6), including two new structures (1 and 2). In a HepG2 cell model, compounds 2 and 6 significantly inhibited intracellular lipid accumulation. Mechanistic studies revealed that these active diterpenoids exert their anti-NAFLD effects by interfering with the maturation of the lipogenic transcription factor SREBP1, thereby suppressing the de novo lipogenesis (DNL) pathway. These findings not only expand the chemical profile of C. rosthornianus Lose., but also highlight specific diterpenoids as promising candidates for further development as NAFLD therapeutics.
Vyas J, Jamenis AS, Kaku K
… +8 more, Shah Y, Miner KM, Bhatia TN, Kim RE, Bai R, Hamel E, Leak RK, Gangjee A
Bioorg Med Chem Lett
· 2026 Apr · PMID 41513181
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There are no cures for neurodegenerative diseases. The biggest hurdle to treating these disorders is that their clinical manifestation is rooted in multiple physiological processes. Therefore, efficacious pharmaceutical...There are no cures for neurodegenerative diseases. The biggest hurdle to treating these disorders is that their clinical manifestation is rooted in multiple physiological processes. Therefore, efficacious pharmaceutical options will likely require two or more agents with different mechanisms of action. However, drug combinations have significant drawbacks, including overlapping toxicities and unique pharmacokinetic properties, particularly the rate and extent of central nervous system (CNS) penetration. A single agent with multiple mechanisms of action could overcome these drawbacks. We have recently discovered first-in-class novel single agents (compounds 1 and 2) that mildly inhibit clinically important kinases and subtly favor microtubule stability at concentrations that show no evidence of neuronal toxicity in primary neurons, while maintaining their ability to penetrate the CNS in vivo. It is important to note that the effects of these analogs are mild and are predicated on avoiding neurotoxicity. These multitargeting single agents provide a new structural modality with the potential to influence treatments for Parkinson's and Alzheimer's disease and serve as lead compounds for further optimization.
Xu Y, Sun Y, Yu Z
… +5 more, Zhang X, Liu Z, Xin J, Liu S, Zhao F
Bioorg Med Chem Lett
· 2026 Apr · PMID 41506584
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The tetrahydro-β-carboline (THβC) scaffold is a promising chemotype in anticancer drug discovery whose development is hindered by poor aqueous solubility and underexplored functionalization at the N-2 position. To overco...The tetrahydro-β-carboline (THβC) scaffold is a promising chemotype in anticancer drug discovery whose development is hindered by poor aqueous solubility and underexplored functionalization at the N-2 position. To overcome these limitations, we designed a series of novel THβC derivatives via molecular hybridization at the N-2 site using natural unsaturated carboxylic acids, aiming to improve solubility and biological activity. Among the synthesized compounds, derivative 9 exhibited potent and selective anti-proliferative activity against MCF-7 breast cancer cells. Based on this promising activity, we first investigated its effect on key oncogenic pathways. Western blot analysis revealed that compound 9 significantly downregulated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) without affecting the NF-κB p65 subunit, suggesting a selective mechanism of action. Subsequent molecular docking studies provided a structural rationale for this selectivity, showing favorable binding modes of 9 within the ERK1/2 kinase domains. Collectively, this work establishes N-2 functionalization as a viable strategy for developing THβC-based anticancer agents with optimized pharmacological profiles.
Cai C, Tian W, Wei M
… +5 more, Yang T, Hu Q, Huang Y, Liu Z, Cui J
Bioorg Med Chem Lett
· 2026 Apr · PMID 41485563
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Motivated by the significant physiological activities of selenocyanate pharmacophores in biomedicine and the relative scarcity of research on diselenocyanates, this study designed and synthesized a series of novel aromat...Motivated by the significant physiological activities of selenocyanate pharmacophores in biomedicine and the relative scarcity of research on diselenocyanates, this study designed and synthesized a series of novel aromatic diselenocyanate derivatives (including aniline-type 3a-3f, phenol-type 6a-6f, and biphenyl-type 8) using aniline and phenol as parent structures through aromatic ring electrophilic substitution and amide bond/ether bond bridging strategies, and systematically evaluated their biological activities. The results demonstrated that multiple compounds exhibited significant inhibitory activity against specific cancer cell lines. Among them, compound 3f showed an IC value of 2.93 μmol/L against breast cancer MCF-7 cells, while compound 6c displayed superior IC values compared to Cisplatin against SK-OV-3, HepG-2, and MCF-7 cells. The compounds also demonstrated excellent activity against drug-resistant bacteria MRSA/VRE (3f exhibited an MIC of 2 μg mL against MRSA, outperforming Vancomycin) and agricultural crop pathogens (citrus canker, rice bacterial leaf streak/leaf blight pathogens). Notably, compound 8 achieved sub-microgram EC values against these phytopathogens. Structure-activity relationship analysis revealed that aniline derivatives showed better activity against breast cancer, while phenol derivatives exhibited stronger inhibition against ovarian cancer and phytopathogens. Molecular-docking studies corroborate enhanced binding stability of optimized compounds to validated biological targets. Collectively, these findings provide both mechanistic insight and lead candidates for novel antineoplastic agents and low-toxicity agricultural antimicrobials.
Bioorg Med Chem Lett
· 2026 Apr · PMID 41483861
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This study optimized the oxidation of theaflavin-3'-gallate (TF-3'-G), yielding two isolated products: theadibenzotropolone and theanaphthoquinone-3-gallate (TNQ-3-G). All compounds exhibited significant α-amylase inhibi...This study optimized the oxidation of theaflavin-3'-gallate (TF-3'-G), yielding two isolated products: theadibenzotropolone and theanaphthoquinone-3-gallate (TNQ-3-G). All compounds exhibited significant α-amylase inhibitory activity, with potency descending in the order: theadibenzotropolone>TNQ-3-G>TF-3'-G ≈ acarbose. IC analysis revealed that TNQ-3-G and theadibenzotropolone were over 2-fold and 5-fold more potent than acarbose, respectively. These findings provide a foundation for developing efficient and low-toxicity α-amylase inhibitors.
Anderson C, Tsai JH, Ingham O
… +7 more, Deibler RW, Kreger B, Chaturvedi P, Hung KYS, Nasveschuk CG, Henderson JA, Sowa ME
Bioorg Med Chem Lett
· 2026 Apr · PMID 41483860
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Aberrant NTRK gene fusions leading to constitutively activated NTRK proteins are a key driver for a range of adult and pediatric tumors. Small molecule NTRK inhibitors targeting the NTRK ATP site have shown success in th...Aberrant NTRK gene fusions leading to constitutively activated NTRK proteins are a key driver for a range of adult and pediatric tumors. Small molecule NTRK inhibitors targeting the NTRK ATP site have shown success in the clinic resulting in two approved drugs. Unfortunately, resistance mutations have created the need for additional therapies. In this study, we detail the design, synthesis, and evaluation of novel NTRK BiDAC™ degraders containing a macrocyclic, mutant active, NTRK targeting ligand.
Sun J, Wang Y, Wang R
… +5 more, Yao Y, Wang J, Pan G, Zhang R, Zhao X
Bioorg Med Chem Lett
· 2026 Apr · PMID 41482133
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Dioscin, a natural steroidal saponin derived from Dioscorea species, has been reported to exhibit lipid-lowering activity despite its extremely low oral bioavailability. This study aimed to elucidate whether dioscin exer...Dioscin, a natural steroidal saponin derived from Dioscorea species, has been reported to exhibit lipid-lowering activity despite its extremely low oral bioavailability. This study aimed to elucidate whether dioscin exerts its lipid-lowering effects through intestinal mechanisms. Using both high-fat diet (HFD)-induced and acute lipid-challenge rat models, dioscin significantly reduced plasma triglyceride (TG) and total cholesterol (TC) levels, indicating an inhibitory effect on intestinal lipid absorption. In vitro assays demonstrated that dioscin inhibited pancreatic triglyceride lipase (PTL) activity with moderate potency and suppressed Niemann-Pick C1-Like 1 (NPC1L1)-mediated cholesterol uptake in Caco-2 cells. Surface plasmon resonance (SPR) analysis and molecular docking suggested direct interactions between dioscin and both PTL and NPC1L1, suggesting that dioscin interferes with intestinal lipid absorption through mechanisms involving TG hydrolysis and cholesterol transport. These findings provide mechanistic insight into the intestinal lipid-lowering activity of dioscin and highlight its potential as a natural lead compound for the development of safe and intestine- restricted lipid-lowering agents.
Mesbahi N, McAllister BC, Yoon H
… +4 more, Hendricksen AT, Fulton MD, Caromile LA, Berkman CE
Bioorg Med Chem Lett
· 2026 Apr · PMID 41482132
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Targeted payload release in cancer cells can be modulated by tuning both the linker, spacer, and the payload chemistries. In previous studies, a PSMA-targeted probe incorporating a 7-amino-4-methylcoumarin (AMC) payload...Targeted payload release in cancer cells can be modulated by tuning both the linker, spacer, and the payload chemistries. In previous studies, a PSMA-targeted probe incorporating a 7-amino-4-methylcoumarin (AMC) payload and a PEG linker resulted in predominant payload release in the lysosome (pH ∼5.0). Here, we introduce a second-generation PSMA-targeted turn-on probe with a shorter, hydrophobic linker and a 7-hydroxy-4-methylcoumarin (HMC) payload. Based on pH-dependent kinetic studies, the HMC payload exhibits faster cleavage at a slightly higher pH (pH 5.5), suggesting an earlier release-potentially more in early endosomes than lysosomes. Our results demonstrate that subtle changes in linker and payload structures can alter intracellular release kinetics, offering improved control over the cellular release site, which is critical for optimizing targeted therapeutic and imaging strategies in prostate cancer cells.
Kawamoto Y, Takase S, Ashutosh K
… +5 more, Maruo H, Maemoto Y, Zhang KYJ, Ito H, Ito A
Bioorg Med Chem Lett
· 2026 Apr · PMID 41478308
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CBX2 protein plays an important role in methyl-lysine recognition involved in epigenetic regulation. In contrast to CBX7 modulators, there are few reported CBX2 inhibitors, most of which are peptidergic molecules. This f...CBX2 protein plays an important role in methyl-lysine recognition involved in epigenetic regulation. In contrast to CBX7 modulators, there are few reported CBX2 inhibitors, most of which are peptidergic molecules. This fact encouraged us to search non-peptidic small molecule CBX2 inhibitors with sufficient cell permeability by in silico screening followed by synthetic evolution. In virtual screening, we identified a 4-aminobenzamide scaffold with high in silico score and Nano BRET activities. Based on several in silico hit compounds, we synthesized a series of 4-aminobenzamide derivatives and tested their Nano BRET activities. Among them, compound 37 showed moderate CBX2 inhibitory activity with an IC value of 9.6 μM, a potential lead compound. This is a first small molecule CBX2 inhibitor identified as a result of SAR studies and lead optimization by medicinal chemistry.
Unnikrishnan VK, Sundaramoorthy NS, Manivannan R
… +6 more, Shanthi M, Gnanadhas DP, Alexander S, Ulaganathan V, Subburethinam R, Nagarajan S
Bioorg Med Chem Lett
· 2026 Apr · PMID 41478307
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Candida albicans is an opportunistic fungus that causes infections in people with weakened immune system. Candida has the propensity to gain drug resistance by mutation, and its ability to extrude antifungals through dru...Candida albicans is an opportunistic fungus that causes infections in people with weakened immune system. Candida has the propensity to gain drug resistance by mutation, and its ability to extrude antifungals through drug transporters. Efflux pump inhibitors increase the intracellular drug concentration and restore drug sensitivity in resistant strains. We synthesized and screened 10 azole heterocyclic derivatives (pyrazole-5-amine and 2H-indazole) against Mdr1p/Cdr1p overexpressing and knock-out strains of Candida albicans. Among the derivatives screened, sulfenylated pyrazole-5-amine (designated as 4a) displayed strong efflux inhibitory potential and caused a 64-fold reduction in the fluconazole MIC. Compound 4a inhibited the Mdr1p pump, as MIC reversal was not observed in the Mdr1p knock-out strain. 4a exhibited synergy with fluconazole only against Mdr1p harboring strains, as discerned by the Checkerboard assay. Combining 4a with fluconazole restricted microbial growth and reduced cell counts by 4 log fold relative to treatment with fluconazole in a time-kill assay. Infection of RAW macrophages followed by treatment with a combination of sulfenylated aminopyrazole & fluconazole resulted in a significant 2 log reduction in intracellular cell counts relative to treatment with fluconazole. 4a also inhibited biofilm formation and yeast to hyphal shift in Candida, thereby reducing virulence. Combining EPIs with antifungal drugs has the potential to improve the treatment of C. albicans infections and reduce the risk of drug resistance. However, further research is needed to determine the safety and efficacy of these compounds in humans.
Yamada N, Suzuki S, Fukahori N
… +5 more, Yamaoka Y, Komiyama Y, Kimura N, Umezawa K, Kii I
Bioorg Med Chem Lett
· 2026 Apr · PMID 41461351
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A folding intermediate of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in the non-native state autophosphorylates intramolecularly, whereas the folded conformation of DYRK1A in the native state...A folding intermediate of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in the non-native state autophosphorylates intramolecularly, whereas the folded conformation of DYRK1A in the native state no longer catalyzes this reaction. We identified FINDY, a small molecule that selectively inhibits the DYRK1A folding intermediate but not its fully folded conformation. These findings indicated the presence of a unique binding site that is exposed only in the folding intermediate. In the previous study, we developed a facile method for screening of inhibitors that target the folding intermediate in the non-native state using recombinant folded proteins in the native state. We found that FINDY and its derivatives target both DYRK1A and DYRK1B in their non-native states. In this study, we examined the potency of these inhibitors on DYRK2, another member of the DYRK family. FINDY inhibited DYRK2 in the non-native state slightly greater than that in the native state. Although RD0448, a FINDY derivative, selectively targets DYRK1A/1B in their non-native states, RD0448 exhibited no selectivity between the native and non-native states of DYRK2, indicating that the RD0448-binding site is hidden in the native state of DYRK1A/1B but is exposed in the native state of DYRK2. Furthermore, RD0448 bound tightly to DYRK1A/1B, whereas RD0448 showed weak affinity for DYRK2 and rapidly dissociated from the binding complex. These results suggest a correlation between the tight binding of the inhibitors and their target selectivity toward the non-native state in DYRK family kinases.
Zhang M, Xiao S, Yan K
… +5 more, Sun J, Xi C, Qin Y, Dong C, Chen D
Bioorg Med Chem Lett
· 2026 Apr · PMID 41461350
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The proteolysis-targeting chimera (PROTAC) technology utilizes heterobifunctional molecules to induce targeted protein degradation through the ubiquitin-proteasome system. Structurally, PROTAC molecules consist of a targ...The proteolysis-targeting chimera (PROTAC) technology utilizes heterobifunctional molecules to induce targeted protein degradation through the ubiquitin-proteasome system. Structurally, PROTAC molecules consist of a target protein ligand and an E3 ligase ligand covalently linked by a suitable linker arm, forming the target protein-PROTAC-E3 ligase stable ternary complex and bringing the target protein in proximity to the E3 ligase for ubiquitination and subsequent proteasomal degradation. However, only a few E3 ligases have been used to generate effective PROTACs with limited small molecule E3 ligase ligands. Therefore, there is an urgent need to discover novel E3 ligase ligands to expand the toolbox for PROTACs. Unlike traditional E3 ligases such as CRBN and VHL, GID4 E3 ligase recognizes substrates bearing N-terminal proline or other small residues through the Pro/N-degron pathway, and has already been successfully leveraged in PROTAC technology. Here, we reported the development of a fluorescent probe YG11, with a K value of 8.1 ± 0.7 nM for GID4. With this probe, we established a robust fluorescence polarization (FP)-based competition assay for evaluation of GID4 ligands. The assay exhibited a high signal-to-noise ratio of over 20, 2.5 % DMSO tolerance, and a Z'-factor of 0.84, confirming its suitability and robustness for high-throughput screening. Thus, by enabling rapid identification of GID4 ligands, this FP competition assay promises to substantially advance PROTAC development initiatives.