Structural Motifs Research Articles

XtalOpt version 13: Multi-objective evolutionary search for novel functional materials

Version 13 of XtalOpt, an evolutionary algorithm for crystal structure prediction, is now available for download from the CPC program library or the XtalOpt website, https://xtalopt.github.io. In the new version of the XtalOpt code, a general platform for multi-objective global optimization is implemented. This functionality is designed to facilitate the search for (meta)stable phases of functional materials through minimization of the enthalpy of a crystalline system coupled with the simultaneous optimization of any desired properties that are specified by the user. The code is also able to perform a constrained search by filtering the parent pool of structures based on a user-specified feature, while optimizing multiple objectives. Here, we present the implementation and various technical details, and we provide a brief overview of additional improvements that have been introduced in the new version of XtalOpt. Program summaryProgram Title: XtalOptCPC Library link to program files:https://doi.org/10.17632/jt5pvnnm39.4Developer's repository link:https://github.com/xtalopt/XtalOptLicensing provisions: BSD 3-clauseProgramming language: C++.Journal reference of previous version: Comput. Phys. Commun. 237 (2019) 274–275.Does the new version supersede the previous version?: Yes.Reasons for the new version: Implementation of a multi-objective evolutionary search within the XtalOpt program package.Summary of revisions: Implemented a general user-friendly multi-objective search capability, made various improvements to user interface and functionalities, performed bug fixes.Nature of problem: The XtalOpt algorithm is designed to search for (meta)stable crystal structures, optionally with specific functionalities – a grand challenge in computational materials science, chemistry and physics.Solution method: A generalized scalar fitness function, where a set of user-specified objectives contribute to the fitness value for candidate structures, is implemented within XtalOpt. This generalized fitness biases the search towards the discovery of (meta)stable phases with structural motifs that are key for the desired characteristics. As a result, the evolutionary search explores regions of the energy landscape of higher relevance in terms of target properties.

LncRNA FGD5-AS1 is required for gastric cancer proliferation by inhibiting cell senescence and ROS production via stabilizing YBX1

BackgroundThe vast majority of lncRNAs have low expression abundance, which greatly limits their functional range and impact. As a high expression abundance lncRNA, FGD5-AS1’s non-ceRNA biological function in cancer is unclear.MethodsRNA-seq studies and chromatin immunoprecipitation (Chip) assays were performed to identify ZEB1-regulated lncRNAs. RNA sequencing, RNA pulldown, RNA Immunoprecipitation assays, and rescue assays were conducted to explore the molecular mechanisms of FGD5-AS1 in GC.ResultsAs one of the most abundant lncRNAs in cells, FGD5-AS1 has been shown to be transcriptionally activated by ZEB1, thus closely related to epithelial-mesenchymal transition (EMT) signaling. Clinical analysis showed that FGD5-AS1 overexpression was clinically associated with lymph node metastasis, and predicted poor survival in GC. Loss-of-function studies confirmed that FGD5-AS1 knockdown inhibited GC proliferation and induced cisplatin chemosensibility, cell senescence, and DNA damage in GC cells. Mechanismically, FGD5-AS1 is a YBX1-binding lncRNA due to its mRNA contains three adjacent structural motifs (UAAUCCCA, ACCAGCCU, and CAGUGAGC) that can be recognized and bound by YBX1. And this RNA-protein interaction prolonged the half-life of the YBX1 protein in GC. Additionally, a rescue assay showed that FGD5-AS1 promotes GC by repressing cell senescence and ROS production via YBX1.ConclusionFGD5-AS1 is a cellular high-abundant lncRNA that is transcriptionally regulated by ZEB1. FGD5-AS1 overexpression promoted GC progression by inhibiting cell senescence and ROS production through binding and stabilizing the YBX1 protein.

Tailoring a decatungstate-incorporated metal-organic framework for light-driven [3+2] cyclization of phenols with olefins

Photocatalytic oxidative [3+2] cycloaddition of phenol-olefin is an economy and green strategy to synthesize 2,3-Dihydrobenzofurans (2,3-DHBs) compared with the thermal catalysis with noble metals under harsh conditions. Thus, it is urgent to design noble metal-free heterogeneous photocatalyst that combined single-electron transfer (SET) and hydrogen-atom transfer (HAT) dual function. Decatungstate [W10O32]4− is considered as an ecofriendly photocatalyst for HAT and SET, but it is commonly used in homogeneous catalysis. Herein, we report CuW10-TIPA as a white-light-activated heterogeneous photocatalyst for synthesizing 2,3-dihydrobenzofurans via [3+2] cycloaddition of phenols with olefins, a crucial step in relevant pharmaceutical structural motifs. The coordination bonds between Cu(I) and TIPA, strong H-bonds between TIPA and [W10O32]4− and anion∙∙∙π interactions between [W10O32]4− and TIPA dramatically promote the separation of photoinduced electron-hole and facilitate the charge transfer among each component. Our approach is characterized by its mildness, scalability, and recyclability. We delve into the discussion on [W10O32]4− anions-mediated C-H bond activation via the HAT pathway, with the cooperation of the photosensitizer TIPA and Cu(I), which enhances absorption in the visible region and narrows the energy band.

Structural Basis for the Interaction Between Yeast Chromatin Assembly Factor 1 and Proliferating Cell Nuclear Antigen

Proliferating cell nuclear antigen (PCNA), the homotrimeric eukaryotic sliding clamp protein, recruits and coordinates the activities of a multitude of proteins that function on DNA at the replication fork. Chromatin assembly factor 1 (CAF-1), one such protein, is a histone chaperone that deposits histone proteins onto DNA immediately following replication. The interaction between CAF-1 and PCNA is essential for proper nucleosome assembly at silenced genomic regions. Most proteins that bind PCNA contain a PCNA-interacting peptide (PIP) motif, a conserved motif containing only eight amino acids. Precisely how PCNA is able to discriminate between binding partners at the replication fork using only these small motifs remains unclear. Yeast CAF-1 contains a PIP motif on its largest subunit, Cac1. We solved the crystal structure of the PIP motif of CAF-1 bound to PCNA using a new strategy to produce stoichiometric quantities of one PIP motif bound to each monomer of PCNA. The PIP motif of CAF-1 binds to the hydrophobic pocket on the front face of PCNA in a similar manner to most known PIP-PCNA interactions. However, several amino acids immediately flanking either side of the PIP motif bind the IDCL or C-terminus of PCNA, as observed for only a couple other known PIP-PCNA interactions. Furthermore, mutational analysis suggests positively charged amino acids in these flanking regions are responsible for the low micromolar affinity of CAF-1 for PCNA, whereas the presence of a negative charge upstream of the PIP prevents a more robust interaction with PCNA. These results provide additional evidence that positive charges within PIP-flanking regions of PCNA-interacting proteins are crucial for specificity and affinity of their recruitment to PCNA at the replication fork.

Trigonal Planar [PN3]4− Anion in the Nitridophosphate Oxide Ba3[PN3

AbstractNitridophosphates, with their primary structural motif of isolated or condensed PN4 tetrahedra, meet many requirements for high performance materials. Their properties are associated with their structural diversity, which is mainly limited by this specific building block. Herein, we present the alkaline earth metal nitridophosphate oxide Ba3[PN3]O featuring a trigonal planar [PN3]4− anion. Ba3[PN3]O was obtained using a hot isostatic press by medium‐pressure high‐temperature synthesis (MP/HT) at 200 MPa and 880 °C. The crystal structure was solved and refined from single‐crystal X‐ray diffraction data in space group R c (no. 167) and confirmed by SEM‐EDX, magic angle spinning (MAS) NMR, vibrational spectroscopy (Raman, IR) and low‐cost crystallographic calculations (LCC). MP/HT synthesis reveals great potential by extending the structural chemistry of P to include trigonal planar [PN3]4− motifs.

Trigonal Planar [PN3]4- Anion in the Nitridophosphate Oxide Ba3[PN3]O.

Nitridophosphates, with their primary structural motif of isolated or condensed PN4 tetrahedra, meet many requirements for high performance materials. Their properties are associated with their structural diversity, which is mainly limited by this specific building block. Herein, we present the alkaline earth metal nitridophosphate oxide Ba3[PN3]O featuring a trigonal planar [PN3]4- anion. Ba3[PN3]O was obtained using a hot isostatic press by medium-pressure high-temperature synthesis (MP/HT) at 200 MPa and 880 °C. The crystal structure was solved and refined from single-crystal X-ray diffraction data in space group R c (no. 167) and confirmed by SEM-EDX, magic angle spinning (MAS) NMR, vibrational spectroscopy (Raman, IR) and low-cost crystallographic calculations (LCC). MP/HT synthesis reveals great potential by extending the structural chemistry of P to include trigonal planar [PN3]4- motifs.

Sulphated glycosaminoglycan isolated from the edible slipper oyster Magallana bilineata (Röding, 1798) attenuates inflammatory cytokines on lipopolysaccharide-prompted macrophages

The slipper oyster Magallana bilineata (Ostreidae) is considered as culinary delicacy among marine bivalves, and a sulphated glycosaminoglycan, 4,6-O-SO3-β-(1→3)-GalNAcp (unit A) and β-(1→4)-GlcAp (unit B) as principle structural motif containing laterally branched 4-O-SO3-β-glucopyranose (unit C) (MBP-3) was isolated from this species. Nuclear magnetic resonance (NMR), Fourier transform infra-red (FTIR), and mass spectroscopy techniques were used to characterise MBP-3. MBP-3 exhibited anti-inflammatory activities against inflammatory 5-lipoxygenase (IC50 0.11 mg mL−1) and cyclooxygenase-2 (IC50 0.12 mg mL−1) enzymes. MBP-3 (at 100 μg mL−1) showed effective downregulation against pro-inflammatory cytokines generation, namely interleukins-6, 1β, (IL-6, 1β) (1–1.7 pg mL−1) and tumour necrosis factor-α (TNF-α) (4 pg mL−1) along with substantial downregulation of ROS production in lipopolysaccharide (LPS)-inflamed cells. MBP-3 blocked the mRNA of NF-κB, cyclooxygenase-2 (COX-2), and other cytokines, in lipopolysaccharide-induced macrophages. The potential to constrain inflammatory cytokine production revealed its application to develop functional food to attenuate inflammation-associated disorders.

The Antimicrobial Activity of Human Defensins at Physiological Non-Permeabilizing Concentrations Is Caused by the Inhibition of the Plasma Membrane H+-ATPases.

Human defensins are cysteine-rich peptides (Cys-rich peptides) of the innate immune system. Defensins contain an ancestral structural motif (i.e., γ-core motif) associated with the antimicrobial activity of natural Cys-rich peptides. In this study, low concentrations of human α- and β-defensins showed microbicidal activity that was not associated with cell membrane permeabilization. The cell death pathway was similar to that previously described for human lactoferrin, also an immunoprotein containing a γ-core motif. The common features were (1) cell death not related to plasma membrane (PM) disruption, (2) the inhibition of microbicidal activity via extracellular potassium, (3) the influence of cellular respiration on microbicidal activity, and (4) the influence of intracellular pH on bactericidal activity. In addition, in yeast, we also observed (1) partial K+-efflux mediated via Tok1p K+-channels, (2) the essential role of mitochondrial ATP synthase in cell death, (3) the increment of intracellular ATP, (4) plasma membrane depolarization, and (5) the inhibition of external acidification mediated via PM Pma1p H+-ATPase. Similar features were also observed with BM2, an antifungal peptide that inhibits Pma1p H+-ATPase, showing that the above coincident characteristics were a consequence of PM H+-ATPase inhibition. These findings suggest, for the first time, that human defensins inhibit PM H+-ATPases at physiological concentrations, and that the subsequent cytosolic acidification is responsible for the in vitro microbicidal activity. This mechanism of action is shared with human lactoferrin and probably other antimicrobial peptides containing γ-core motifs.

Machine Learning Classification of Local Environments in Molecular Crystals.

Identifying local structural motifs and packing patterns of molecular solids is a challenging task for both simulation and experiment. We demonstrate two novel approaches to characterize local environments in different polymorphs of molecular crystals using learning models that employ either flexibly learned or handcrafted molecular representations. In the first case, we follow our earlier work on graph learning in molecular crystals, deploying an atomistic graph convolutional network combined with molecule-wise aggregation to enable per-molecule environmental classification. For the second model, we develop a new set of descriptors based on symmetry functions combined with a point-vector representation of the molecules, encoding information about the positions and relative orientations of the molecule. We demonstrate very high classification accuracy for both approaches on urea and nicotinamide crystal polymorphs and practical applications to the analysis of dynamical trajectory data for nanocrystals and solid-solid interfaces. Both architectures are applicable to a wide range of molecules and diverse topologies, providing an essential step in the exploration of complex condensed matter phenomena.

High-Pressure oC16-YBr3 Polymorph Recoverable to Ambient Conditions: From 3D Framework to Layered Material.

Exfoliation of graphite and the discovery of the unique properties of graphene─graphite's single layer─have raised significant attention to layered compounds as potential precursors to 2D materials with applications in optoelectronics, spintronics, sensors, and solar cells. In this work, a new orthorhombic polymorph of yttrium bromide, oC16-YBr3 was synthesized from yttrium and CBr4 in a laser-heated diamond anvil cell at 45 GPa and 3000 K. The structure of oC16-YBr3 was solved and refined using in situ synchrotron single-crystal X-ray diffraction. At high pressure, it can be described as a 3D framework of YBr9 polyhedra, but upon decompression below 15 GPa, the structure motif changes to layered, with layers comprising edge-sharing YBr8 polyhedra weakly bonded by van der Waals interactions. The layered oC16-YBr3 material can be recovered to ambient conditions, and according to Perdew-Burke-Ernzerhof-density functional theory calculations, it exhibits semiconductor properties with a band gap that is highly sensitive to pressure. This polymorph possesses a low exfoliation energy of 0.30 J/m2. Our results expand the list of layered trivalent rare-earth metal halides and provide insights into how high pressure alters their structural motifs and physical properties.

Exploring fingerprints for antidiabetic therapeutics related to peroxisome proliferator-activated receptor gamma (PPARγ) modulators: A chemometric modeling approach

This study demonstrated the correlation of molecular structures of Peroxisome proliferator-activated receptor gamma (PPARγ) modulators and their biological activities. Bayesian classification, and recursive partitioning (RP) studies have been applied to a dataset of 323 PPARγ modulators with diverse scaffolds. The results provide a deep insight into the important sub-structural features modulating PPARγ. The molecular docking analysis again confirmed the significance of the identified sub-structural features in the modulation of PPARγ activity. Molecular dynamics simulations further underscored the stability of the complexes formed by investigated modulators with PPARγ. Overall, the integration of many computational approaches unveiled key structural motifs essential for PPARγ modulatory activity that will shed light on the development of effective modulators in the future.

Recent Advances on the Synthesis and Application of Tetrahydro‐β‐Carbolines

AbstractTetrahydro‐β‐carbolines (THβCs) also known as tryptolines serve as important structural elements in natural products and pharmaceutical compounds, and they are also utilized in drug discovery. They display diverse bioactivities, including anticancer, antifungal, antiparasitic, anti‐ischemic, anti‐inflammatory, and other activities. Besides their pharmacological and biological significance, these structural motifs are also extensively used in the production of other bioactive compounds. This review is intended to summarize recent advancements in the chemistry of this compound class, including the synthesis and the applications as organic synthetic intermediates and bioactive molecules.

Transcriptomic analyses reveals a diverse venom composition in Agelena limbata (Araneae: Agelenaidae)

Spider venom is a natural source of diverse biomolecules, but due to technical limitations, only a small fraction has been studied. With the advancement of omics technologies, research on spider venom has broadened, greatly promoting systematic studies of spider venom. Agelena limbata is a common spider found in vegetation, known for constructing funnel-shaped webs, and feeding on insects such as Diptera and Homoptera. However, due to its small size and the difficulty in obtaining venom, the composition of Agelena limbata venom has never been studied. In this study, a transcriptomics approach was used to analyze the toxin components in the venom of Agelena limbata, resulting in the identification of 28 novel toxin-like sequences and 24 peptidases. Based on sequence similarity and differences in cysteine motifs, the 28-novel toxin-like sequences were classified into 10 superfamilies. According to the results annotated in the database, the 24 peptidases were divided into six distinct families, with the serine protease family being the most common. A phylogenetic tree was constructed using the toxin-like sequences of Agelena limbata along with Psechrus triangulus and Hippasa lycosina. An analysis of the structural domains and motifs of Agelena limbata was also conducted. The results indicated that Agelena limbata is more distantly related to the other two species of funnel-web spiders, and that the toxin superfamily IX has a unique function compared to the other superfamilies. This study reveals the components of the Agelena limbata venom, deepening our understanding of it, and through bioinformatics analysis, has identified unique functions of the toxin superfamilies, providing a scientific basis for the development of bioactive drugs in the future.

Accessing the Low-Polar Molecular Composition of Boreal and Arctic Peat-Burning Organic Aerosol via Thermal Analysis and Ultrahigh-Resolution Mass Spectrometry: Structural Motifs and Their Formation.

Peatland fires emit organic carbon-rich particulate matter into the atmosphere. Boreal and Arctic peatlands are becoming more vulnerable to wildfires, resulting in a need for better understanding of the emissions of these special fires. Extractable, nonpolar, and low-polar organic aerosol species emitted from laboratory-based boreal and Arctic peat-burning experiments are analyzed by direct-infusion atmospheric pressure photoionization (APPI) ultrahigh-resolution mass spectrometry (UHRMS) and compared to time-resolved APPI UHRMS evolved gas analysis from the thermal analysis of peat under inert nitrogen (pyrolysis) and oxidative atmosphere. The chemical composition is characterized on a molecular level, revealing abundant aromatic compounds that partially contain oxygen, nitrogen, or sulfur and are formed at characteristic temperatures. Two main structural motifs are identified, single core and multicore, and their temperature-dependent formation is assigned to the thermal degradation of the lignocellulose building blocks and other parts of peat.

Copper-Catalyzed Remote Asymmetric Yne-Allylic Substitution of Yne-Allylic Esters with Anthrones.

Anthrones are key structural motifs in many natural products and pharmaceutical chemicals. However, due to its unique tricyclic aromatic structure, the synthetic space for the development of chiral anthrone derivatives is largely limited. By utilizing the potential of the copper-catalyzed remote asymmetric yne-allylic substitution reaction, we describe the first example of copper-catalyzed highly regio- and enantioselective remote yne-allylic substitution on various yne-allylic esters with anthrones under a mild reaction condition, which afforded a range of enantioenriched 1,3-enynes with exhibiting broad functional group tolerance across 51 examples.

Structure-based mechanism of riboregulation of the metabolic enzyme SHMT1

RNA can directly control protein activity in a process called riboregulation; only a few mechanisms of riboregulation have been described in detail, none of which have been characterized on structural grounds. Here, we present a comprehensive structural, functional, and phylogenetic analysis of riboregulation of cytosolic serine hydroxymethyltransferase (SHMT1), the enzyme interconverting serine and glycine in one-carbon metabolism. We have determined the cryoelectron microscopy (cryo-EM) structure of human SHMT1 in its free- and RNA-bound states, and we show that the RNA modulator competes with polyglutamylated folates and acts as an allosteric switch, selectively altering the enzyme's reactivity vs. serine. In addition, we identify the tetrameric assembly and a flap structural motif as key structural elements necessary for binding of RNA to eukaryotic SHMT1. The results presented here suggest that riboregulation may have played a role in evolution of eukaryotic SHMT1 and in compartmentalization of one-carbon metabolism. Our findings provide insights for RNA-based therapeutic strategies targeting this cancer-linked metabolic pathway.

Metal (Mn2+, Co2+ and Cd2+) ions induced differentiation in mixed-ligands MOFs constructed from H3btb and H2bdc: Highly porous Structures, new topology nets and two-step gate-opening behaviors

Mix-ligands strategy is highly efficient for the rational construction of MOFs with particular structure motifs and high porosity, yet challenging and requiring matching in hierarchical coordination assembly and synergetic crystallization. The solvothermal reactions of 1,3,5-tris[4-carboxyphenyl]benzene (H3btb) and 1,4-benzenedicarboxylic acid (H2bdc) with different 3d metal ions, generated highly porous mixed-ligands MOFs of [(CH3)2NH2]2[Mn3(btb)2 (bdc)]·12DMF·3MeOH (Mn-btb-bdc) having anionic 3D frameworks constructed from linear [Mn3(COO)8] nodes, [Co4(btb)2(bdc)(H2O)3]·15DMF·7H2O (Co-btb-bdc) processing neutral frameworks constituted by linear [Co3(COO)6(H2O)4] and paddle-wheel [Co2(COO)4(H2O)2] nodes, as well as one single-ligand MOFs of [(CH3)2NH2][Cd(btb)(H2O)]·8DMF (Cd-btb-2fold) exhibiting 2-fold interpenetrated ths net frameworks due to the unsuccessful introduce of the coexisted bdc ligand. Two new topology net of 2,3,8-connected net with point symbol of (42·6)2(44·66·812·105·12)(6) and 2,3,4,6-connected net with Point Symbol of (4·82)4(42·811·102)2(84·122)(82) were found for Mn-btb-bdc and Co-btb-bdc. All these three MOFs are highly porous with void fractions of 60.9%, 52.2% and 61.4%, stemming from 3D-penetrated, 3D-penetrated and 1D channels, respectively. Such structural differentiations are attributed to the diversified electronic structure and coordination preference of different 3d metal ions, as well as the solvent template and temperature effects. Two-steps gate-opening behaviour in gas sorption isotherms was found in the flexible Mn-btb-bdc MOFs.

Partial RNA design.

RNA design is a key technique to achieve new functionality in fields like synthetic biology or biotechnology. Computational tools could help to find such RNA sequences but they are often limited in their formulation of the search space. In this work, we propose partial RNA design, a novel RNA design paradigm that addresses the limitations of current RNA design formulations. Partial RNA design describes the problem of designing RNAs from arbitrary RNA sequences and structure motifs with multiple design goals. By separating the design space from the objectives, our formulation enables the design of RNAs with variable lengths and desired properties, while still allowing precise control over sequence and structure constraints at individual positions. Based on this formulation, we introduce a new algorithm, libLEARNA, capable of efficiently solving different constraint RNA design tasks. A comprehensive analysis of various problems, including a realistic riboswitch design task, reveals the outstanding performance of libLEARNA and its robustness. libLEARNA is open-source and publicly available at: https://github.com/automl/learna_tools.

REPRESENTATION OF THE GOSPEL CODE IN THE NOVEL “GETTING INTO CHARACTERˮ BY H.L. OLDIE THROUGH THE PRISM OF SHAKESPEARE’S THEATRICAL METAPHOR

In the presented study the novel “Getting into Characterˮ (1991) by Henry Lyon Oldie (the pen name of Dmytro Hromov and Oleh Ladyzhens’ky) is considered as a part of Hamlet`s text of modern Russian-language literature. The peculiarities of the representation of the Gospel code of the novel are analysed. They are conditioned by the author’s concept of the artistic world, which assumes the recreation of reality according to the stage laws. It is established that the transformation of the Gospel code in the novel occurs at the level of the image system (Actor-Hamlet-Christ, mentor/Master-Messiah, pupil/apprentice-follower, stage word as Logos, theatre as religion, abyss as unrealised creative work), motif structure (motifs of mentoring, faith, salvation and resurrection of the soul). The ideological and thematic content of the artistic work is changed (the theme of art and its Creator, the problem of faith and faithlessness, the idea of redemption of human sins – the humanistic mission of the protagonist). It is determined by the theatricality as the most important category of the novel`s poetics, underlying the construction of the artistic reality of “Getting into Characterˮ. Special attention is paid to the representation of Shakespearean theatrical metaphor, as well as to the intertextual connection of H.L. Oldie’s novel with Shakespeare’s “Hamletˮ tragedy.

Discovery of 1H-benzo[d]imidazole-(halogenated) Benzylidenebenzohydrazide Hybrids as Potential Multi-Kinase Inhibitors.

In an effort to develop improved and effective targeted tyrosine kinase inhibitors (TKIs), a series of twelve novel compounds with the structural motif "(E)-4-(((1H-benzo[d]imidazol-2-yl)methyl)amino)-N'-(halogenated)benzylidenebenzohydrazide" were successfully synthesized in three steps, yielding high product yields (53-97%). Among this new class of compounds, 6c and 6h-j exhibited excellent cytotoxic effects against four different cancer cell lines, with half-maximal inhibitory concentration (IC50) values ranging from 7.82 to 21.48 μM. Notably, compounds 6h and 6i emerged as the most potent inhibitors, demonstrating significant activity against key kinases such as EGFR, HER2, and CDK2. Furthermore, compound 6h displayed potent inhibitory activity against AURKC, while 6i showed potent inhibitory effects against the mTOR enzyme, with excellent IC50 values comparable with well-established TKIs. The mechanistic study of lead compound 6i revealed its ability to induce cell cycle arrest and apoptosis in HepG2 liver cancer cells. This was accompanied by upregulation of pro-apoptotic caspase-3 and Bax and downregulation of anti-apoptotic Bcl-2. Additionally, molecular docking studies indicated that the binding interactions of compounds 6h and 6i with the target enzymes give multiple interactions. These results underscore the ability of compound 6i as a compelling lead candidate warranting further optimization and development as a potent multi-targeted kinase inhibitor, which could have significant implications for the treatment of various cancers. The detailed structural optimization, mechanism of action, and in vivo evaluation of this class of compounds warrant further investigation to assess their therapeutic potential.