Parkinson's disease (PD) is the second most common age-related motor neurodegenerative disease (ND) that has critically posed a global health burden since the 18th century. There is also no full therapy for the clinical syndrome, nor halts the progression of the disease. This study aimed to investigate multidisciplinary potentials of the acetamidosulfonamides (1-16) in PD via systematic biology-based in vitro, in silico, and network pharmacology assessments. The biological effects of the synthetic compounds, especially 8, 13, 14, and 16, provided potent neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced Parkinsonian SH-SY5Y model through the modulation of antioxidant defenses, antiapoptotic signaling, mitochondrial balance, and the regulation of both acetylcholinesterase (AChE) and sirtuin 1 (SIRT1). Molecular docking confirmed that these synthetic compounds interact favorably with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE, as well as the active binding pocket of SIRT1. The network pharmacology and target enrichment analysis also revealed a close correlation with APP, MAOA, MAOB, SLC6A3, and DRD1, governing the regulation of neurotransmitters. In summary, this research highlights four acetamidosulfonamides as promising candidates to be further developed as multitarget anti-PD agents for PD prevention and management.

Eleven 8-aminoquinoline-based sulfonamide derivatives (3-13) were synthesized and experimentally investigated for their antioxidant effects (using superoxide dismutase [SOD] and 2,2-diphenyl-1-picrylhydrazyl [DPPH] assays) and antimicrobial activities (using agar dilution method). Most of the tested compounds were active antioxidants as indicated by SOD assay, affording SOD half-maximal inhibitory concentration in the range of 83.34 to 600.81 μM. However, their DPPH activities were considerably weak (%DPPH = 7.74% to 36.49%). Additionally, 7 compounds (3, 4, 5, 6, 8, 10, and 12) displayed growth-inhibiting effects against various gram-positive and gram-negative microbes (minimum inhibitory concentration values = ≤4 to 256 μg/ml). Quantitative structure-activity/property relationship (QSAR/QSPR) modeling was performed to obtain predictive models, including antioxidant QSAR (SOD and DPPH) and antimicrobial QSPR models. The constructed models displayed acceptable predictive performance and robustness (QSAR models: R2 Tr = 0.9980 to 0.9996, Q2 LOO-CV = 0.9930 to 0.9978, RMSETr = 0.0121 to 0.1677, RMSE LOO-CV = 0.0233 to 0.3830 and QSPR model: accuracy = 90.91% for training and 63.64% for leave-one-out cross-validation [LOO-CV] sets). The constructed models were subsequently utilized to guide rational design and predict activities of an additional set of 84 structurally modified compounds. Finally, newly designed compounds with promising predicted antioxidant activity (SOD: 13c, 13f, 8c, 12e, and 11c; DPPH: 9b, 6f, 9c, 11h, and 3d) as well as a set of 34 compounds predicted as active antimicrobial agents are summarized for potential investigations. Furthermore, key essential properties influencing bioactivities (electronegativity, polarizability, I-state, van der Waals volume, connectivity, and ionization potential) were also revealed for future beneficial design of the related compounds for medical applications.

Bacterial infections and antibiotic resistance remain a major global health concern, underscoring the need for new therapies. Poor bioavailability of bioactive compounds poses challenges in successful clinical applications, rendering nanoparticle conjugation which is one of the effective strategies for overcoming. Macluraxanthone (MCX), a naturally derived compound exhibiting antioxidant and antimicrobial properties, but displayed poor bioavailability and limited antimicrobial effect against Gram-negative bacteria. Herein, MCX was conjugated with gold nanoparticles (AuNPs) to enhance its bioactivity, stability, and targeted delivery. Transmission electron microscopy (TEM) analysis confirmed the formation of spherical AuNPs with uniform distribution, while the faint halo surrounding some AuNPs-MCX particles suggested successful MCX adsorption. The synthesized AuNPs-MCX conjugates displayed a preferred particle size of 25.1 nm, providing maximum MCX release after 48 h, reaching approximately 78% at pH 7.4 and 82% at pH 5.04. Antioxidant assay indicated that MCX is a strong antioxidant agent, but its activity was impaired upon conjugation with AuNPs. Compared to the free MCX, the AuNPs-MCX conjugates exhibited considerably enhanced antimicrobial activities against Gram-negative bacteria (E. coli, S. flexneri, V. cholerae, and S. enterica serovar Typhi) but impaired activities against Grampositive ones (S. aureus, MRSA, and L. monocytogenes). Scanning electron microscope (SEM) further confirmed significant bacterial cell damage after treatment with both MCX and AuNPs-MCX, including cell wall degradation, deep pits, and cavity formation. Further investigations also revealed that the mechanisms behind the altered antimicrobial activities of AuNPs-MCX conjugates could be partly due to the changes in their abilities to produce reactive oxygen species (ROS) and eradicate biofilm. Interestingly, free MCX exhibited moderate cytotoxicity toward Vero cells (IC50 = 17.12 mu g/mL), whereas AuNPs-MCX showed non-cytotoxicity, indicating improved biocompatibility. These findings highlight the potential of AuNPs-MCX conjugates as an effective nanoformulation, offering selective antibacterial activity against Gram-negative pathogens.

Sulfonamide-based compounds have been a clinically attractive scaffold for drug development and proven as antioxidant and antimicrobial agents, but their pharmacological derivatives containing anthranilates (SA1-4) and therapeutic targets are not clearly clarified. To unravel the neuroprotective roles and underlying mechanisms of SA1-4 against oxidative injury and healthy longevity crosstalk, a combination of in vitro experiments, in silico modeling, and network pharmacology was employed. Pretreatment with SA1-4 in human neuronal SH-SY5Y cells significantly regulated sirtuins (SIRTs)/forkhead box class O 3a (FOXO3a)-mediated longevity signaling pathway via targeting endogenous antioxidant enzymes (i.e., superoxide dismutase 2 [SOD2] and catalase [CAT]), apoptotic cascades (i.e., Bcl-2-associated X-protein [BAX] and B-cell lymphoma-2 [BCL-2]), mitochondrial balance, and ultimately led to the neuronal rescue. Molecular docking simulations support the possibility of the SA1-4 modulatory effect within the active binding site of SIRT1. Importantly, in silico predictions of pharmacokinetic profiles suggested that the synthetic compounds possessed preferable drug-like properties, good oral bioavailability, and safety profiles. Network pharmacology also revealed the involvement of SA1-4 and key targets-regulated SIRTs in neurodegeneration, including non-amyloidogenic cascade, tau phosphorylation, calcium homeostasis, insulin-mediated glucose uptake, and neuroinflammation. Therefore, SA1-4 exert promising multi-target therapeutic strategies against oxidative damage, potentially offering alternative anti-Alzheimer candidates for further clinical neurodegenerative and anti-aging therapeutics.

Terpinen-4-ol (TP4O) is a key monoterpene alcohol commonly used as a quality and authenticity marker in essential oils, cosmetics, herbal products, and pharmaceutical formulations. However, reliable and comparable quantification of TP4O across laboratories is challenged by variability in natural matrices and the limited availability of well-characterized, traceable reference materials. In this study, a high-purity certified reference material (CRM) of TP4O was developed and characterized by the National Institute of Metrology (Thailand). The material's purity was determined using two independent and complementary approaches: a mass balance method (MB) method based on gas chromatography with flame ionization detection (GC-FID), Karl Fischer coulometric titration (KFT), and thermogravimetric analysis (TGA), and a quantitative H-1 NMR (qNMR) method employing DSS-d(6) as an internal standard. The purity values obtained using the MB (98.41 +/- 0.09%) and qNMR (99.13 +/- 0.94%) methods were statistically equivalent (p > 0.05). Based on the combined evaluation, a certified purity value of 98.77% with an expanded uncertainty of 3.05% (k = 2) was assigned. Homogeneity and short- and long-term stability assessments confirmed the suitability of the material for its intended use. This TP4O CRM provides an SI-traceable, high-purity reference to support calibration, method validation, and quality assurance in analytical applications involving essential oil components.

Colorectal cancer is strongly associated with chronic inflammation, in which cyclooxygenase-2 (COX-2) plays a pivotal role in tumor progression, making it an important therapeutic target. In this study, the antiproliferative activity of 1,4-naphthoquinones (3-18) in SW480 cells was investigated, and selected derivatives were characterized using computational and in vitro approaches. Initial antiproliferative screening identified compounds 3, 8, and 12 as the most potent candidates, prompting further investigation into their molecular mechanisms. These compounds were further assessed for their predicted interactions with COX-2 using AutoDock Vina and molecular dynamics (MD) simulations, followed by in vitro COX-2 inhibition and cell-based cytokine assays. Hoechst 33342, JC-1 staining, cell cycle analysis, and apoptosis assays were used to evaluate cellular responses. Through integrated computational and experimental approaches, we demonstrated that three compounds bind favorably within the COX-2 active site with key residues in a manner comparable to that of rofecoxib. Consistent with their ability to target COX-2, compounds 3, 8, and 12 showed potent in vitro COX-2 inhibitory at nanomolar (IC50 values of 10-18 nM) and modulated LPS-induced inflammatory responses, significantly reducing TNF-α, IL-8, and IL-10 release. The compounds were also associated with mitochondrial dysfunction, cell cycle changes, and apoptosis, with compound 12 emerging as the most active derivative and showing the strongest antiproliferative and pro-apoptotic effects. Our findings establish compound 12 as a promising lead candidate for the development of new anti-colorectal cancer agents and provide mechanistic insights into the interplay between COX-2 inhibition, inflammatory modulation, and apoptosis induction in inflammation-associated colorectal carcinogenesis.

Tyrosinase is a key enzyme that catalyzes the rate-limiting step in melanogenesis. Although numerous mushroom-derived tyrosinase inhibitors have been identified, many exhibit limited efficacy against human tyrosinase. In this study, in silico approaches were employed to evaluate the inhibitory potential of aminonaphthoquinone-chalcone hybrids against human tyrosinase. Molecular docking analysis revealed that all 10 hybrids showed higher binding affinity than kojic acid. Among them, six hybrids (3, 4, 5, 7, 9, and 10) displayed higher binding affinity than the others and interacted with amino acid residues within the active site of tyrosinase. Molecular dynamics simulations revealed that the six selected hybrids maintained stable binding to human tyrosinase throughout the simulations. Among them, compound 9 exhibited the highest structural stability, consistent with its most favorable MM/PBSA-predicted binding free energy and the greatest number of key residue interactions (K306, K334, S358, S360, N364, H367, I368, S375, Q376, and V377). Van der Waals interactions were identified as the predominant driving force governing ligand-protein binding in all complexes. These findings provide atomistic insights into the interactions between aminonaphthoquinone-chalcone hybrids and human tyrosinase and may facilitate the future development of novel human tyrosinase inhibitors.

Aromatase enzyme is a rate-limiting enzyme playing a key role in estrogen biosynthesis, and its inhibition has been noted as a strategy for the management of hormone-dependent breast cancers. Naphthoquinone and triazole are attractive pharmacophores due to their wide-ranging bioactivities and unique chemical properties. Molecular hybridization is a strategy widely applied in drug design to create several novel compounds with promising therapeutic advantages. In this study, a series of hybridized naphthoquinone-triazoles (1-17) were investigated for their aromatase inhibitory effects. Twelve compounds were found to be active aromatase inhibitors (IC50= 1.3-14.9 μM). Molecular docking was conducted to reveal that the three most potent inhibitors (2, 5, and 7, IC50= 1.3-1.8 μM) could occupy the allosteric binding site of human aromatase. These three most potent inhibitors (2, 5, and 7) were further explored for their antiproliferative and apoptosis-inducing activities against the estrogen-positive MCF-7 breast cancer cell line. Interestingly, these three aromatase inhibitors exhibited antiproliferative activity (IC50= 17.51-36.54 μM) and apoptosis-inducing effects, as observed by increased levels of the cell accumulated in the sub-G1 phase. Notably, methyl derivative 2 outperformed the other derivatives with its comparable potency (IC50 = 17.51, SI = 4.60) and higher selectivity index than the standard drug, tamoxifen (IC50 = 18.11, SI = 1.56). Collectively, this study suggested that these naphthoquinone-triazole derivatives were aromatase inhibitors possessing the apoptosis-inducing effect, which could be further developed as multi-acting anticancer agents for combating estrogen-dependent breast cancer.

DNA topoisomerase IIα (Topo IIα) is essential for maintaining genomic stability during DNA replication and mitosis and is highly expressed in cancer cells, making it a promising target for anticancer therapy. In this study, bis-thiourea derivatives were investigated for their Topo IIα inhibitory activity and anticancer potential using in silico and in vitro studies. Molecular modeling demonstrated that compound 8 exhibited favorable binding affinity and stability within the ATPase domain of Topo IIα. Biochemical assays revealed that compound 8 inhibited Topo IIα activity and showed potent cytotoxicity against several cancer cell lines, particularly A549 cells. Mechanistic studies showed that compound 8 inhibited A549 cell migration and invasion by upregulating E-cadherin while downregulating the mesenchymal markers N-cadherin and vimentin, as well as the EMT-associated transcription factor Slug. Furthermore, compound 8 induced G1-phase arrest by downregulating cyclins D1 and E2 while upregulating p21. These results suggest that compound 8 represents a promising lead for Topo IIα-targeted cancer therapy.

Tyrosinase, a key enzyme in melanin synthesis, serves as a primary target for developing depigmenting agents. The search for novel tyrosinase inhibitors is needed due to the adverse effects of current inhibitors. This study evaluated 16 bis-thiourea derivatives using in vitro and in silico methods, identifying compound 4, with chlorine substituents, as the most potent inhibitor. Compound 4 outperformed kojic acid in inhibiting mushroom tyrosinase activity and interacted with catalytic copper ions and active site residues, as revealed by molecular docking and copper-chelating assay. Molecular dynamics simulation and MM/PBSA-based free energy calculations confirmed the greater stability and binding affinity of the compound 4-tyrosinase complex in an aqueous environment compared to kojic acid-tyrosinase complex. Melanin assay revealed that compound 4 significantly suppressed melanin production in B16F10 melanoma cells, showing stronger anti-melanogenic activity than kojic acid. Drug-likeness predictions confirmed its compliance with Lipinski's rule of five, supporting bis-thiourea derivatives as promising tyrosinase inhibitors.

Antioxidant compounds have gained current interest as potential protective agents for several therapeutic applications. Antimicrobial drug resistance and infectious diseases also still be concerning globally health issues. Accordingly, the discovery of new antioxidative and antimicrobial agents is essential for human well-being. Thiazole and sulfonamide are privileged scaffolds in drug discovery due to their various bioactive properties. In this study, a series of 2-aminothiazole sulfonamide derivatives (1 - 12) were synthesized and investigated for their antioxidant (i.e., DPPH and SOD-mimic) and antimicrobial activities. Among tested compounds, compound 8 was the most promising one with potent DPPH and SOD (%DPPH = 90.09 %, %SOD = 99.02 %). However, none of these compounds are active antimicrobial agents. Quantitative structure-activity relationship (QSAR) modeling was performed in which the key findings were further used to guide the rational design of additional derivatives. Two antioxidant QSAR models (i.e., DPPH and SOD) were constructed using multiple linear regression (MLR) with good predictive performance. An additional set of structurally modified compounds were designed based on QSAR findings to finally obtain 112 newly designed compounds in which their activities (DPPH and SOD) were predicted. Most of the modified compounds performed better activities than their prototypes. Mass, polarizability, electronegativity, the presence of C-F bond, van der Waals volume, and structural symmetry were revealed as key properties influencing antioxidant activities. In summary, this study demonstrated the combination used of chemical synthesis, experimental assays, and computer-aided drug design for developing novel antioxidants for potential medicinal applications. See also the graphical abstract(Fig. 1).

1,4-Naphthoquinone is a promising pharmacophore in drug discovery due to its unique redox reactive nature and wide-ranging bioactivities. Herein, a series of 1,4-naphthoquinones (1-14) were investigated for their anticancer activities against 4 cancer cell lines (i.e., HepG2, HuCCA-1, A549, and MOLT-3). Compound 11 was found to be the most potent and selective anticancer agent against all tested cell lines (IC50 = 0.15 - 1.55 μM, selectivity index = 4.14 - 43.57). QSAR modelling was performed to elucidate key structural features influencing activities against four cancer cell lines. Four QSAR models were successfully constructed using multiple linear regression (MLR) algorithm providing good predictive performance (R: training set = 0.8928-0.9664; testing set = 0.7824-0.9157; RMSE: training set = 0.1755-0.2600; testing set = 0.2726-0.3748). QSAR models suggested that the potent anticancer activities of these naphthoquinones were mainly influenced by polarizability (MATS3p and BELp8), van der Waals volume (GATS5v, GATS6v, and Mor16v), mass (G1m), electronegativity (E1e), and dipole moment (Dipole and EEig15d) as well as ring complexity (RCI) and shape of the compound (SHP2). The models were further applied for guiding the design and predicting activities of an additional set of 248 structurally modified compounds in which the ones with promising predicted activities were highlighted for potential further development. Additionally, pharmacokinetic profiles and possible binding modes towards potential biological targets of the compounds were virtually assessed. Structure-activity relationship analysis was also conducted to highlight key structural features beneficial for further successful design of the related naphthoquinones.

Breast cancer is one of the most common cancers found in women worldwide. Besides the availability of clinical drugs, drug resistance and considerable side effects are concerning issues driven the needs for the discovery of novel anticancer agents. Aromatase inhibition is one of the effective strategies for management of hormone-dependent breast cancer. Triazole, coumarin, and isatin are heterocyclic scaffolds holding great attention in the field of drug design. Molecular hybridization is a well-known strategy to achieve new molecules with improved potency and properties. Herein, a set of 27 triazole-based hybrids (i.e., coumarin-triazoles series 5-6 and isatin-triazoles series 7) were synthesized and investigated for their anti-proliferation, apoptosis induction, and aromatase inhibitory potentials. Anti-proliferative study against the hormone-dependent breast cancer (T47D) cell line indicated that coumarin-triazoles 5h (R=NO2) and 6i (R=SO2NH2) were the two most potent antiproliferative agents. Particularly, compound 5h showed comparable potency and superior selectivity index than that of the reference drug, doxorubicin. Moreover, the coumarin-triazole 5h induced cellular apoptosis of the estrogen-dependent breast cancer (MCF-7) cells. Additionally, findings from the aromatase inhibitory assay suggested four compounds as potential aromatase inhibitors (i.e., 5i, 6f, 6g and 6i, IC50 = 1.4-2.4 μM). Two QSAR models with preferable predictive performances were constructed to reveal key properties influencing antiproliferative and aromatase inhibitory effects. Molecular docking was conducted to elucidate the possible binding modalities against the target aromatase enzyme. Key structural features essential for the binding were highlighted. Moreover, the drug-like properties of top-ranking compounds were assessed to ensure their possibilities for successful development.

Due to the irreversible destructive nature of Parkinson's disease (PD), the development of neuroprotective agents is crucially needed as its current medications are only symptomatic treatments. 1,2,3-Triazole is an attractive scaffold for the discovery of novel therapeutic agents due to its versatile biological activities. This study aimed to investigate the neuroprotective effect of 1,2,3-triazole-based sulfonamides against 6-hydroxydopamine (6-OHDA)-induced neuronal SH-SY5Y cells. The effects of triazole derivatives on cell viability, intracellular reactive oxygen species (ROS) production, lactate dehydrogenase (LDH) leakage, and sirtuin 1 (SIRT1) activity were evaluated in the 6-OHDA-induced cells. The results indicated that six compounds (2a - 5a and 3b - 4b) exhibited promising neuroprotective potentials due to their abilities to decrease intracellular ROS production and LDH leakage, along with increasing SIRT1 activity. Molecular docking was also conducted to reveal possible binding modes and interactions against the SIRT1 target through the key interacting residues of ILE223, LEU215, and PRO212. In silico pharmacokinetic prediction indicated that these compounds are drug-like molecules, possibly further developed as oral neuroprotective drugs. A set of possible PD-related targets of these six compounds is also highlighted for further investigations. Cytotoxicity assays in normal lung MRC-5 fibroblasts showed relatively high IC50 values, indicating low toxicity and favorable safety profiles. In summary, these six 1,2,3-triazole-based sulfonamides might potentially be neuroprotective agents for further PD therapeutic development.

The limitations of currently existing medications in delaying or halting the development of Parkinson's disease (PD) remain dramatically problematic, making it the second most prevalent neurodegenerative disorder. Moreover, it is expected that the number of PD cases will double within the next 30 years. Herein, to discover a novel neuroprotective therapeutic strategy, a series of multifunctional thiazole sulfonamides underwent preliminary assessment owing to their neuroprotective capabilities against 6-hydroxydopamine (6-OHDA)-induced damage in human neuronal SH-SY5Y cells. Pretreatment with novel synthetic hybrids, including 1, 2, and 8, significantly improved cell viability, reduced lactate dehydrogenase (LDH) leakage, prevented mitochondrial dysfunction, and mitigated intracellular oxidative stress. Insight molecular mechanisms and potential targets of these compounds were elucidated through their activation and binding interaction with sirtuin 1 (SIRT1), suggesting their influencing roles on relevant downstream cascades of PD. Furthermore, in silico pharmacokinetic analysis revealed the drug-likeness of these three hybrids, which are capable of being distributed into the central nervous system (CNS) with slight toxicity. Therefore, these novel neuroprotective thiazole sulfonamides are promising candidates for further development (i.e., in vivo and clinical trials) of effective PD therapy.

A set of 1,4-naphthoquinone (1,4-NQ) derivatives possesses various pharmaceutical activities. Among them, a synthetic 2-(4-methoxyanilino)naphthalene-1,4-dione (MN) is found to be non-cytotoxic to the normal MRC-5 cells and prevent neuronal SH-SY5Y cell damage. To explore the underlying interaction mechanism of MN in the circulatory system, in silico and multi-spectroscopic techniques were employed to investigate the complex of human serum albumin (HSA) and MN. The interaction between HSA and MN exhibited static fluorescence with a potential dynamic mechanism, as Ksv×105 (M-1) decreased with increasing temperatures. Thermodynamic parameters and molecular dynamics (MD) simulations indicated a stable and spontaneous binding process driven by hydrophobic interactions and endothermic characteristics. Both circular dichroism (CD) and Fourier transform infrared (FT-IR) spectroscopy analyses revealed that MN induced conformational changes in HSA, affecting α-helix, β-turn, β-sheet, and random coil components, thereby altering the secondary structure of HSA. Competitive binding and molecular docking showed that MN preferentially binds to subdomain IIA in site I of HSA with the lowest binding affinity (‒7.15 kcal/mol), though it also has some affinities for subdomains IB and IIIA in site III and II, respectively. Additionally, the esterase activity of HSA showed no significant changes in the presence of MN. Understanding the binding interaction between MN and HSA provides valuable insights for further investigating the pharmacodynamic mechanism of MN and its potential applications in the area of medicinal chemistry.

The binding nature of bioactive compounds with serum proteins, especially albumin, is noteworthy studied to achieve successful clinical drug development. Macluraxanthone (MCX), a bioactive xanthone, exhibits diverse pharmacological properties, but its binding interaction with albumin remains poorly understood. In this study, the binding mechanism of MCX and bovine serum albumin (BSA) was investigated using multiple experimental and computational methods. The UV absorption and steady-state fluorescence studies showed that MCX interacts with BSA through a ground-state association. The decrease in the Stern-Volmer constant (Ksv) values with increasing temperatures, and the bimolecular quenching rate constant (kq) values in the order of 1012 M-1 s-1 indicated a static fluorescence quenching mechanism. The association constant (Ka) values in the order of 106 M-1 indicated a strong interaction. Thermodynamic parameters suggested that the binding is spontaneously enthalpically controlled. Circular dichroism (CD) and Fourier transform infrared spectroscopy (FTIR) analyses revealed minimal perturbation in the secondary structure of albumin upon interaction with MCX at 0.5 and 2.0 μM, accompanied by a slight reduction in α-helix content. Molecular docking results showed that MCX could interact with multiple binding sites on the BSA. Experimental antioxidants (DPPH and ABTS) were also conducted to explore the effects of the BSA binding towards the biological activities of the compound. Collectively, this study demonstrates the preferable pharmacokinetic profile of MCX, providing beneficial insights and offering a foundation for future therapeutic applications of natural xanthone.

A new series of 1,4-naphthoquinone-triazole derivatives 5-21 were synthesized using nucleophilic substitution and CuAAC reactions. The compounds were investigated for their cytotoxic activities against four cancer cell lines (i. e., HuCCA-1, T47D, MOLT-3, and HepG2) as well as a normal cell line (Vero). Most of the compounds showed active cytotoxic effects on all tested cancer cells without cytotoxicity to the normal cells. Particularly, compound 20 showed promising activity against the T47D with comparable effect to that of the known drug, doxorubicin. Compounds 16 and 21 exhibited the greatest FGFR1 inhibitory potency with nanomolar IC50 values of 1.31 +/- 0.51 and 3.17 +/- 0.33 nM, respectively. Interestingly, the derivative 16 showed comparable inhibitory potency with the known FGFR1 inhibitor, AZD4547. Molecular docking and molecular dynamics simulations were conducted and revealed that both compounds could occupy within the ATP-binding pocket of the target FGFR1 and shared common interacting key amino acids residues (i. e., Leu484, Val492, and Leu630) with those of inhibitor, AZD4547. The simulations also suggested that the naphthoquinone-triazole skeleton was found to be a promising structural characteristic essential for effective inhibition of FGFR1. Additionally, the drug-likeness prediction displayed that these compounds (16 and 21) are drug-like molecules with possibility for further development.

4-Bromo-N-(thiazol-2-yl)benzenesulfonamide (1) is enriched with bioactive components and is highlighted for its pharmacological properties. However, its pharmacokinetic characteristics are yet to be reported. The interaction of compound 1 with carrier proteins in the bloodstream is an important factor that affects its potential therapeutic efficacy. This study aimed to elucidate the pharmacokinetic mechanisms of compound 1 in relation to human serum albumin (HSA) using multi-spectroscopic and computational techniques. Its predicted drug-like properties revealed no mutagenicity, although potential hepatotoxicity and interactions with certain cytochrome P450 enzymes were observed. Spectroscopic analyses extensively provided the interaction between HSA and 1 through a static fluorescence quenching mechanism with spontaneous hydrophobic interactions and hydrogen bonding. The binding constant of the HSA-1 complex was relatively moderate to strong at a level of 106 M- 1 . Various spectroscopic techniques including ultraviolet-visible, Fourier transform infrared, and circular dichroism spectroscopies indicated that its binding induced alteration in the alpha-helix content of HSA. Competitive binding and molecular docking studies designated the preferential binding of 1 to sub-structural domain IIA binding site I of HSA. Molecular dynamic simulations further illustrated the formation of a stable complex between 1 and HSA, accompanied by conformational changes in the protein. Importantly, esterase capacity of the HSA-1 complex increased compared to the free HSA. Therefore, elucidation of the HSA-1 binding mechanism provides valuable insights into the pharmacokinetics, suggesting potential benefits for the further development of 1 as a therapeutic agent.

4-Fluoro-N-(thiazol-2-yl)benzenesulfonamide (3) is a novel fluorinated compound, containing various biological activities. Therefore, absorption spectroscopy, fluorescence quenching, molecular docking, and molecular simulation were employed to investigate the interaction between 3 and human serum albumin (HSA). Firstly, compound 3 meets all criteria for drug-likeness prediction. UV absorption spectra revealed the interaction of 3 with HSA altered the microenvironment of protein, as well as circular dichroism spectroscopic analysis indicated slightly conformational changes and a reduction in α-helical content. The binding parameters of the HSA-3 complex suggested that fluorescence quenching is driven by combined static and dynamic processes. Additionally, the stability of the complex is attributed to conventional hydrogen and hydrophobic bonding interactions. Furthermore, esterase-like activity indicated that the binding of 3 might disrupt HSA's bond networks, leading to structural alterations. Consequently, the strong binding constant (Ka ≈ 1.204 × 106 M-1) aligns with the predicted unbound fraction (0.28) in serum, indicating that thiazole 3 has good bioavailability in plasma and can be effectively transported to target sites, thereby exerting its pharmaceutical effects. However, careful dosage management is essential to prevent potential adverse effects. Overall, these findings highlight the potential of 3 as a therapeutic agent, emphasizing the need for further research to optimize its uses.