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COX-2-selective drugs were withdrawn from the market just a few years after their development due to cardiovascular side effects. As a result, developing a selective COX-2 inhibitor as an anti-inflammatory agent with cardioprotective characteristics has become a prominent objective in medicinal chemistry. New 15 diaryl-1,2,4-triazolo[3,4-a]pyrimidine hybrids 8a-o were synthesized and investigated in vitro as dual COX-2/sEH inhibitors. Compounds 8b, 8m, and 8o have the highest potency and selectivity as COX-2 inhibitors (IC50 = 15.20, 11.60, and 10.50 µM, respectively; selectivity index (COX-1/COX-2) = 13, 20, and 25, respectively), compared to celecoxib (COX-2; IC50 = 42 µM; SI = 8). The 5-LOX inhibitory activity of compounds 8b, 8m, and 8o was further examined in vitro. Compounds 8m and 8o, the most effective COX-2 selective inhibitors, demonstrated stronger 5-LOX inhibitory action than the reference quercetin, with IC50 values of 2.90 and 3.05 µM, respectively. Additionally, compounds 8b, 8m, and 8o were the most potent dual COX-2/sEH inhibitors, with IC50 values against sEH of 3.20, 2.95, and 2.20 nM, respectively, and were equivalent to AUDA (IC50 = 1.2 nM). In vivo investigations also demonstrated that these compounds were the most efficacious as analgesic/anti-inflammatory derivatives with a high cardioprotective profile against cardiac biomarkers and inflammatory cytokines. The docking data analysis inquiry helped better understand the binding mechanisms of the most active hybrids within the COX-2 active site and supported their COX-2 selectivity. Compounds 8b, 8m, and 8o exhibited a similar orientation to rofecoxib and celecoxib, with a larger proclivity to enter the selectivity side pocket than the reference compounds.
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Conjugates of benzothiophene-fused azacyclononyne BT9N-NH2 with fluorescent dyes were developed to visualise azidoglycans intracellularly. The significance of the cycloalkyne core was demonstrated by comparing new reagents with DBCO- and BCN-dye conjugates. To reduce non-specificity during intracellular bioconjugation using SPAAC, less reactive BT9N-dye reagents are preferred over highly reactive DBCO- and BCN-dye conjugates.
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The current study focuses on developing a single molecule that acts as an antiproliferative agent with dual or multi-targeted action, reducing drug resistance and adverse effects. A new series of 4-pyrazolylquinolin-2-ones (5a-j) with apoptotic antiproliferative effects as dual EGFR/BRAFV600E inhibitors were designed and synthesized. Compounds 5a-j were investigated for their cell viability effect against a normal cell line (MCF-10A). Results showed that none of the compounds were cytotoxic, and all 5a-j demonstrated more than 90% cell viability at 50 µM concentration. Using erlotinib as a reference, the MTT assay investigated the antiproliferative impact of targets 5a-j against four human cancer cell lines. Compounds 5e, 5f, 5h, 5i, and 5j were the most potent antiproliferative agents with GI50 values of 42, 26, 29, 34, and 37 nM, making compounds 5f and 5h more potent than erlotinib (GI50 = 33 nM). Moreover, compounds 5e, 5f, 5h, 5i, and 5j were further investigated as dual EGFR/BRAFV600E inhibitors, and results revealed that compounds 5f, 5h, and 5i are potent antiproliferative agents that act as dual EGFR/BRAFV600E inhibitors. Cell cycle analysis and apoptosis detection revealed that compound 5h displaying cell cycle arrest at the G1 transition could induce apoptosis with a high necrosis percentage. Docking studies revealed that compound 5f exhibited a strong affinity for EGFR and BRAFV600E, with high docking scores of -8.55 kcal mol-1 and -8.22 kcal mol-1, respectively. Furthermore, the ADME analysis of compounds 5a-j highlighted the diversity in their pharmacokinetic properties, emphasizing the importance of experimental validation.
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Materials exhibiting thermally activated delayed fluorescence (TADF) based on transition metal complexes are currently gathering significant attention due to their technological potential. Their application extends beyond optoelectronics, in particular organic light-emitting diodes (OLEDs) and light-emitting electrochemical cells (LECs), and include also photocatalysis, sensing, and X-ray scintillators. From the perspective of sustainability, earth-abundant metal centers are preferred to rarer second- and third-transition series elements, thus determining a reduction in costs and toxicity but without compromising the overall performances. This review offers an overview of earth-abundant transition metal complexes exhibiting TADF and their application as photoconversion materials. Particular attention is devoted to the types of ligands employed, helping in the design of novel systems with enhanced TADF properties.
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Over the past decades, the research on optically active polymers (OAPs) has significantly grown, and extensive studies have been carried out on their syntheses, conformations, and applications. The most commonly used OAPs are based on natural products such as sugars or amino acids, which limits their scope. A broader range of applications can be achieved by synthesizing lab-tailored monomers, which allow precise control over structure and properties. This research developed a four-step synthetic route to a previously unreported chiral [2.2]paracyclophane-based epoxide monomer. An aluminum catalyst and an alkylammonium initiating system were applied and optimized for its polymerization to provide access to a novel class of chiral polyethers. Furthermore, we demonstrated the copolymerization viability of the (4-[2.2]paracyclophanyl)oxirane monomer using phthalic anhydride.
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A synthesis route to access triazole-pyrazole hybrids via triazenylpyrazoles was developed. Contrary to existing methods, this route allows the facile N-functionalization of the pyrazole before the attachment of the triazole unit via a copper-catalyzed azide-alkyne cycloaddition. The developed methodology was used to synthesize a library of over fifty new multi-substituted pyrazole-triazole hybrids. We also demonstrate a one-pot strategy that renders the isolation of potentially hazardous azides obsolete. In addition, the compatibility of the method with solid-phase synthesis is shown exemplarily.
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A new series of 1,3,4-thiadiazin-3-ium bromide derivatives 9a-g were prepared as a six-member ring by interactions between 4-substituted thiosemicarbazides 8a-e and α-halo ketones 2a,b. The reaction was conducted using hydrazine-NH2 and yielded a hexagonal shape. The structures of all obtained compounds have been verified using IR, NMR spectra, mass spectrometry, elemental analysis, and X-ray crystallography. The X-ray crystallographic analysis of compounds 9a and 9b has revealed that the salt is formed with the nitrogen atom N3 when the aromatic substituents 9a and 9d are present, but in the case of compounds 9b, 9c, 9e, 9f, and 9g with the aliphatic substituent, the salt is formed outside the ring. Compounds 9a-g were evaluated for antiproliferative activity as multitargeted inhibitors. Results revealed that targets 9a-g displayed good antiproliferative activity, with GI50 ranging from 38 nM to 66 nM against a panel of four cancer cell lines compared to the reference Erlotinib (GI50 = 33 nM). Compounds 9a, 9c, and 9d were the most potent antiproliferative derivatives, with GI50 values of 43, 38, and 47 nM, respectively. Compounds 9a, 9c, and 9d were evaluated for their inhibitory activity against EGFR, BRAFV600E, and VEGFR-2. The in vitro experiments demonstrated that the compounds being examined exhibit potent antiproliferative properties and have the potential to function as multitargeted inhibitors. In addition, the western blotting investigation demonstrated the inhibitory effects of 9c on EGFR, BRAFV600E, and VEGFR-2.
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Chronic inflammation is driven by proinflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and chemokines, such as c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10. Inflammatory processes of the central nervous system (CNS) play an important role in the pathogenesis of various neurological and psychiatric disorders like Alzheimer's disease, Parkinson's disease, and depression. Therefore, identifying novel anti-inflammatory drugs may be beneficial for treating disorders with a neuroinflammatory background. The G-protein-coupled receptor 55 (GPR55) gained interest due to its role in inflammatory processes and possible involvement in different disorders. This study aims to identify the anti-inflammatory effects of the coumarin-based compound KIT C, acting as an antagonist with inverse agonistic activity at GPR55, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells in comparison to the commercial GPR55 agonist O-1602 and antagonist ML-193. All compounds significantly suppressed IL-6, TNF-α, CCL2, CCL3, CXCL2, and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compounds are partially explained by modulation of the phosphorylation of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC) pathways, and the transcription factor nuclear factor (NF)-κB, respectively. Due to its potent anti-inflammatory properties, KIT C is a promising compound for further research and potential use in inflammatory-related disorders.
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Organic light-emitting diodes (OLEDs) are promising lighting solutions for sustainability and energy efficiency. Incorporating thermally activated delayed fluorescence (TADF) molecules enables OLEDs to achieve internal quantum efficiency (IQE), in principle, up to 100%; therefore, new classes of promising TADF emitters and modifications of existing ones are sought after. This study explores the TADF emission properties of six designed TADF emitters, examining their photophysical responses using experimental and theoretical methods. The design strategy involves creating six distinct types of a donor-acceptor (D-A) system, where tert-butylcarbazoles are used as donors, while the acceptor component incorporates three different functional groups: nitrile, tetrazole and oxadiazole, with varying electron-withdrawing character. Additionally, the donor-acceptor distance is adjusted using a phenylene spacer, and its influence on TADF functionality is examined. The clear dependency of an additional spacer, inhibiting TADF, could be revealed. Emitters with a direct donor-acceptor connection are demonstrated to exhibit TADF moderate emissive behavior. The analysis emphasizes the impact of charge transfer, singlet-triplet energy gaps (ΔEST), and other microscopic parameters on photophysical rates, permitting TADF. Among the emitters, TCz-CN shows optimal performance as a blue-green emitter with an 88% photoluminescence quantum yield (PLQY) and fast rate of reversible intersystem crossing of 2x106 s-1.
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DNA gyrase and topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been identified; however, none have been effective in the market. For the first time, we developed a series of disalicylic acid methylene/Schiff bases hybrids (5a-k) to act as antibacterial agents targeting DNA gyrase and topoisomerase IV. The findings indicated that the new targets 5f-k exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, with efficacy ranging from 75% to 115% of the standard ciprofloxacin levels. Compound 5h demonstrated the greatest efficacy compared to the other compounds tested, with minimum inhibitory concentration (MIC) values of 0.030, 0.065, and 0.060 µg/mL against S. aureus, E. coli, and P. aeruginosa. 5h had a MIC value of 0.050 µg/mL against B. subtilis, which is five times less potent than ciprofloxacin. The inhibitory efficacy of the most potent antibacterial derivatives 5f, 5h, 5i, and 5k against E. coli DNA gyrase was assessed. The tested compounds demonstrated inhibitory effects on E. coli DNA gyrase, with IC50 values ranging from 92 to 112 nM. These results indicate that 5f, 5h, 5i, and 5k are more effective than the reference novobiocin, which had an IC50 value of 170 nM. Compounds 5f, 5h, 5i, and 5k were subjected to additional assessment against E. coli topoisomerase IV. Compounds 5h and 5i, which have the highest efficacy in inhibiting E. coli gyrase, also demonstrated promising effects on topoisomerase IV. Compounds 5h and 5i exhibit IC50 values of 3.50 µM and 5.80 µM, respectively. These results are much lower and more potent than novobiocin's IC50 value of 11 µM. Docking studies demonstrate the potential of compound 5h as an effective dual inhibitor against E. coli DNA gyrase and topoisomerase IV, with ADMET analysis indicating promising pharmacokinetic profiles for antibacterial drug development.
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Pharmacological treatment of psychiatric disorders remains challenging in clinical, pharmacological, and scientific practice. Even if many different substances are established for treating different psychiatric conditions, subgroups of patients show only small or no response to the treatment. The neuroinflammatory hypothesis of the genesis of psychiatric disorders might explain underlying mechanisms in these non-responders. For that reason, recent research focus on neuroinflammatory processes and oxidative stress as possible causes of psychiatric disorders. G-protein coupled receptors (GPCRs) form the biggest superfamily of membrane-bound receptors and are already well known as pharmacological targets in various diseases. The G-protein coupled receptor 55 (GPR55), a receptor considered part of the endocannabinoid system, reveals promising modulation of neuroinflammatory and oxidative processes. Different agonists and antagonists reduce pro-inflammatory cytokine release, enhance the synthesis of anti-inflammatory mediators, and protect cells from oxidative damage. For this reason, GPR55 ligands might be promising compounds in treating subgroups of patients suffering from psychiatric disorders related to neuroinflammation or oxidative stress. New approaches in drug design might lead to new compounds targeting different pathomechanisms of those disorders in just one molecule.
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Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms associated with the mentioned diseases after the treatment with anti-inflammatory drugs. Therefore, the investigation of novel anti-inflammatory drugs could hold substantial potential in the treatment of disorders with a neuroinflammatory background. In this in vitro study, we report the anti-inflammatory effects of a novel hexacyclic peptide-peptoid hybrid in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The macrocyclic compound X15856 significantly suppressed Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compound are partially explained by the modulation of the phosphorylation of p38 mitogen-activated protein kinases (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC), and the nuclear factor (NF)-κB, respectively. Due to its remarkable anti-inflammatory properties, this compound emerges as an encouraging option for additional research and potential utilization in disorders influenced by inflammation, such as depression.
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Antiinflamatorios , Lipopolisacáridos , Microglía , Microglía/efectos de los fármacos , Microglía/metabolismo , Animales , Ratones , Antiinflamatorios/farmacología , Línea Celular , Peptoides/farmacología , Peptoides/química , Interleucina-6/metabolismo , FN-kappa B/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Péptidos/farmacología , Péptidos/química , Factor de Necrosis Tumoral alfa/metabolismo , Quimiocina CXCL2/metabolismo , Citocinas/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Quimiocina CCL3/metabolismo , Quimiocina CCL3/genética , Compuestos Macrocíclicos/farmacología , Compuestos Macrocíclicos/químicaRESUMEN
In this report, a new series of mono-, di-, tri-, and tetra-cationic pyridinium and vinyl pyridinium-modified [2.2]paracyclophanes as useful molecular tectons for supramolecular systems are described. Regioselective functionalization at specific positions, followed by resolution step and successive transformations through Pd-catalyzed Suzuki-Miyaura and Mizoroki-Heck cross-coupling chemistry furnish a series of modular PCP scaffolds. In our proof-of-concept study, on N-methylation, the PCPs bearing (cationic) pyridyl functionalities were demonstrated as useful molecular receptors in host-guest supramolecular assays. The PCPs on grafting with light-responsive azobenzene (-N=N-) functional core as side-groups impart photosensitivity that can be remotely transformed on irradiation, offering photo-controlled smart molecular functions. Furthermore, the symmetrical PCPs bearing bi-, and tetra-pyridyl functionalities at the peripheries have enormous potential to serve as ditopic and tetratopic 3D molecular tectons for engineering non-covalent supramolecular assemblies with new structural and functional attributes.
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Macrocyclic hosts, such as cucurbit[8]uril (CB8), can significantly influence the outcomes of chemical reactions involving encapsulated reactive guests. In this study, we demonstrate that CB8 completely reverses the stereoselectivity of intramolecular [2+2] photo-cycloaddition reactions. Notably, it was also found that CB8 can trigger the unreactive diene to be reactive.
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A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids (7a-o) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds 7a-o were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI50 values ranging from 28 to 104 nM, compared to Erlotinib (GI50 = 33 nM), and compounds 7i-m were the most potent. Compounds 7h, 7i, 7j, 7k, and 7l were evaluated as dual EGFR/VEGFR-2 inhibitors. These in vitro experiments demonstrated that compounds 7j, 7k, and 7l are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds 7j, 7k, and 7l were evaluated for their apoptotic potential activity, where findings indicated that compounds 7j, 7k, and 7l promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites.
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Antineoplásicos , Triazoles , Estructura Molecular , Relación Estructura-Actividad , Clorhidrato de Erlotinib/farmacología , Simulación del Acoplamiento Molecular , Triazoles/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Antineoplásicos/química , Receptores ErbB/metabolismo , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Proteínas Quinasas/farmacología , Línea Celular TumoralRESUMEN
A novel series of 1,2-dihydroquinolinhydrazonopropanoate have been synthesized via a convenient aza-Michael addition reaction between hydrazinylquinolinones and ethyl propiolate in ethanol under refluxing temperature. The structures for all obtained products were confirmed with FTIR, NMR spectrums, as well as mass spectrometry. In addition, the monoclinic structure for compounds 8a, 8c, and 8d was also confirmed via X-ray crystallography analyses. The E-configuration for the obtained products was confirmed form the X-ray analysis. On the other hand, the crystal packing shows that the intermolecular and hydrogen bonds between atoms are parallel to the bc plan.
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Metal-organic frameworks (MOFs), with their well-defined and highly flexible nanoporous architectures, provide a material platform ideal for fabricating sensors. We demonstrate that the efficacy and specificity of detecting and differentiating volatile organic compounds (VOCs) can be significantly enhanced using a range of slightly varied MOFs. These variations are obtained via postsynthetic modification (PSM) of a primary framework. We alter the original MOF's guest adsorption affinities by incorporating functional groups into the MOF linkers, which yields subtle changes in responses. These responses are subsequently evaluated by using machine learning (ML) techniques. Under severe conditions, such as high humidity and acidic environments, sensor stability and lifespan are of utmost importance. The UiO-66-X MOFs demonstrate the necessary durability in acidic, neutral, and basic environments with pH values ranging from 2 to 11, thus surpassing most other similar materials. The UiO-66-NH2 thin films were deposited on quartz-crystal microbalance (QCM) sensors in a high-temperature QCM liquid cell using a layer-by-layer pump method. Three different, highly stable surface-anchored MOFs (SURMOFs) of UiO-66-X obtained via the PSM approach (X: NH2, Cl, and N3) were employed to fabricate arrays suitable for electronic nose applications. These fabricated sensors were tested for their capability to distinguish between eight VOCs. Data from the sensor array were processed using three distinct ML techniques: linear discriminant (LDA), nearest neighbor (k-NN), and neural network analysis methods. The discrimination accuracies achieved were nearly 100% at high concentrations and over 95% at lower concentrations (50-100 ppm).
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Estructuras Metalorgánicas , Ácidos Ftálicos , Compuestos Orgánicos Volátiles , AdsorciónRESUMEN
Therapies that abrogate persistent androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BCL-2-associated athanogene-1 (BAG-1) mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are implicated in the development and progression of CRPC. In addition, interrogation of geometric and physiochemical properties of the BAG domain of BAG-1 isoforms identifies it to be a tractable but challenging drug target. Furthermore, through BAG-1 isoform mouse knockout studies, we confirm that BAG-1 isoforms regulate hormone physiology and that therapies targeting the BAG domain will be associated with limited "on-target" toxicity. Importantly, the postulated inhibitor of BAG-1 isoforms, Thio-2, suppressed AR signaling and other important pathways implicated in the development and progression of CRPC to reduce the growth of treatment-resistant prostate cancer cell lines and patient-derived models. However, the mechanism by which Thio-2 elicits the observed phenotype needs further elucidation as the genomic abrogation of BAG-1 isoforms was unable to recapitulate the Thio-2-mediated phenotype. Overall, these data support the interrogation of related compounds with improved drug-like properties as a novel therapeutic approach in CRPC, and further highlight the clinical potential of treatments that block persistent AR signaling which are currently undergoing clinical evaluation in CRPC.
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Progresión de la Enfermedad , Neoplasias de la Próstata Resistentes a la Castración , Transducción de Señal , Masculino , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Humanos , Animales , Ratones , Transducción de Señal/efectos de los fármacos , Receptores Androgénicos/metabolismo , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proliferación Celular , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
A series of monometallic Ag(I) and Cu(I) halide complexes bearing 2-(diphenylphosphino)pyridine (PyrPhos, L) as a ligand were synthesized and spectroscopically characterized. The structure of most of the derivatives was unambiguously established by X-ray diffraction analysis, revealing the formation of mono-, di-, and tetranuclear complexes having general formulas MXL3 (M = Cu, X = Cl, Br; M = Ag, X = Cl, Br, I), Ag2X2L3 (X = Cl, Br), and Ag4X4L4 (X = Cl, Br, I). The Ag(I) species were compared to the corresponding Cu(I) analogues from a structural point of view. The formation of Cu(I)/Ag(I) heterobimetallic complexes MM'X2L3 (M/M' = Cu, Ag; X = Cl, Br, I) was also investigated. The X-ray structure of the bromo-derivatives revealed the formation of two possible MM'Br2L3 complexes with Cu/Ag ratios, respectively, of 7:1 and 1:7. The ratio between Cu and Ag was studied by scanning electron microscopy-energy-dispersive X-ray analysis (SEM-EDX) measurements. The structure of the binuclear homo- and heterometallic derivatives was investigated using density functional theory (DFT) calculations, revealing the tendency of the PyrPhos ligands not to maintain the bridging motif in the presence of Ag(I) as the metal center.
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A new class of benzimidazole-based derivatives (4a-j, 5, and 6) with potential dual inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized compounds 4a-j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single concentration of 10 µM. Some compounds tested demonstrated remarkable antiproliferative activity against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against 60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2 protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act as dual EGFR/BRAFV600E inhibitors.