Drug resistance caused by single-point amino acid substitutions in target proteins represents a serious problem in modern therapy of oncological, infectious and viral diseases. This review systematizes modern computational modeling methods that allow studying the molecular mechanisms of such resistance and predicting its emergence. Contemporary databases and machine learning tools used for resistance prediction from genomic data are analyzed. The potential of the emerging direction of physics-informed artificial intelligence models for enhancing the interpretability of predictions is noted.
Objective: The spread of multidrug-resistant (MDR) strains significantly limits the efficacy of existing antibiotics and necessitates the development of new therapeutic approaches. This problem is particularly relevant for Gram-negative ESKAPE pathogens, especially MDR strains of Klebsiella pneumoniae. Antimicrobial peptides (AMPs) can be considered promising alternative antimicrobial agents with high activity against MDR pathogen strains. Furthermore, the development of approaches based on the combined action of multiple AMPs or combinations of AMPs with classical antibiotics will allow a multiple potentiation of their antimicrobial action due to the synergistic effect of antimicrobial agents. We aimed to evaluate the synergistic action of AMPs with orthogonal mechanisms of action against MDR clinical isolates of K. pneumoniae, and to explore the translation of these synergistic principles to potentiate the clinically relevant glycopeptide antibiotic vancomycin. Methods: We utilized a screening approach based on the recombinant production of a panel of AMPs in the methylotrophic yeast Pichia pastoris to identify synergistic interactions. Promising synergistic combinations were subsequently validated in vitro using the checkerboard assay against clinical MDR isolates of K. pneumoniae. Results and Discussion: While individual recombinant AMP producers showed limited activity against clinical K. pneumoniae isolates, combining AMPs with distinct molecular targets resulted in pronounced synergistic effects. Unlike combinations of two membranolytic AMPs, pairing the membrane-disrupting peptide cecropin P1 with thanatin (an inhibitor of lipopolysaccharide transport) demonstrated true antimicrobial synergy, reducing individual minimum inhibitory concentrations fourfold. Furthermore, cecropin P1 effectively potentiated vancomycin (an antibiotic naturally inactive against Gram-negative bacteria), sensitizing MDR K. pneumoniae strains to this agent. Conclusions: Our findings demonstrate that combining orthogonal antimicrobial agents targeting at the membrane and cell wall components yields a universal synergistic effect. This approach provides a robust framework for developing highly effective antimicrobial regimens based on peptide synergy and the sensitization of MDR pathogens, thereby expanding the therapeutic spectrum of clinically vital antibiotics against drug-resistant infections.
Objective: This study evaluates established low-molecular-weight activators of lysozyme and reports a novel lysozyme-based antibacterial composition containing charged amino acids and a pharmaceutically acceptable surfactant. These compounds exhibit biocompatibility and safety, both individually and in combination. Methods: The bacteriolytic effect of the composition was tested on live bacteria from various families, specifically, Micrococcus luteus (non-pathogenic Gram-positive cocci with some similarity in cell wall structure to pathogenic streptococci and staphylococci), Escherichia coli (a Gram-negative rod-shaped bacterium, a non-pathogenic analogue of the causative agents of salmonellosis, typhoid fever, bacterial dysentery, and plague), and Priestia megaterium (spore-forming Gram-positive bacilli, a non-pathogenic analogue of the causative agent of anthrax). Results and Discussion: This antibacterial composition can be used to kill bacteria on various surfaces in public places and at home, including antibiotic-resistant bacteria, since the mechanism of its antibacterial action is fundamentally different from that of antibiotics. Conclusions: The constituents of the proposed antibacterial composition also have the potential to be developed into food supplements. Our findings provide a basis for enhancing the antibacterial activity of lysozyme within the body, both in extracellular biological fluids and within the lysosomes of immune cells, which are responsible for the destruction of pathogenic cells and antigen presentation, followed by the regulation of antibody synthesis.
Antimicrobial resistance (AMR), or antibiotic resistance of microorganisms, is becoming a global threat to healthcare, and strains with multidrug resistance (MDR) pose significant challenges for drug development programs. New mechanisms of antimicrobial traits render existing drugs ineffective, leading to prolonged illnesses and increased costs. The misuse of traditional and widely available antibiotics in healthcare, hygiene, veterinary medicine and agriculture is the main reason for the evolution, maintenance and alarming rate of spread of antimicrobial resistance. The continuing decline in antibiotic efficacy exacerbates the situation, necessitating urgent efforts by the global community aimed at developing innovative antibacterial drugs and treatments for infections caused by MDR pathogens. In addition to various natural and synthetic agents currently undergoing preclinical and clinical testing, secondary plant metabolites, or phytochemicals, are proving effective in combating drug-resistant strains. Various phytochemicals from classes such as alkaloids, phenolic derivatives, terpenoids, coumarins, organosulfur compounds and polypeptides have successfully demonstrated their antibacterial potential against MDR pathogens. Phytochemicals have been shown to be effective against molecular factors such as membranes, proteins, biofilms, efflux pumps and bacterial cell communication. However, despite promising results, further in-depth studies are needed to implement these approaches in clinical practice. The review examines successful examples, current challenges and prospects for the further application of phytochemicals in combating antimicrobial resistance of microbial pathogens.
Objective: A novel fluoroquinolone (PFQA) with biological activity was developed and obtained via a four-step synthesis. This study aimed to characterize its interaction with human serum albumin (HSA) and compare its binding efficiency and mechanism with other representatives of the fluoroquinolone class. Methods: The compound of interest was obtained by a four-step synthesis. Spectroscopic methods (fluorescence, FTIR, CD, etc.) were utilized to investigate PFQA complex formation with HSA. Results and Discussion: PFQA demonstrates moderate binding affinity to human serum albumin (Kbinding = 3 × 102 M–1) at site II (subdomain IIIA), as shown by fluorescence spectroscopy. According to thermodynamic parameters, the new compound forms a complex with the protein primarily through hydrophobic interactions. The introduction of a bulky hydrophobic substituent at position 3 of the fluoroquinolone does not cause significant conformational changes in albumin. The obtained results were compared with data for known representatives of fluoroquinolones of different generations in terms of the most important physicochemical and biological properties that must be considered for the design of new drug molecules. Conclusions: The characteristics obtained for PFQA correspond to the parameters of the fluoroquinolones used, suggesting similar pharmacokinetic parameters in vivo.
Objective: The rise of antibiotic resistance among bacterial pathogens poses a critical threat to modern medicine, driving the need for novel chemical scaffolds to develop antibacterial drugs with original mechanisms of action. Although arylidene-imidazolones, which form the structural core of the green fluorescent protein (GFP) chromophore, are widely used in bioimaging, their potential as drug precursors remains poorly understood. This work aimed to screen a library of 584 arylidene-imidazolone derivatives to identify compounds targeting bacterial replication and translation. Methods: Primary screening was conducted using the pDualRep2 reporter system and antibiotic-hypersensitive Escherichia coli strains. This approach enabled the simultaneous assessment of antibacterial activity and the collection of preliminary data on the mechanism of action. Based on these results, six candidate compounds were selected for subsequent mechanistic evaluation. Results and discussion: It was established that compounds I and II inhibit DNA polymerase I, whereas compounds IV–VI suppress bacterial translation in a cell-free system. Conclusions: The obtained results demonstrate that the arylidene-imidazolone framework represents a promising scaffold for the development of novel antibacterial agents.
The global expansion of antimicrobial resistance poses a formidable threat to public health. Ongoing bacterial evolution and phenotypic adaptation progressively render conventional antimicrobial strategies resource-intensive and less efficacious, while concurrently exacerbating treatment-associated adverse effects. Consequently, there is an imperative demand to refine existing therapeutic modalities, implement synergistic combinations, and pioneer fundamentally novel strategies to combat infections precipitated by multidrug-resistant pathogens. This review delineates the primary molecular mechanisms governing bacterial resistance and underscores the clinical impact of key infectious diseases. The cornerstone of this work lies in a comprehensive analysis of both canonical and innovative paradigms in antibacterial therapy. By synthesizing state-of-the-art scientific data, this paper provides a definitive perspective on the most promising frontiers in infectious disease management.
Objective: Using neural networks, we previously identified linear fragments of spider venom peptides active against methicillin-resistant Staphylococcus aureus (MRSA). Among them, peptide IX (IWLSLMKFAGKHL-NH2) with a C-terminal amide displayed high antibacterial potency, whereas its non-amidated analogue, peptide X, was inactive. Peptide IX incorporates into zwitterionic multilamellar liposomes of dioleoylphosphatidylcholine (DOPC) without disrupting them, and also into anionic liposomes of dioleoylphosphatidylglycerol (DOPG) mimicking the MRSA cell membrane, leading to bilayer disruption. This study aims to elucidate the reasons for peptide X inactivation. Methods: According to ¹H NMR spectroscopy, peptide X in water is governed by the ionization of the His12 residue. ³¹P NMR data show that peptide X interacts with DOPC and DOPG membranes. Monte Carlo simulations revealed conformational differences between peptides IX and X upon interaction with an implicit membrane model. Results and Discussion: At pH 7.0 (net charge +2), peptide X aggregates, whereas at pH 5.0 (charge +3), it is monomeric. In contrast, peptide IX (+3 at pH 7.0 and +4 at pH 5.0) does not aggregate in this pH range. ³¹P NMR data show that peptide X has a weaker effect on bilayer packing than peptide IX and does not disrupt the bilayer in either case, consistent with its lack of anti-MRSA activity at pH 5–7. Monte Carlo simulations revealed conformational differences between peptides IX and X. We propose that the inactivation of peptide X arises from both reduced affinity and suboptimal binding to anionic bilayers, driven by aggregation in solution and weaker electrostatic peptide–membrane interactions. Conclusions: Thus, C-terminal amidation is a key modification required for anti-MRSA activity of short linear antimicrobial peptides.
Objective: The animal oral microbiota represents a promising reservoir of microorganisms that produce antimicrobial metabolites and compounds capable of modulating bacterial antibiotic sensitivity. Here, we aimed to screen the oral microbiota of alpacas to identify microbial strains exhibiting antimicrobial activity against Gram-negative and Gram-positive bacteria, fungi, and yeasts. Methods: To dissect the underlying antimicrobial mechanisms, we selected Pseudomonas isolates that displayed targeted activity against Gram-negative bacteria and subjected them to metabolomic profiling. Results and Discussion: The analysis revealed that this antimicrobial activity is driven by the production of pyoluteorin, a membrane-active metabolite. Although pyoluteorin alone exhibited limited antimicrobial efficacy, it strongly potentiated the action of clinically relevant antibiotics. Notably, at a sub-cytotoxic concentration of 1.5 μg/mL (IC50 = 2.0 ± 0.3 μg/mL), pyoluteorin sensitized antibiotic-resistant Klebsiella pneumoniae strains, enhancing their susceptibility to the membrane-disrupting antibiotic polymyxin B by an order of magnitude. Conclusions: The future development of bacterio-selective membrane-active agents will facilitate the deployment of such synergistic approaches for the emergency treatment of infectious diseases caused by multidrug-resistant pathogens.
Objective: Candida albicans is a critical priority fungal pathogen and one of the most common causes of invasive candidiasis in immunocompromised patients. The high toxicity of existing antifungals and the spread of drug-resistant fungi create a need for new agents, for which antimicrobial peptides (AMPs) with both antifungal and immunomodulatory effects are promising candidates. Methods: In this study, we used real-time PCR and sandwich ELISA to investigate the immunomodulatory effects on epithelial and immune cells of the tobacco defensin NaD1, which exhibits fungicidal activity against C. albicans, as well as its modified analogs NaD1-2, NaD1-3, and NaD1-4 with reduced cytotoxicity. Results and Discussion: We demonstrate that NaD1 exerts immunomodulatory effects on a Caco-2 cell monolayer modeling the human intestinal epithelial barrier, and its action differs from that of the human β-defensin HBD2. In the absence of infection, NaD1 at a concentration of 2 μM activates epithelial immune defense after 4 h of cell stimulation by upregulating the expression of genes encoding CXCL8, cathelicidin LL-37, and the patternrecognition receptors Dectin1 and TLR9, while not affecting IL-1β production. Under C. albicans infection, NaD1 predominantly exhibits antiinflammatory properties. In contrast, the effect of HBD2 becomes pronounced upon prolonged stimulation (24 h) and is proinflammatory both in the presence and absence of infection. Furthermore, unlike the tobacco defensin, the modified NaD1 analogs show virtually no immunomodulatory effects and do not affect IL-1β production by THP-1-derived macrophages. Finally, the TLR2 inhibitor C29 and the TLR4 inhibitor C34 reduce the stimulatory effect of NaD1 on IL-1β production by macrophages. Conclusions: Thus, the tobacco defensin NaD1, unlike its modified analogues, exhibits immunomodulatory activities on human epithelial and immune cells, and the TLR2 and TLR4 receptors may be involved in mediating these effects.
The widespread prevalence of antibiotic-resistant pathogenic microorganisms that cause infectious diseases in humans and animals severely limits the possibilities of chemotherapy. Large families of enzymes play a key role in the various mechanisms of bacterial antibiotic resistance; in particular, resistance to β-lactam antibiotics in Gram-negative pathogens is due to the production of β-lactamases involving serine hydrolases and metalloenzymes. Due to the high cost of developing new antibacterial drugs, the main approach to overcoming bacterial antibiotic resistance is to combine β-lactams with β-lactamase inhibitors. This review analyzes information about two generations of inhibitors of this superfamily of enzymes: first-generation inhibitors are structural analogs of β-lactams and inhibit only class A serine β-lactamases. Second-generation inhibitors include compounds of the diazabicyclooctane class and boronic acid derivatives. They form complexes with β-lactamases that mimic the structure of acyl-enzyme complexes with antibiotics or the structure of the transition state of these complexes. Second-generation inhibitors are characterized by broader inhibitory specificity compared to first-generation inhibitors. Derivatives of cyclic boronic acids (oxoborines) have the broadest specificity for serine and metallo-β-lactamases. The development of new combinations of antibiotics with inhibitors that target various β-lactamases will restore the therapeutic efficacy of β-lactam antibacterial agents.
Objective: Bacterium Curtobacterium flaccumfaciens pv. flaccumfaciens is a Gram-positive pathogen causing bacterial wilt and tan spot of legumes. Organic agriculture requests for new biosafe antibacterials that can specifically target pathogenic bacteria without depressing beneficial bacterial bioadditives. Endolysin gp11 of the Curtobacterium phage Ayka could potentially be an active component of the new antibacterial agent to prevent wilt caused by Curtobacterium flaccumfaciens pv. flaccumfaciens. The goal of this work was to produce its recombinant form and to carry out an investigation of its biochemical properties. Methods: We performed bioinformatic analysis of phage Ayka lytic enzyme gp11 and obtained the expression construct based on the vector pEEva2 carrying the gp11 gene. This construction was used to transform Escherichia coli BL21(DE3)pLysS cells. Active purified form of endolysin gp11 was obtained as a result of combination of biomass extract fractionation with ammonium sulfate precipitation with subsequent metal-chelate chromatography of fractions containing target protein on Co-IDA-agarose. Bacteriolytic activity of gp11 was characterized by turbidimetry. Results and Discussion: Accumulation of the target enzyme occurred predominantly in insoluble form in inclusion bodies. The fraction of the active soluble form of the enzyme increased under lowtemperature conditions of protein synthesis. After purification the enzyme demonstrated high bacteriolytic activity against C. flaccumfaciens in a wide range of pH. Gp11 exhibited a wider range of activity compared to phage Ayka while remaining specific to the Curtobacterium genus. Conclusions: We obtained and characterized a recombinant form of Curtobacterium phage Ayka endolysin gp11. Its high activity and specificity can potentially help it find use as an antibacterial agent to prevent C. flaccumfaciens infections in legumes.
Microbial resistance to drugs and the search for ways to overcome it are a global public health problem. It has now been established that the venoms of snakes from various families and genera are capable of suppressing the proliferation and killing resistant species and strains of microorganisms. This review focuses on the components of snake venom (toxins) that exhibit pronounced antimicrobial activity against pathogenic bacteria, fungi, and protozoa with known drug resistance, with indication of the resistant species and strain. The antimicrobial activity of enzymatic toxins (phospholipases A2, including enzymatically inactive homologues, L-amino acid oxidases, and metalloproteinases), toxins lacking enzymatic activity (proteins of the CRISP family, C-type lectins, and lectin-like proteins), polypeptides (three-finger toxins and Kunitz-type serine proteinase inhibitors), and cationic peptides (cathelicidins, crotamine, and omwaprin) is discussed. The problems of using snake venom toxins with antimicrobial activity and approaches to solve these problems are considered. Methods for increasing the efficacy and reducing the toxicity of such compounds are proposed: the use of bioinformatics and molecular modeling methods to identify active fragments of the molecule and design more effective synthetic analogues, encapsulation and nanoencapsulation. The immunomodulatory properties of toxins and their synergistic action with other antimicrobial substances are noted. Although currently the use of snake venom toxins is primarily at the research stage, they represent a promising reserve for the creation of new types of antimicrobial drugs capable of overcoming microbial resistance.
Objective: The rise of antibiotic resistance necessitates exploring natural antimicrobial peptides like bacteriocins. This study aimed to investigate the anti-adhesive and anti-biofilm activities of acidocin A from Lactobacillus acidophilus against clinically relevant pathogens and its synergistic potential with nisin and human defensin HD-5. Methods: Recombinant peptides were obtained via heterologous expression in Escherichia coli. Anti-adhesive activity against Candida albicans was assessed on polystyrene using MTT assays and on Caco-2 monolayers by colony counting. Biofilm inhibition was tested against fungal and bacterial isolates, using resazurin and crystal violet, correspondingly. Synergy between the peptides was analyzed using checkerboard assays. Results and Discussion: Acidocin A inhibited C. albicans adhesion to polystyrene and Caco-2 model of intestinal epithelium. It effectively prevented biofilm formation by C. albicans and a number of bacterial strains, with inhibitory concentrations generally matching MICs. However, the peptide was inactive against mature biofilms. An additive effect of the peptide with human defensin HD-5 and acidocin 8912 was revealed. More importantly, acidocin A displayed synergism with nisin against E. coli (FICI 0.25–0.375), likely by permeabilizing the outer membrane to facilitate nisin entry. Conclusions: This study provides the first evidence of acidocin A’s anti-adhesive properties and efficacy in preventing biofilm formation by resistant pathogens. Its ability to synergize with nisin against Gram-negative bacteria highlights its potential for prophylactic and combination therapies.
At present, antibiotics remain widely administered to prevent bacterial infections in livestock. Therefore, antibiotics and their metabolites inevitably contaminate target food products, specifically meat and milk. This trend promotes the development of bacterial resistance, either multidrug or pandrug, across all therapeutic classes. This review presents a systematic examination of endogenous antibacterial factors in mammals, comparing their profiles and combined action in blood and milk. Lysozyme and lysozyme-related proteins, transferrins, antibacterial cationic peptides, milk protein hydrolysis products, and other endogenous agents are considered. These classes of antibacterial factors share two structural features: a net positive charge and the presence of hydrophobic (primarily aromatic) functional groups. Although their mechanisms of action against bacteria vary, both the synthesis and activity of these factors are strictly regulated by the host immune system. These structural properties and biochemical hallmarks facilitate the development of therapeutic agents based not only on xenobiotics but also on endogenous mammalian metabolites. More in-depth study of the antibacterial activity of proteins and peptides in both mammalian milk and blood is required to develop viable alternatives to conventional antibiotics.
Objective: To address the global threat of multi-drug resistant tuberculosis (MDR-TB), which compromises roughly 20
Triazole-thiazole hybrids represent highly privileged scaffolds in medicinal chemistry, characterized by exceptional structural versatility and a broad spectrum of pharmacological profiles, including anticancer, antimicrobial, antidiabetic, and anti-inflammatory activities. This review provides a critical overview of recent advancements in the synthesis, structure–activity relationships (SAR), and therapeutic applications of these dual-heterocyclic frameworks. We highlight strategic methodologies for integrating triazole and thiazole cores with complementary pharmacophores to enhance potency, optimize pharmacokinetic profiles, and circumvent multi-drug resistance. Furthermore, current optimization bottlenecks and emerging computational paradigms are systematically evaluated. Ultimately, this survey delineates key design principles for leveraging the modularity of triazole-thiazole scaffolds in the development of next-generation, multi-target directed ligands (MTDLs) against complex etiologies.
Objective: Herein, we describe a facile and efficient protocol for the synthesis of bioactive 2-amino-3,5-dicarbonitrile-6-sulfanylpyridines via a one-pot, multicomponent reaction of aldehydes, malononitrile, and thiophenols. The transformation is catalyzed by mild, readily accessible copper(II) triflate in an environmentally benign aqueous medium. Methods: The antimicrobial efficacy of the title compounds was evaluated against select bacterial and fungal strains using disc diffusion and minimum inhibitory concentration (MIC) assays. Advanced computational tools were deployed for comprehensive molecular docking and toxicogenomics profiling. Ensemble docking simulations were performed to elucidate the binding modes and affinity of the leading candidates within the active sites of glucosamine-6-phosphate (GlcN-6-P) synthase (PDB IDs: 2VF5 and 2POC). Results and Discussion: In vitro assays revealed robust antimicrobial activity, with derivatives 4i, 4e, 4d, and 4j exhibiting exceptional potency that outperformed or closely matched standard antibiotics. In silico ADMET evaluations validated that these target scaffolds possess highly promising drug-like attributes, optimal pharmacokinetic parameters, and clear compliance with established drug-likeness rules. Conclusions: The seamless integration of green synthesis, computational modeling, and biological validation highlights these 2-amino-3,5-dicarbonitrile-6-sulfanylpyridine hybrids as compelling lead candidates for multi-target therapeutic applications against invasive bacterial and fungal infections.
Objective: The objective of this study was to design, synthesize, and evaluate the antibacterial efficacy of a novel library of hybrid heterocycles structuralized around a bio-sourced, O-alkylated vanillin framework to expand the chemical space of available antimicrobial agents. Methods: O-Alkylated vanillin (I) was functionalized through two divergent synthetic pathways. First, Knoevenagel condensation of I with diverse active methylene heterocycles yielded ylidene derivatives (II–V). Second, condensation of I with thiosemicarbazide afforded thiosemicarbazone (VI), which subsequently underwent regioselective cyclization with various active halo-compounds to generate thiazole derivatives (VII–IXa–IXe). Semicarbazone analogue (X) was synthesized using an optimized base-catalyzed method to evaluate comparative reactivity. All newly synthesized hybrids were evaluated in vitro for their antibacterial activity against Gram-positive (Staphylococcus aureus, Bacillus cereus) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) strains via the agar diffusion assay. Results and Discussion: A library of novel vanillin-centered hybrid heterocycles was successfully synthesized and structurally validated by IR and NMR spectroscopies. Chemical reactivity profiling revealed that while thiosemicarbazone VI readily underwent cyclization to form the corresponding thiazoles, the semicarbazone analogue X remained chemically refractory to cyclization under identical conditions. Antibacterial screening demonstrated potent, concentration-dependent inhibitory profiles across the synthesized derivatives. Notably, hybrid ylidene V, incorporating a thiazolo[3, 2-a]benzimidazol-3(2H)-one moiety, exhibited exceptional broad-spectrum antibacterial efficacy, consistently outperforming the other functionalized derivatives. Conclusions: Conjugating a bio-sourced vanillin core with tailored heterocyclic scaffolds provides a robust chemical strategy to enhance antimicrobial potency. The structurally optimized hybrid V represents a compelling lead candidate for the development of next-generation broad-spectrum antibacterial agents.
Objective: Malignant neoplasms remain a paramount global challenge, imposing severe socioeconomic costs and high morbidity and mortality rates worldwide. To address the urgent demand for novel therapeutics, this study focuses on the development of new heterocyclic architectures—specifically pyrazole and acyl hydrazone derivatives—designed to modulate key oncogenic signaling pathways and act as compelling chemotherapeutic candidates. Methods: A novel series of pyrazole and acyl hydrazone derivatives was synthesized and evaluated in vitro for their cytotoxic profiles against HepG2, HCT-116, MCF-7, and A549 human cancer cell lines utilizing the MTT assay, with doxorubicin serving as the reference drug. To evaluate their electronic properties and chemical stability, density functional theory (DFT) computations were performed. Furthermore, molecular docking simulations were executed against Aurora A kinase (PDB ID: 5EW9) and PDZ-binding kinase (PDB ID: 5J0A) to elucidate their binding modes and potential as targeted kinase inhibitors. Results and Discussion: Specifically, IVd and Vc yielded IC50 values of 32.17 and 34.43 µM against HepG2, 11.37 and 13.56 µM against HCT-116, 24.39 and 27.51 µM against MCF-7, and 56.36 and 62.13 µM against A549 cells, respectively, displaying potencies comparable to or exceeding that of doxorubicin. DFT computations revealed optimized frontier molecular orbital profiles, where the calculated HOMO–LUMO energy gaps rationalized the observed chemical stability and electronic properties. In docking studies, compound IVd exhibited a robust binding affinity of –7.7 kcal/mol within the active pocket of Aurora A kinase, whereas Vc demonstrated a binding energy of –7.6 kcal/mol toward PDZ-binding kinase. Conclusions: Collectively, these findings underscore the potential of these dual scaffolds as targeted kinase inhibitors. The demonstrated cytotoxicity and molecular interaction profiles offer a valuable structural and electronic rationale for the design of next-generation anticancer therapeutics.
