Butyrylcholinesterase (BChE) is recognized as a promising therapeutic target for the late stages of Alzheimer's disease (AD) due to its role in the hydrolysis of acetylcholine (ACh), while acetylcholinesterase (AChE) activity declines during disease progression. Here, we have reported an efficient chemistry procedure for the naturally occurring Amaryllidaceae alkaloid carltonine B, along with the design and synthesis of 36 novel carltonine-based analogues to determine structure-activity relationship (SAR). Most of the synthesized compounds exhibited potent and selective human BChE (hBChE) inhibition, with IC50 values ranging from low micromolar to nanomolar concentrations. The drug-like properties of the molecules were assessed by in silico tools, using the blood-brain barrier (BBB) score algorithm, and subsequently validated by in vitro permeability assessment via parallel artificial membrane permeability assay (PAMPA). The derivatives exhibited potent hBChE inhibition in the low micromolar to submicromolar range, while their cytotoxicity against human neuroblastoma (SH-SY5Y) cells was observed only at higher micromolar concentrations, indicating a favorable safety profile. The synthesized alkaloid carltonine B (37) and its N-ethyl derivative (38) emerged as the most potent and selective hBChE inhibitors, with IC50 values of 0.014 ± 0.002 μM and 0.013 ± 0.001 μM, respectively. Enzyme kinetic studies were conducted to elucidate the inhibition mechanism toward hBChE enzyme. Compound 37 demonstrated competitive inhibition with Ki value of 0.055 μM. In contrast, compound 38 showed a noncompetitive inhibition profile, with a Ki value of 0.067 μM. Molecular modeling suggested that the superior potency of compounds 37 and 38 arises from their more optimal engagement of the BChE active-site gorge compared to compound 33. For the additional safety assessment, CYP inhibition assay revealed that compounds 37 and 38 may pose a risk of CYP3A4-mediated drug-drug interactions during chronic administration.
Cbl-b, an E3 ubiquitin ligase, is a critical negative regulator of T-cell activation and an attractive target for cancer immunotherapy. Current small-molecule inhibitors largely rely on hydrophobic π-π stacking interactions with the gatekeeper residue Tyr363, which restricts the structural diversity of Cbl-b inhibitors and hinders the discovery of inhibitors with novel scaffolds. This study reports the stepwise optimization of the cyclic carbamate lead compound 5, eventually leading to the discovery of novel, representative alkylamine-based Cbl-b inhibitors. Our optimization process comprised three stages: (1) conformational restriction via lactamization, which yielded initial hit 12 (IC50 = 31.99 ± 3.88 μM); (2) hydrophobic cavity filling, which provided the improved analog 22 (IC50 = 8.58 ± 0.25 μM); and (3) SeeSAR-guided scaffold hopping, which ultimately identified the representative lead compound 27 (IC50 = 6.83 ± 0.51 μM). Molecular docking and molecular dynamics (MD) simulations confirmed that 27 binds to the TKB-LH interface and stabilizes the inactive conformation of Cbl-b. Notably, MD simulations revealed that 27 engages Tyr363 through a unique polar interaction mode dominated by hydrogen bonds and water bridges, a distinct departure from traditional hydrophobic stacking. This novel alkylamine scaffold provides a new approach for developing structurally diverse Cbl-b inhibitors.
The progression of type 2 diabetes mellitus (T2DM) is closely linked to oxidative stress-induced damage. Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation. Its underlying mechanism involves an imbalance between reactive oxygen species (ROS) accumulation and cellular antioxidant defense, ultimately resulting in cell death. While puerarin has been shown to exhibit antioxidant properties, its ability to ameliorate T2DM via the ferroptosis pathway remains unclear. In this study, we combined network pharmacology, proteomics, and experimental validation to investigate the regulatory mechanisms of puerarin. Potential targets of puerarin in T2DM were identified using network pharmacology and proteomics. Oxidative stress markers-including ROS, malondialdehyde (MDA), manganese-dependent superoxide dismutase (Mn-SOD), and glutathione (GSH)-as well as insulin levels and ferroptosis-related markers such as glutathione peroxidase 4 (GPX4), cyclooxygenase-2 (COX2), and acyl-CoA synthetase long-chain family member 4 (ACSL4) were measured to assess the effect of puerarin on ferroptosis. Protein kinase B (AKT1) overexpression and knockdown models, together with nuclear factor erythroid 2-related factor 2 (NRF2) inhibitors, were used alongside Western blot analysis to investigate the pathway through which puerarin regulates ferroptosis. Results showed that palmitic acid-induced oxidative stress triggered ferroptosis in mouse pancreatic β-cells (MIN6). Under puerarin intervention, ferroptosis biomarkers including ROS, MDA, Mn-SOD, iron ions, and GSH, as well as mitochondrial morphology, were significantly altered. Mechanistic studies revealed that puerarin upregulates AKT1, leading to enhanced phosphorylation of GSK3β and increased expression of NRF2. Consequently, expression of GPX4, a key enzyme in glutathione metabolism, was elevated, thereby suppressing ferroptosis. This study is the first to identify targets of puerarin in T2DM through an integrated network pharmacology and proteomics approach. It demonstrates that puerarin may upregulate GPX4 via the AKT/GSK3β/NRF2 pathway, thereby mitigating oxidative stress damage and reducing ferroptosis, offering novel mechanistic insight for diabetes treatment.
This review focuses on thieno[3,2-b]pyrrole-fused BODIPYs, which serve as a heavy-atom-free alternative to traditional halogenated photosensitizers. This annulation strategy overcomes the limitations of the core platform, enabling efficient triplet state population while maintaining fluorescence and intense near-infrared (NIR) absorption. The review examines the physicochemical aspects of the photoinduced charge transfer-assisted intersystem crossing (PCT-ISC) mechanism underlying this phenomenon, alongside approaches to the synthesis and structural modification of these compounds. Furthermore, a directed shift from the classical oxygen-dependent photochemical pathway (Type II) to a radical-based mechanism (Type I) is outlined, driven by the necessity to overcome tumor hypoxia. Additionally, within the context of prospective biomedical applications, challenges related to dye aggregation, the influence of delivery systems on in vivo efficacy, and the standardization of light dosimetry are addressed. The presented material systematizes current data to facilitate the further rational design of NIR photosensitizers with predictable properties.
Aberrant activation of the NLRP3 inflammasome drives the pathogenesis of numerous human inflammatory diseases, highlighting the urgent need for small-molecule inhibitors targeting NLRP3. Building upon the lead compound 15z, we designed and synthesized a novel series of benzoxazole derivatives and conducted preliminary structure-activity relationship (SAR) studies. The representative compound D12 exhibited more potent NLRP3 inflammasome inhibitory activity than compound 15z, with an IC50 value of 94.15 nM. Mechanistic studies revealed that D12 directly targets the NACHT domain of NLRP3 protein (KD = 558.4 nM), effectively blocking inflammasome assembly and activation, thereby exerting anti-inflammatory effects. In vivo study showed that D12 significantly increased the survival time in a murine model of LPS-induced sepsis. Our findings indicate that compound D12 is a promising NLRP3 inhibitor, providing a new approach for the discovery of anti-inflammatory drugs.
Osteosarcoma (OS) is an aggressive bone malignancy with limited therapeutic advances and persistent chemoresistance, highlighting the need for safer and more effective treatments. Ganoderma microsporum immunomodulatory protein (GMI) is a fungal-derived bioactive molecule with reported antitumor activity, yet its effects in OS remain unknown. Here, we investigated the anticancer potential and mechanisms of GMI in osteosarcoma. GMI selectively reduced the viability of HOS and U2OS cells while exhibiting low toxicity toward normal osteoblasts. GMI induced morphological alterations, chromatin condensation, reduced colony formation, apoptosis, and G2/M arrest. RNA sequencing identified 292 upregulated and 158 downregulated genes, indicating suppression of DNA repair, proliferation, cell-cycle progression, and mitochondrial pathways, alongside activation of autophagy-related signatures. Mechanistically, GMI elevated intracellular reactive oxygen species (ROS), and N-acetylcysteine (NAC) attenuated GMI-induced apoptosis and restored viability. GMI-induced ER stress was associated with JNK activation, and sustained JNK activation disrupts the balance of BCL-2 family proteins by repressing anti-apoptotic BCL-2 and augmenting pro-apoptotic members, thereby driving mitochondria-dependent apoptosis in osteosarcoma cells. In addition, GMI treatment increases the formation of acidic vesicular organelles and autophagosome-like structures, accompanied by elevated LC3B-II and reduced p62 levels. Pharmacological blockade of autophagy using Baf A1, CQ, or 3-MA further augments GMI-induced apoptosis and exacerbates the reduction in cell viability. Finally, GMI significantly inhibited tumor growth in a xenograft model without affecting body weight. These findings identify GMI as a promising natural therapeutic candidate for osteosarcoma and warrants further preclinical and translational evaluation.
Pyridinium quaternary ammonium disinfectants (PYRs) are cationic surfactants widely used as disinfectants, antiseptics, and preservatives since COVID-19 and their potential effects on neurosteroidogenesis remain unknown. This study explored the inhibitions of eleven PYRs (C1-C20) on human and rat 5α-reductase 1 (5α-R1), identifying carbon-chain length dependent inhibition on human enzyme, with a V-shaped pattern, increasing potency from C12 (nadir activity, IC50 = 97.87 μM) to C16 (peak activity, 5.78 μM) and then decreases to C20 (IC50 = 75.93 μM). Enzyme kinetics and SPR (Surface Plasmon Resonance) showed similar high binding of PYRs to human 5α-R1 (C16's KD = 5.24 μM, C18's KD = 19.4 μM). Mechanistic analysis revealed that they exerted mixed/noncompetitive inhibition via binding to the NADPH binding pocket. SAR/QSAR modeling highlighted lipophilicity (LogP), molecular weight, carbon chain length and heavy atoms as key determinants of potency. Notably, these chemicals showed stronger inhibition in human 5α-R1 than in rat, underscoring species-specific pharmacodynamics. Molecular docking confirmed interactions with critical residues in NADPH binding site. Despite exhibiting greater microsomal activity compared to C14 PYR, the efficacy of C16 PYR in intact SF126 cells was diminished relative to C14 PYR due to its limited cellular permeability. The findings provide insights into 5α-R1 inhibition and support the identification of these disinfectants as neurosteroid endocrine disrupting actions.
One of the major applications of the CRISPR-Cas9 system is the visualization of DNA by using nuclease-deactivated Cas9 (dCas9), which, following complexation with a single-guide RNA (sgRNA), specifically binds to target genomic sequences without inducing DNA breaks. In this approach, either dCas9 or the sgRNA is labeled with fluorescent proteins or dyes, or they are engineered to recruit such molecules. A key advantage of CRISPR-based imaging is that genomic elements in living cells can be tracked, because of the ability to express all system components in vivo. Although CRISPR-based imaging has been successfully used to label repetitive sequences in living cells, the visualization of nonrepetitive loci remains a challenging issue. The primary obstacles are a low signal-to-noise ratio and the potential for nonspecific DNA binding by the dCas9-sgRNA complex, which can generate fluorescent puncta at off-target sites. Efficient intracellular delivery of system components and their sustained expression over time are also a major concern. Consequently, CRISPR-based imaging remains a highly time- and labor-intensive process that requires ongoing optimization. Here, we summarize recent advances in labeling nonrepetitive genomic loci, outline key challenges associated with CRISPR-based imaging, and present insights derived from our own experimental findings and research experience.
Neurological disorders represent a leading cause of global mortality and disability, yet treatment options remain limited due to the challenges of targeting pathogenic proteins, particularly those considered "undruggable" by conventional small molecules. Targeted protein degradation (TPD) has expanded the druggable proteome by harnessing proteasomal and lysosomal pathway to eliminate these targets, offering the advantages of lower toxicity and reduced resistance compared to traditional modulation. This review systematically delineates TPD mechanisms according to their degradation pathways, including proteasomal, endosomal-lysosomal, and autophagy-lysosomal systems, and highlights their unique applications in brain diseases. However, the translation of TPD to neurological disease is limited by physicochemical liabilities, cell-type dependence, risks associated with whole-protein ablation, the blood-brain barrier (BBB) and poor brain bioavailability. To address these translational barriers, we emphasize the integration of TPD with drug delivery systems (DDS) as a pivotal strategy. By optimizing pharmacokinetics, stability, and BBB penetration, nano-DDS significantly enhances brain targeting and therapeutic precision. Finally, we evaluate recent progress in nano-TPD systems and offer critical insights into their future trajectory in treating complex brain disorders.
The transformation of paired appendage structure from aquatic fins to terrestrial limbs represents a pivotal event in vertebrate evolution, underpinning the colonization of land by early tetrapods. This transition involved profound morphological and genetic modifications, particularly in the distal limb region known as the autopod and in the dorsoventral plane of paired appendages. Recent advances in paleontology, comparative and functional genomics, as well as evo-devo studies have shed light on several key events and evolutionary pathways and have improved our understanding of the direction of changes in regulatory mechanisms underlying the fin-to-limb transition. In this review, we aim to summarize current knowledge on limb evolution, with particular emphasis on studies of phylogenetically pivotal vertebrate groups - cartilaginous fishes and chondrosteans, which represent basally diverging evolutionary lineages of extant vertebrates, as well as sarcopterygians, the group of lobe-finned fishes most closely related to tetrapods. We consider the principal hypotheses concerning the prerequisites for vertebrate terrestrialization, key aspects in the search for structural homology between the morphological elements of fins and limbs, as well as the genetic mechanisms of spatial limb bud development described to date and the possible modifications of these mechanisms associated with the transformation of ancestral fins into pentadactyl terrestrial limbs.
Anaplastic lymphoma kinase (ALK) serves as a new target for therapy in non-small cell lung cancer (NSCLC) associated with the presence of the ALK fusion gene. This study reports the development of a series of pyrazole-5-carboxamide derivatives C01-C17 based on the lead compound 7 and hit compound A06 obtained through virtual screening, which was identified through fragment-based drug design. After structural optimization, the selected compound C04 exhibits significant anti-proliferative effects against the ALK-overexpressing cell line H2228 (IC50 = 0.10 μM), as well as promising ALK inhibition (9.58 nM). Molecular docking studies suggest that C04 functions as a type I₁/₂ allosteric inhibitor by forming critical interactions within the ATP-binding region and the hydrophobic pocket of ALK. Furthermore, C04 induces apoptosis in H2228 cells in a dose-dependent manner, inhibits colony formation, and suppresses tumor cell migration. These findings provide new insights into the search for novel ALK inhibitors.
Targeting autophagy initiation represents a promising strategy to disrupt the metabolic resilience of cancer cells. In this study, we identified ATI-1 as a novel small-molecule inhibitor that selectively blocks the early stages of autophagosome formation. Importantly, we discovered that ATI-1-mediated de novo inhibition of autophagy initiation leads to a synergistic surge in cell death under nutrient-deprived conditions, revealing a critical, context-specific vulnerability in autophagy-dependent malignancies. Mechanistically, ATI-1 appears to target valosin-containing protein (VCP/p97) and disrupt its interaction with the UFM1-specific E3 ligase UFL1. This disruption may promote the polyubiquitination and subsequent degradation of Beclin1, thereby contributing to the inhibition of autophagy initiation. Furthermore, ATI-1 demonstrates potent antitumor efficacy in xenograft models with minimal overt toxicity. This work collectively suggests that the VCP-UFL1-Beclin1 axis may represent a potentially targetable node in autophagy regulation, and identifies ATI-1 as a potential small-molecule modulator of this pathway, thereby providing a promising therapeutic lead for cancer treatment.
This study presents a comparative analysis of the effect of methylene blue (MB) loading strategy on the physicochemical and colloidal properties of ethosomes prepared by the cold method. Two synthesis protocols differing in the phase of introduction of the cationic hydrophilic dye were investigated: a classical approach with MB loading into the aqueous phase and an alternative approach involving MB incorporation into the ethanolic lipid phase. It is shown that the loading strategy is a critical technological factor determining vesicle size, encapsulation efficiency, loading capacity, and electrokinetic properties of the systems. The alternative method results in the formation of smaller ethosomes (Rh ≈ 78 nm) compared to the classical protocol (Rh ≈ 96 nm), but is accompanied by a lower encapsulation efficiency (EE ≈ 36% versus 48%). The results indicate that a reduction in vesicle size does not necessarily lead to higher encapsulation of hydrophilic cationic MB and may be associated with a decrease in the total internal aqueous volume as well as an increased contribution of a weakly bound surface-associated dye fraction. Spectral analysis indicates the preservation of a predominantly monomeric form of MB within ethosomes, while differences in ζ-potential suggest distinct localization of the dye within the vesicular systems. Overall, the results highlight the importance of optimizing the loading protocol in the development of ethosomal drug delivery systems for photodynamic therapy and topical applications.
Ureteral stents are among the most frequently used devices in urology, yet their high susceptibility to biofilm and encrustation continues to evade current surface-coating strategies. The development of emerging coatings faces significant challenges due to the complex physiological environment of the urinary tract, featuring high salinity, continuous shear stress, fluctuating pH, and microbial contamination. Here, we report an effective anti-fouling and anti-encrustation surface-engineering strategy by developing a coating from intrinsically disordered protein condensates of fused in sarcoma (FUS) protein (IDPFUS) and applying it to ureteral stents via a polydopamine-assisted two-step modified method. The IDPFUS-modified surface exhibited markedly enhanced hydrophilicity and demonstrated strong resistance to nonspecific protein adsorption, urinary tract infection-related bacteria adhesion, and ureteral epithelial cell attachment, significantly outperforming the benchmark polyethylene glycol (PEG) coating. In a rat model of infection-induced urolithiasis, the IDPFUS coating reduced stent encrustation by over 80% compared to clinical polyurethane and Percuflex™ stents, and markedly mitigated local tissue inflammation. Mechanistically, IDPFUS is thought to form a hydrating, densely entangled network through coacervation, which can help minimize surface contamination. This dynamic network could also inhibit stone nucleation near the stent surfaces by regulating local pH and ionic strength through charge neutralization and non-ionic interactions. These findings address the long-standing challenge of biofilm and encrustation on urinary implants by leveraging the integrated capabilities of IDPFUS condensate, including strong hydration, fouling resistance, and dynamic buffering, highlighting its translational potential for use in complex biofluids. STATEMENT OF SIGNIFICANCE: Ureteral stent encrustation remains a major clinical problem that is inadequately addressed by current hydrophilic coatings in the challenging urinary environment. This work introduces a bioinspired anti-encrustation coating made from intrinsically disordered proteins that forms highly hydrated, tightly tangled networks. Unlike conventional materials, this protein-based layer can spontaneously coacervate and locally regulate pH and ionic strength, preventing the initial attachment of proteins, bacteria and cells, while reducing stone formation. By demonstrating over 80% reduction of infection-induced encrustation compared with clinical stents, this study establishes intrinsically disordered proteins as a promising class of functional biomaterials with broad potential for improving urinary implants and other medical devices exposed to harsh biological environments.
Quorum sensing inhibitors against Pseudomonas aeruginosa focus on the "antivirulence strategy" rather than the traditional "bactericidal strategy", promoting the transformation of anti-infective therapy from directly killing bacteria to regulating bacterial behavior. Nine undescribed lovastatin derivatives, aculeatoxides A-I (1-9), along with four previously reported analogs (10-13), were isolated from Aspergillus aculeatus under the guidance of HSQC-based DeepSAT analysis. Spectroscopic analysis, ECD and NMR calculations, and single-crystal X-ray crystallography elucidated their structures and absolute configurations. Aculeatoxides A-E (1-5) represent a rare class of lovastatin derivatives incorporating diverse O-heterocycles, from which compounds 1 and 2 possess a unique 10-oxatricyclo[7.2.1.02,7]dodecane motif and a 2-oxatricyclo[6.3.1.04,12]dodecane motif, respectively. Interestingly, compound 11 showed potent quorum sensing inhibitory activity against the las system, accompanied by significant downregulation of key virulence factors, including elastase, rhamnolipid, and pyoverdine.
Camellia reticulata Lindl., an ornamental plant cultivated in Southwest China, was investigated as a potential source of novel natural tyrosinase inhibitors. Three tannins, 1,2,3,6-tetragalloylglucose (TeGG), procyanidin B2, and procyanidin C1, were identified from the plant extracts as potential active components. Among them, gallotannin TeGG exhibited higher activity than β-arbutin, while its tyrosinase inhibitory mechanism is unclear. So, the kinetic study and multi-spectroscopic study were applied to elucidate the tyrosinase inhibitory mechanism of TeGG. As a result, TeGG was suggested as a competitive inhibitor of tyrosinase and predicted to occupy the channel of tyrosinase towards its copper catalytic site. The TeGG would not chelate with copper nor change the conformation of tyrosinase, but bind reversibly to the enzyme, suggesting TeGG and its derivatives are potential tyrosinase inhibitors, both safe and effective.
The article investigates the influence of extracellular vesicles (EVs) isolated from donor seminal plasma (SP) on the expression of key reproductive genes AURKA and KLHL10 in human spermatozoa before and after cryopreservation. This study arises from the necessity to improve the effectiveness of assisted reproductive technologies (ART) and to advance the comprehension of how cryopreservation affects male gamete quality. A total of 17 sperm samples were examined. EVs were isolated from SP by asymmetric depth filtration and used for co-culturing with sperm samples prior to cryopreservation. Gene expression was analyzed by real-time PCR. The results demonstrated that sperm co-culturing with donor SP-EVs helped maintain or upregulate the expression of AURKA and KLHL10 genes that play critical roles in cell division and acrosome formation, respectively. These findings indicate a protective effect of EVs on spermatozoa during cryopreservation. The study highlights the potential utility of SP-EVs for augmenting sperm cryotolerance and boosting the efficacy of ART programs. Further research is warranted to investigate protein-level changes and functional implications of the observed gene expression patterns.
Conventional non-covalent bc1 complex inhibitors are widely used in plant fungal disease control, but their efficacy is increasingly compromised by resistance, underscoring the need for new agents. To address this, a series of cytochrome bc1 inhibitors featuring covalent warheads were designed and synthesized. In vitro antifungal results demonstrated that compound G2 exhibited significantly lower EC50 values compared to kresoxim-methyl against A. solani (0.05 μg/mL), G. zeae (6.80 μg/mL), C. gloeosporioides (17.37 μg/mL), and F. oxysporum f. sp. melonis (21.33 μg/mL). In vivo assays against A. solani demonstrated the highly effective curative efficacy of tomato early blight by compound G2. Further mechanistic investigation revealed that G2 inhibits the cytochrome bc1 complex, thereby impairing ATP synthesis and suppressing ATPase activity, while also inducing a burst of reactive oxygen species. These effects collectively compromise plasma membrane integrity and ultimately suppress fungal growth. Molecular docking studies suggested a potential covalent binding mode between G2 and Cys39 of cytochrome b. Through an innovative exploration of the covalent drug strategy in agrochemical design, this work provides valuable insights for the development of novel cytochrome bc1 complex inhibitors.
Dual inhibition of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2) represents an effective strategy for achieving synergistic antitumor activity by simultaneously suppressing tumor proliferation and angiogenesis. In this study, a series of quinoxaline-based derivatives (7-15) was rationally designed, synthesized, and biologically evaluated as dual EGFR/VEGFR-2 inhibitors. In vitro cytotoxicity screening against breast (MCF-7), liver (HepG2), and colon (HCT116) cancer cell lines identified compounds 9, 11, 12, and 13 as the most potent antiproliferative agents, exhibiting activities comparable to or exceeding those of the reference drugs Sorafenib and Erlotinib. Among them, compound 12 demonstrated the highest potency, as evidenced by cellular fold inhibition values of 0.288 and 0.227 against EGFR and VEGFR-2, respectively. Enzymatic assays further confirmed its strong inhibitory activity, with IC₅₀ values of 0.06 μM (EGFR) and 0.204 μM (VEGFR-2), comparable to Erlotinib (0.052 μM) and Sorafenib (0.131 μM). Mechanistic investigations revealed that compound 12 exhibited interesting selectivity, with 2.4-fold lower cytotoxicity toward normal MCF10A cells compared to doxorubicin. It induced a pronounced G2/M phase arrest in MCF-7 cells and significantly promoted apoptosis, resulting in a 12-fold increase in apoptotic cell population. Gene expression analysis indicated activation of both intrinsic and extrinsic apoptotic pathways, demonstrated by a marked increase in the Bax/Bcl-2 ratio (∼20-fold) and upregulation of caspase-9 (7.9-fold) and caspase-8 (2.9-fold). Molecular docking studies supported the experimental findings, revealing a strong binding affinity of compound 12 within the active sites of EGFR and VEGFR-2. Molecular dynamics simulations further confirmed the stability of these interactions over time. Additionally, in silico ADME profiling demonstrated good drug-likeness, fulfilling Lipinski, Veber, Egan, and Muegge criteria. Collectively, these findings highlight compound 12 as a promising dual EGFR/VEGFR-2 inhibitor with significant potential for further development as a multitarget anticancer candidate.
Wide-bandgap (WBG) perovskite solar cells (PSCs) are promising candidates for indoor photovoltaics (IPVs), but their efficiency is limited by non-radiative recombination at the buried perovskite/transport layer interface. To reduce these losses, this study proposes using self-assembled monolayers (SAMs) combining a triphenylamine (TPA) donor with rhodanine (RH) or rhodanine-3-acetic acid (RA) anchoring groups, as effective hole-selective layers (HSLs). Using NiOx/SAM double HSLs, we found that the heteroatom-rich RA group with a carboxymethyl co-anchor enhances NiOx surface oxidation and provides strong interfacial passivation. DFT calculations, electrochemical analysis, and characterization via XPS, UPS, PL, and SEM were used to elucidate the HSL-perovskite interface relationship. Structural studies revealed that the molecular spacer influences perovskite growth. Sterically hindered TPA-AN-RA yields smaller grains with more defects, while planar TPA-PH-RA enables larger grains and fewer traps. The optimized TPA-RA structure ensures balanced energetics and improved charge extraction, delivering an impressive indoor iPCE of 41.81% under a 1000 lux white LED. Under AM 1.5G conditions, it achieves 18.68% PCE, making it suitable for hybrid lighting environments. Furthermore, the unencapsulated TPA-RA device retained 84% of its indoor efficiency after 1600 h in an inert atmosphere, demonstrating excellent intrinsic stability. This work highlights the potential of molecular engineering for producing high-efficiency stable indoor PSCs.