The emergence of multidrug-resistant Candida strains especially, Candida auris, C. dubliniensis, and C. inconspicua has accelerated the research on antifungal novel molecules. Sesquiterpene lactones, abundant in the Asteraceae family, have drawn attention with their antifungal activity. Therefore, three extracts obtained from the aerial part of Turkish endemic Centaurea polypodiifolia were investigated against Candida albicans (ATCC 90028), C. krusei (ATCC 6258), C. dubliniensis (NCPF 3949a), C. inconspicua (NCPF 8523), and C. auris (NCPF 8977) and gave MIC values between 6.25 and 12.5 mu g/mL. Dichloromethane (DCM-M) extract yielded five known (cynaropicrin, cynarinin A, aguerin B, grosheimin, and dehydrocynaropi-crin) and one novel (nourolide) guaianolide-type sesquiterpene lactones. Two semi-synthetic cynaropicrin derivatives were obtained to enhance the molecular diversity of the present study. 1D (1H and 13C APT) and 2D (COSY, HSQC, HMBC, and NOESY) NMR experiments were employed for structure elucidation. MIC values of the tested sesquiterpene lactones against the above-mentioned strains ranged between 3.12 and 50 mu g/mL. Molecular dynamics simulations were conducted to investigate the interaction of 4 (aguerin B), which demon-strated the highest antifungal activity, with the exo-beta-(1,3)-glucanase and 14-alpha-demethylase enzymes. These findings revealed stable binding interactions, suggesting that aguerin B has potential as a lead for further antifungal drug development.

In aqueous media, enzyme–ligand recognition is shaped not only by direct contacts but also by solvent-mediated interaction networks that persist across time scales. Here, cholinesterases (AChE and BChE) and cytosolic human carbonic anhydrases (hCA I and hCA II) were investigated as two disease-relevant enzyme systems in solution, and twelve thiourea–pyrimidine benzenesulfonamide derivatives were synthesized and structurally characterized. Enzyme inhibition was quantified by steady-state kinetics; inhibition constants (KI) were obtained by nonlinear global fitting of untransformed rate data, with Lineweaver–Burk plots used only for visualization. To connect solution-phase inhibition with molecular recognition, docking was validated by redocking (heavy-atom RMSD <2.0 Å across targets), and representative complexes were examined by 500 ns explicit-solvent MD simulations (TIP3P, 0.15 M NaCl, NPT), revealing stable binding modes and persistent, frequently water-mediated interaction patterns consistent with experimental trends. Cellular relevance was assessed in MKN-28 gastric cancer cells with L929 fibroblasts as a non-malignant control. Compounds with improved cytotoxic selectivity toward MKN-28 were identified, and the lead compound (11) was further evaluated by Annexin V/PI flow cytometry, showing a shift from viable cells toward apoptotic populations under the tested conditions. In silico ADMET profiling suggested moderate lipophilicity across the series, while highlighting elevated polar surface area and compound-dependent toxicity flags as parameters to monitor during optimization. Overall, thiourea–pyrimidine benzenesulfonamides emerge as multifunctional modulators of ChEs and cytosolic hCAs within the applied biochemical and cellular assays.

INTRODUCTION:Recent studies have reported a correlation between SRC and EGFR as key factors contributing to tumor aggressiveness in cancers, such as glioblastoma, colon, breast, and lung cancers. Resistance to therapy remains a major obstacle in cancer treatment. Therefore, the discovery of novel compounds with inhibitory potential is crucial. In this study, urea- and pyrimidine-containing compounds structurally similar to osimertinib were designed as potential inhibitors of both SRC and EGFR kinases, with the aim of identifying compounds that may also overcome resistance conferred by mutations. METHODS:The compounds were synthesized through the development of new synthetic routes. Their structure-activity relationships (SAR) were evaluated using in vitro enzyme inhibition assays, cell culture experiments, molecular docking, and molecular dynamics studies. RESULTS:Compounds 19, 20, and 21, which bear substitutions at the third position of the indole ring, inhibited SRC kinase with 77.75-89.22% activity. These compounds also demonstrated notable cytotoxicity against the PC3 cell line, with IC50 values of 7.89, 6.92, and 9.85 μM, respectively, comparable to reference compounds cisplatin (IC50 = 5.16 μM) and dasatinib (IC50 = 0.9 μM). Notably, compound 20 was active against both EGFR and SRC kinases, with IC50 values of 3.91 μM and 0.00058 μM, respectively. Compound 20 also exhibited the strongest cytotoxic effect on prostate cancer cells (IC50 = 6.92 μM). Further analyses indicated that compound 20 induced apoptosis in cancer cells by increasing the levels of caspase-3, caspase-8, and Bax, while reducing Bcl-2 expression. Molecular docking and dynamics studies revealed strong interactions of compound 20 with the target receptors. DISCUSSION:Docking and biological activity studies indicated that compound 20 (1-(2- Fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidine-2-yl)amino)phenyl)-3- phenylurea) is a promising dual inhibitor of both EGFR and SRC kinases. In silico analyses further support the potential therapeutic efficacy of compound 20. CONCLUSION:Overall, compound 20 emerged as the most promising candidate from this study, warranting further investigation for its therapeutic potential.

Caspase-1 is a crucial inflammatory cysteine protease that facilitates the maturation of pro-inflammatory cytokines such as interleukin-1β and interleukin-18, making it a significant therapeutic target for inflammatory diseases. However, existing caspase-1 inhibitors often face challenges like toxicity and suboptimal drug-like properties, underscoring the need for new inhibitors. This study employed an integrated computational strategy, combining quantitative structure–activity relationship (QSAR) modeling and application of this validated model to a large natural product database followed by molecular docking, rigorous binding free energy analysis and extended molecular dynamics simulations. Initially, a dataset of 185 caspase-1 inhibitors with experimentally reported pKi values (ranging from 4.05 to 9.24) was used to construct a QSAR model using Partial Least Squares (PLS) regression. The PLS-based QSAR model was developed with 18 descriptors out of 5799 calculated descriptors for each compound and 10 latent variables, demonstrating strong statistical performance with R2 values of 0.870 and 0.838 for the training and test sets, respectively, and leave-one-out cross-validation coefficient Q2LOO and 5-fold cross-validation (Q25-fold) values of 0.819 and 0.814, respectively. Y-randomization tests further confirmed the model’s robustness, as the randomized models exhibited significantly lower statistical parameters than the original model. The validated QSAR model was applied to 276,518 natural products in the LOTUS database. Subsequent molecular docking, Molecular Mechanics/General Born Surface Area (MM/GBSA) scoring, and Pan-Assay INterference Compounds (PAINS) and Chemical Frequent Hitter (ChemFH) filtering identified 14 candidate compounds, which were further evaluated using 300 ns molecular dynamics simulations. Among these, four natural products (LTS0162325, LTS0221286, LTS0016840, and LTS0070407) showed the most stable binding behavior and maintained persistent interactions with key catalytic and substrate-binding residues of caspase-1 in a mimicked physiological condition. Overall, this study highlights natural diterpenoids and coumarin glycosides as promising scaffolds for caspase-1 inhibition and demonstrates that integrating QSAR modeling with structure-based approaches provides an efficient strategy for discovering potential anti-inflammatory drug candidates.

Cat scratch disease (CSD), primarily caused by Bartonella henselae and Bartonella clarridgeiae, presents a global zoonotic concern, particularly in immunocompromised individuals. Conventional antibiotics offer limited protection, necessitating novel preventive strategies. Also, CSD is still one of the most prevalent infections brought on by Bartonella genus. The current study aimed at developing a multi-epitope peptide vaccine by targeting conserved antigenic proteins (Pap31, Omp43, and Omp89) from two Bartonella species utilizing immunoinformatics techniques. Comprehensive immunoinformatics analyses including antigenicity, allergenicity, solubility, and post-translational modification assessments were conducted. The selected epitopes with high antigenicity and non-allergenic, non-toxic properties were fused using appropriate linkers and an adjuvant. The vaccine construct was modeled in 3D, refined, and validated via Ramachandran and ERRAT analyses. Molecular docking followed by molecular dynamics simulations demonstrated strong interaction and structural stability with TLR2 receptor in a mimicked biological environment. Moreover, immune simulations showed strong stimulation of B and T cell responses, elevated IgM and IgG levels, and increased IFN-γ production. These preliminary in silico findings suggest a promising multi-epitope peptide vaccine candidate with a cross-protective potential against both B. henselae and B. clarridgeiae pathogens causing the zoonotic cat scratch disease in humans.

Extracellular exo-β-(1,3)-glucanase is among the cell-wall enzymes that play important roles in cell-wall synthesis. Many antimicrobial agents act by targeting those specific enzymes to inhibit bacterial or fungal cell wall formation. In this context, we aimed to synthesize a novel series of N-substituted-2-[3-(methylsulfonyl)-2-oxoimidazolidine-1-carbonyl]hydrazine-1-carbothioamide derivatives (1-16). The structures of the synthesized compounds (1-16) were elucidated by using spectroscopic methods such as IR, 1H NMR, 13C NMR, 13C APT NMR, and 2D NMR, as well as elemental analysis data. All thiosemicarbazide compounds (1-16) were screened for antimicrobial activity against seven bacteria (Staphylococcus aureus, MRSA, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecalis) and three fungi (Candida albicans, Candida tropicalis, and Candida parapsilosis) strains. Among the compounds, 3 and 14 demonstrated the highest antibacterial activities against S. aureus with the MIC values in the range of 156.24-312.5 µg/mL. On the other hand, compound 9 showed the strongest antifungal activity in the series against all three fungi strains, with the MIC values in the range of 39.06-312.5 µg/mL. Furthermore, compound 9 was found to successfully bind to exo-β-(1,3)-glucanase using molecular docking and dynamics simulations run for 500 ns. The physicochemical, pharmacokinetic, and ADMET properties of compounds were also investigated and analyzed by in silico programs.

Despite significant advances in cancer therapy, the discovery of new anticancer agents with improved efficacy remains an important challenge. Human DNA topoisomerases I and II are well-established therapeutic targets because of their essential roles in DNA replication and transcription. Accordingly, a series of novel etofenamate-based thiosemicarbazide, 1,3-thiazole, and 1,3,4-oxadiazole derivatives were designed and synthesized, including a new synthetic approach for the preparation of the oxadiazole derivatives, and evaluated as potential topoisomerase-targeting anticancer agents. All synthesized compounds were structurally characterized and evaluated for antiproliferative activity against the A549 human lung cancer cell line and for their inhibitory effects on human DNA topoisomerases I and II. Based on their overall biological performance, compounds 3h, 5 h, and 5i were selected for further biological characterization, including thioredoxin reductase 1 (TrxR1) inhibition, total oxidative status (TOS), Bax/Bcl-2 protein expression, Annexin V analysis, and crystal violet staining. Molecular docking studies were performed to investigate the binding modes of the lead compounds toward topoisomerases I and II. Biological evaluation identified compounds 3 h, 5h, and 5i as the most promising derivatives. Enzymatic assays revealed distinct topoisomerase inhibition profiles, with compound 5h acting as a selective topoisomerase I inhibitor and compound 5i exhibiting dual inhibitory activity against topoisomerases I and II. Molecular docking analyses supported these findings by revealing target-specific binding modes consistent with the observed inhibition profiles. Complementary cellular studies demonstrated TrxR1 inhibition, increased oxidative stress, apoptosis-associated cellular responses, and morphological alterations, providing additional mechanistic characterization of the lead compounds. Collectively, these findings establish topoisomerases I and II as relevant molecular targets for the synthesized series while broadening the biological characterization of the lead compounds through complementary cellular investigations. Compound 5i emerged as the most promising dual topoisomerase I/II inhibitor and represents a valuable lead for the further development of novel topoisomerase-targeting anticancer agents.

Aldose reductase (ALR2; AKR1B1) is implicated in hyperglycemia-driven tissue injury and remains a tractable enzymatic target. We developed a concise, chromatography-free two-step route to phthalimide-benzoic acid hybrids (5a-5m) and profiled their biochemical activity against human ALR2. Across the series, halogenated analogs were most active, with the para-bromophenyl derivative 5d emerging as the top hit (KI = 7.56 nM). Steady-state kinetic analysis indicated a competitive inhibition mechanism. Molecular docking to the ALR2 active site (PDB 4JIR), supported by MM-GBSA rescoring, yielded a catalytically consistent binding mode featuring hydrogen-bonding within the anion-binding region (Tyr48, His110) and complementary hydrophobic contacts (Trp111, Trp219), with Cys298 contributing as a proximal hydrophobic contact. In cell-based assays (A549, Hep3B, L929), the compounds generally showed low intrinsic cytotoxicity at the tested concentrations, suggesting a favorable preliminary safety margin aligned with their ALR2-directed pharmacology. In silico ADME/Tox assessments further supported oral drug-likeness. Overall, these results identify phthalimide-benzoic acid hybrids as tractable ALR2 inhibitor scaffolds that combine potent biochemical inhibition with a competitive kinetic profile and encouraging early safety signals, warranting in vivo evaluation and SAR-guided optimization.

Phospholipid conjugates consist of functionally different classes of molecules: phospholipid drug conjugates, fluorescent lipid probes and lipid molecular motors. All these conjugates are molecules that bear a functional group– a drug, a fluorophore or a molecular motor attached to the phospholipid. The conjugation is needed to incorporate a functional group into the lipid bilayer of liposome or lipid nanoparticle and thus, either modulate the effect of the drug or bring a new function to the liposome. Here, using NMR spectroscopy and quantum chemistry calculations, we show that phospholipid conjugates can form intramolecular π-cation complexes between quaternary ammonium group of the phosphatidylcholine and aromatic ring of the conjugated moiety. We also report on how to avoid the π-cation complex formation. If the linker between the aromatic moiety and the choline group is long enough the formation of π-cation complex is not observed.

The indane scaffold, prevalent in bioactive natural products, underpins numerous therapeutics. Our group developed a series of 1,2-indane dimers, including PH46A (9), for inflammatory and autoimmune diseases. This study details the design, synthesis and characterisation of 21 compounds, including 2,2-disubstituted indanones (16a-16h), indanols (17a-17h), and indanes (18a-18h). These compounds were tested in vitro and in vivo using the murine dextran sulphate sodium (DSS) model of inflammatory bowel disease (IBD). Cytotoxicity screening in THP-1 macrophages and SW480 cells revealed increased cytotoxicity with indene ring substitution at C2, with 18d emerging as potent. In lipoxygenase (LOX) assays, 18a, 18d, and 18c exhibited significant 5-LOX inhibition, with 18d comparable to zileuton. Selective 5-LOX inhibition over 15-LOX indicated distinct ligand-isozyme interactions, potentially informing novel inhibitor development. Cytokine profiling identified compounds with optimal C1 and C2 substituents, particularly 18d, which inhibited IL-6, IL-1β, TNF-α, and IFN-γ in THP-1 macrophages and IL-8 in SW480 cells. In vivo DSS colitis model testing showed significant disease activity index reduction (p < 0.01) with 18d. Subsequent to molecular docking, molecular docking simulations predicted stable binding of 18c and 18d to 5-LOX under mimicked physiological conditions. These findings offer insights into indane-based therapeutic drug development for IBD, highlighting cost reductions by minimising stereochemistry complexity.

Aldose reductase (ALR2; AKR1B1), a NADPH-dependent cytosolic oxidoreductase, plays a central role in the polyol pathway and is implicated in hyperglycemia-induced tissue injury. Beyond its metabolic function, elevated ALR2 expression has been reported in several malignancies, including hepatocellular and pulmonary carcinomas, highlighting its potential as a therapeutic target in metabolic-oncologic interface. In this study, a novel set of eleven N-substituted phthalimide-carboxylic acid derivatives (5a-5k) was synthesized and evaluated for ALR2 inhibition, pharmacokinetic characteristics, and cancer-selective safety. Among the series, compound 5f demonstrated the highest inhibitory potency (KI = 7.34 nM), outperforming epalrestat (KI = 232.1 nM). Glide docking positioned 5f within the ALR2 active site (GlideScore: -6.71 kcal/mol), stabilized via key contacts with Tyr48, His110, and Cys298, along with π-π stacking at Trp219. MM-GBSA analysis corroborated strong binding affinity (ΔG = -64.86 kcal/mol). DFT-derived quantum descriptors, logP, TPSA, and solvation energies supported its favorable interaction profile. ADME/Tox predictions indicated high GI absorption, no P-gp or CYP liabilities, and acceptable bioavailability. In vitro cytotoxicity assays showed negligible activity of 5f against A549 and Hep3B cancer cell lines (IC₅₀ > 160 μM) and no toxicity toward L929 fibroblasts, reflecting safety for long-term use. Transcriptomic data from CCLE and DepMap confirmed AKR1B1 overexpression in these cancer models. Network analysis linked ALR2 to redox imbalance and inflammation, suggesting its broader role in tumorigenesis.

Background: Despite recent breakthroughs in cancer treatment, non-small cell lung cancer (NSCLC) and breast cancer remain major causes of death from all malignancies. The epidermal growth factor receptor (EGFR) is an important mediator of the pathways involved in cell proliferation, apoptosis, and angiogenesis. Thus, its overexpression triggers several types of cancer, including NSCLC and breast cancer. Methods: In the current study, we synthesized new pyrimidine-tethered compounds (chalcone derivative (B-4), pyrazoline-carbothioamide (B-9), and pyrazoline-thiazole hybrids (BH1-7)). These compounds were then tested for cytotoxicity against A549 NSCLC and MCF-7 breast cancer cells. Results: Of these, B-4 displayed significant cytotoxicity against both cells (IC50 = 6.70 ± 1.02 µM for MCF-7; IC50 = 20.49 ± 2.7 µM for A549) compared to the standard agent lapatinib (IC50 = 9.71 ± 1.12 µM for MCF-7; IC50 = 18.21 ± 3.25 µM for A549). The anticancer potential of B-4 between Jurkat leukemic T cells and peripheral blood mononuclear cells (PBMCs) (healthy) was found to be selective. Mechanistically, 11.9% and 10.2% of A549 and MCF-7 cells treated with B-4, respectively, underwent apoptosis and B-4 produced 46% EGFR inhibition at a concentration of 10 μM. The B-4/EGFR complex obtained after induced fit docking was subjected to 300 ns of molecular dynamics simulation, which confirmed the stability of the complex in a mimicked biological environment. On the other hand, B-4 was shown to have drug-like properties by in silico pharmacokinetic estimation. Conclusions: B-4 is an EGFR inhibitor and apoptosis inducer for future NSCLC and breast cancer studies.

Aldose reductase (ALR2) has emerged as a dual-function therapeutic target, critically involved in diabetic complications and cancer-related redox adaptation. In this study, a novel series of 15 chalcone-inspired heteroaryl-dihydronaphthalenone hybrids bearing indole, carbazole, or phenothiazine motifs (4a-4f, 8a-8e, 12a-12d) were rationally designed, synthesized, and systematically evaluated for their ALR2 inhibitory and anticancer properties. Enzymatic inhibition assays revealed low-nanomolar to low-nanomolar KI values, with compound 8b (KI = 3.59 nM, pKI = 8.44) emerging as the most potent inhibitor, outperforming the reference drug Epalrestat. SAR analysis highlighted the critical role of flexible alkyl side chains and polycyclic aromatic scaffolds in optimizing hydrophobic anchoring. Complementary in silico studies, including MM-GBSA binding energy calculations (ΔGbind = -56.37 kcal/mol), quantum descriptors (HOMO-LUMO gap, solvation energy), and ADME/Tox profiling (SwissADME, QikProp, ADMETlab), provided further mechanistic insight into selectivity and drug-likeness. Lead compound 8b also demonstrated selective antiproliferative activity toward A549 lung carcinoma cells (IC₅₀ = 197.6 μM), with no observed cytotoxicity in Hep3B hepatoma or L929 fibroblast lines. Molecular dynamics simulations confirmed binding stability, while target prediction analyses suggested low off-target risk. This multi-parametric evaluation underscores the translational potential of scaffold-tuned ALR2 inhibitors as oxidative stress-modulating agents with cancer-selective properties.

Aim: The present study aims to identify the synthesis and structural characterization of acyl hydrazone- sulfonamide-containing compounds that were tested in vitro on human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. Methods: Herein, acyl hydrazone derivatives containing the primary sulfonamide moiety were synthesized via a three-step synthetic pathway starting from the commercially available 4-sulfamoyl benzoic acid. Structural characterizations of the final compounds were assessed through IR IR, 1H-NMR, 13C-NMR, and elemental analyses. The in vitro profiling activity of the final compounds on the Carbonic Anhydrases (CAs; EC 4.2.1.1) I, II, IX, and XII were performed by means of the stopped-flow technique and revealed nanomolar inhibitory potencies on the selected targets. Molecular docking and molecular dynamic simulations afforded a detailed understanding of the binding modes of the most effective compounds. Results: We reported the synthesis and structural characterization of 25 acyl hydrazone-sulfonamide-containing compounds that were tested in vitro on the hCAs I, II, IX, and XII isoforms for their inhibitory features. Overall, all compounds showed nanomolar inhibition potencies on the panel of hCAs considered, and their binding modes were deciphered by means of in-silico studies. Molecular docking followed by MD simulations confirmed the stability of 4l-hCA I, 4n-hCA II, 4t-hCA II, 4v-hCA XII, and 4w-hCA XII complexes. Conclusion: This study presents a deep understanding of the structural determinants influencing the affinity and selectivity of the designed compounds towards different hCAs, thus offering valuable insights for further optimization and development in the field.

In this study, new bis-1,2,3-triazole derivatives (4a-h) were synthesized with 60%-95% yield by reacting N,N'-(4,5-dichloro-1,2-phenylene)bis(2-azidoacetamide) with various alkyne compounds in the presence of CuSO4.5H2O and sodium ascorbate. The in vitro anti-proliferative activity of the products was evaluated against prostate (PC3 cells) and breast cancer (SKBR3 cells), along with normal retinal pigment epithelial ARPE-19 cells to assess their cytotoxic effects. 4e, 4f, and 4a showed notable anti-proliferative activities against PC3 cells, with IC50 values of 10.89, 12.49, and 36.13 mu M, respectively, while the reference drug cisplatin showed anti-proliferative activity with IC50 value of 10.5 mu M. 4e also showed remarkable anti-proliferative activity compared with the reference drug cisplatin (IC50 = 15.0 mu M) against SKBR3 cells with an IC50 value of 14.05 mu M. Hoechst DNA staining revealed that compound 4e induced cell death in prostate cancer cells by mediating in a dose-dependent manner. Electrochemical methods were used to study DNA interactions of 4a, 4e, and 4f, using differential pulse voltammetry and cyclic voltammetry. Consequently, binding coefficients for 4a, 4e, and 4f were found to be 6.7x103, 9.12x102, and 2.8x106 M-1, respectively. Molecular docking simulations predicted that the most potent compound 4e interacts with the minor groove of DNA.

In this study, 1,4-naphthoquinone thiazole hybrids were synthesized by reacting 1,4-naphthoquinone thioureas with various alpha-bromoketones in 78-86 % yields and characterized using 1H NMR, 13C NMR, FT-IR, and HRMS techniques. Furthermore, single crystal x-ray diffraction studies were also performed for 3b and 3c hybrids to determine stereochemistry. Density Functional Theory (DFT) calculations were performed to obtain additional information and to support the x-ray studies. The in vitro anti-proliferative activities of 1,4-naphthoquinone thiazoles were investigated against PC3 human prostate cancer cells. The products 3a-h showed antiproliferative activity against PC3 cells, and the cell viability studies showed that the IC50 values of compounds 3f and 3e were 20.10 mu M and 21.14 mu M, respectively, while the other compounds exhibited lesser cytotoxic effects than the former two. Potential target underlying the mechanism of action of the synthesized compounds against prostate cancer was identified using inverse (reverse) docking method. Molecular dynamics simulation was also conducted to confirm the stability of the 3f/enzyme system. It was determined that the solubility in ethanol was better for compounds bearing methyl substituent on X1 location than compounds containing tert-butyl on the same location. Compounds with F atom on X2 position were more soluble than the others in the corresponding groups.

In the present medical epoch, the prevailing approach of drug discovery, which focuses on inhibiting a single target, has been superseded by the concept of designing drugs that target more than one specific site. Herein, we present the design and synthesis of a novel series of 1-oxo-3,4-dihydronaphthalene substituted sulfonamides (5aj) with human carbonic anhydrase (hCA) and acetylcholinesterase (AChE) inhibitory activities as potential dualtarget agents. The design of target compounds 5a-j incorporated two key elements: i) The sulfonamide group, which is widely recognized for its high affinity for the active site of hCAs, and ii) the effectiveness of 2-benzylidene-1-tetralone class compounds in some neurodegenerative disorders. All reported sulfonamides were evaluated for their inhibitory effect against hCA I, II isoforms, and AChE. Both hCAs, and AChE were potently inhibited by 5a-j with KI constants in the nanomolar range; 47.71-113.20 nM, 28.05-206.60 nM, and 87.38-136.60 nM, respectively, compared to standard inhibitors, acetazolamide (KIs of 439.17 and 98.28 nM for hCA I and hCA II, respectively) and tacrine (KI of 159.61 nM). 5i exhibited the best multi-target inhibitory activity against hCA I (KI of 47.71 nM), hCA II (KI of 30.75 nM), and AChE (KI of 88.97 nM), while 5b showed a selectivity index (hCA I/II) of 3.61. Moreover, a cytotoxic activity assay for sulfonamides 5a-j was applied on the human breast adenocarcinoma MCF-7 cell line as well as on the non-tumoral mouse fibroblast L929 cell. Thereafter, extensive molecular dynamics simulations revealed the dynamic behavior of ligand/enzyme complex and predicted vital ligand contacts in the binding pocket.

In the present study, an intermediate namely 2-(3-bromopropylamino)-3-chloronaphthalene-1,4-dione was initially synthesized via the nucleophilic addition-elimination reaction between 2,3-dichloro-1,4-naphthoquinone and 3-bromo-1-aminopropane. Then a coupling reaction between the intermediate and piperazine derivatives yielded a number of 1,4-naphthoquinone derivatives. Spectroscopic analysis successfully characterized the products that were obtained in good yields. In vitro antibacterial properties of the compounds were examined against different bacterial strains. In vitro antibacterial properties of the compounds were examined against the bacterial strains S. Aureus, E. Faecalis, E. Coli and P. Aeruginosa. While compound 9 was found to be effective against all bacterial strains used, compound 12 was active against three strains and compounds 10 and 11 were effective against the two. None of the compounds are effective against C. albicans strain. In silico molecular docking studies revealed that all compounds had docking scores comparable to the antibacterial drugs ciprofloxacin and gentamicin and might be considered as DNA gyrase B inhibitors. Molecular dynamics simulations were also conducted for a better understanding of the stability and the selected docked complexes. Additionally, the drug similarity of the synthesized compounds and ADMET characteristics were examined in conjunction with the antibiotic ciprofloxacin, and drug potentials were then evaluated. Compatible predictions were found with the drug similarity and ADMET parameters.

Designing new compounds from existing chemotherapeutic drugs to enhance inhibitory effects on tumor cells while overcoming multidrug resistance is one of the important strategies for new drug discovery in medicinal chemistry. A new series of urea and thiourea derivatives based on Lenalidomide as potential anticancer agents have been designed and synthesized. In vitro anticancer activity assay against Caki cancer cells and HUVEC endothelial cells revealed that 1-(4-methylphenyl)-3-[2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl]urea (11) exhibited the highest anticancer activity and selectivity in the series with IC50 values of 9.88 and 179.03 mu M, respectively. Among the compounds, 11 showed significant HDAC1 inhibiton of 68.02 +/- 2.44% at 10 mu M concentration. TGF-beta, Bax, Bcl-2 protein levels and scratch assay were analyzed in Caki cells. As a result, compound 11 induced apoptosis in Caki cells. In this study, it has been demonstrated that compound 11 can be a lead compound for further detailed investigation in renal cancer treatment. Through molecular docking studies, it was determined that the most active compound, 11, forms stable interactions with key residues in the enzyme's active site, particularly engaging in hydrogen bonds with GLY149 and coordinating with the zinc ion in the HDAC1 active site. These interactions are crucial for the observed inhibitory activity. Molecular dynamics simulation revealed the binding event of the most active compound with class I histone deacetylase and the stability of the complex in a biological environment.