Integrated synthesis, molecular mechanics, quantum mechanics and in vitro studies of triazine derivatives as anticancer compounds.

Synthesis, DFT Evaluation, and Docking-Based Assessment of Novel Substituted Pyridine Derivatives against Human Spermine Oxidase

This study combines structure-based molecular docking simulations and DFT calculations to investigate interactions between the crystal structure of human Spermine Oxidase (SMOX) and a series of three novel 2,4,6-substituted pyridine compounds as docking-prioritized SMOX-interacting candidates. The synthesis employed tandem iridium-catalyzed borylation and Suzuki-Miyaura coupling. DFT calculations were performed at the B3LYP/6-311(d,p) level to determine the global minimum energy geometries and electronic properties. These optimized structures served as inputs for molecular docking. The interaction potential was simulated using the human SMOX crystal structure (PDB ID: 7OXL). Docking grids were centered on the FAD-binding catalytic domain. The precise coordinates were x = -25, y = 93, and z = 60. These coordinates ensured rigorous active-site definition. The synthesized scaffolds exhibited superior binding affinities with Vina scores ranging from -8.3 to -9.7 kcal/mol. These scores are significantly higher than the natural substrate, spermine (-5.8 kcal/mol). Structural analysis used the FAD cofactor as a landmark, supporting a hypothesized "Channel Plug" mechanism in which the bulky heterocyclic core sterically hinders access to the catalytic center. The results illustrate that the key interacting residues include Ser463, Gly13, Ala36, Glu35, Leu56, Leu14, Ala15, and Thr465. These findings provide a robust theoretical structural rationale for developing site-specific SMOX modulators and prioritize the use of pyridine scaffolds to target polyamine-binding cavities.

Novel 1,2,4-triazole–benzimidazole Hybrids as Potential Bioactive Scaffolds: Synthesis, Mechanistic and Molecular Docking Studies

A Combined Molecular Docking, Dynamics Simulation, and In Vitro Evaluation of Hydroxythioxanthones as Antidiabetic and Antioxidant Candidates

ABSTRACT. This research conducts a comprehensive investigation of hydroxythioxanthone derivatives through an integrated methodology that includes molecular docking, molecular dynamics (MD) simulations, and in vitro evaluations of antidiabetic and antioxidant activities. Molecular docking and MD simulations were performed to elucidate the binding interactions and dynamic stability of these compounds in complex with the α-glucosidase enzyme. The docking results indicated that the hydroxythioxanthone derivatives exhibited binding affinities ranging from −5.48 to −6.42 kcal/mol. In contrast, α-D-glucopyranose and quercetin demonstrated higher binding affinities of −6.99 and −7.01 kcal/mol, respectively. Subsequently, 100 ns MD simulations confirmed the stability of the ligand–protein complexes, as evidenced by consistently low values of root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg). The antidiabetic activity assay revealed that 4-chloro-1-hydroxythioxanthone (TX4) and 2,4-dichloro-1,3-dihydroxythioxanthone (TX5) exhibited strong inhibitory effects against α-glucosidase, with IC₅₀ values of 78.35 and 91.97 µg/mL, respectively, whereas quercetin showed a lower IC₅₀ value of 1.25 µg/mL. Furthermore, the antioxidant evaluation demonstrated that 2-chloro-1-hydroxythioxanthone (TX3) and 4-chloro-1-hydroxythioxanthone (TX4) possessed IC₅₀ values of 87.48 and 17.72 µg/mL, respectively, while ascorbic acid served as the reference compound with an IC₅₀ value of 9.15 µg/mL.   Keywords: antidiabetic, antioxidant, molecular docking, molecular dynamics, thioxanthone

Design, Synthesis and Molecular Docking-Based Evaluation of Piperazine-Linked Triazine Derivatives as Antioxidant Agents

Oxidative stress is a key driver of the pathogenesis of numerous chronic inflammatory and metabolic diseases emphasizing the requirement for the development of potent and selective antioxidant therapeutics. In present study, a series of novel piperazine-linked 1,3,5-triazine derivatives (6a-h) was rationally designed, synthesised and evaluated for antioxidant activity using integrated computational and experimental approaches. Molecular docking studies were carried out against myeloperoxidase (MPO; PDB ID: 1DNU), a heme-containing enzyme involved in reactive oxygen species (ROS) generation, to examine ligand–protein interactions and binding affinities. The synthesized compounds exhibited binding energies ranging from -3.816 to -4.987 kcal/mol. Among them, compound 6f, bearing a para-fluorophenyl substituent, shows the highest binding affinity (-4.987 kcal/mol). The enhanced binding was attributed to the formation of two hydrogen bonds with ARG27 and LEU97 and exceeded the binding energy of the reference antioxidant, ascorbic acid (-4.690 kcal/mol). The antioxidant potential was assessed by the DPPH free radical scavenging assay. Compound 6f displayed the strongest activity with an IC50 value of 14.15 ± 0.14 µM, which was comparable to that of ascorbic acid (IC50 = 14.06 ± 0.18 µM). Structure-activity relationship analysis indicated that the electron-withdrawing substituents at the para-position of aryl ring, together with nitrogen-containing heteroaromatic moieties, improve both binding affinity and free radical scavenging activity. The results identify piperazine-linked 1,3,5-triazine derivatives as promising antioxidant scaffolds and provide a strong basis for future myeloperoxidase inhibition studies and in vivo pharmacological evaluation.

Synthesis, molecular docking and preliminary anticancer activity of product-C as a hybrid compound against PI3K

The present work describes the synthesis, molecular docking, and preliminary anticancer evaluation of a hybrid compound, product- C composed of a fluorinated sulfur heterocyclic core and an adamantane moiety. The synthesis method was designed to tune the electronic, lipophilic and structural properties of the compound through the introduction of CF₃, F and Cl functional groups, which are well known for the improving metabolic stability, physicochemical properties and drug-likeness. The structure of the synthesized compound was confirmed by 1 H and 13 C nuclear magnetic resonance (NMR) spectra. Molecular docking against phosphoinositide 3-kinase (PI3K), a protein target implicated in multiple cancers, showed that product- C exhibited a binding affinity of -10.6 kcal/mol, suggesting favorable interaction with the target. In parallel, the SRB (Sulforhodamine B) assay was used to evaluate the cytotoxicity of product- C toward PANC-1 cells. Preliminary results showed cell viabilities of 98.86% and 95.55% after exposure to 10 μM and 100 μM of product- C , respectively. These findings indicate that product- C displays low cytotoxicity toward PANC-1 cells under the tested conditions; however, they do not by themselves demonstrate marked antiproliferative activity.

Synthesis, Structural Elucidation and DFT Studies of Novel Coumarin Derivative with Docking, ADMET Analysis and Antibacterial Activities