Synthesis, characterization, molecular docking and pharmacokinetics of new pyrimidine carboxylate derivatives as potent VEGFR inhibitors

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, Characterization, Molecular Docking, and In Silico ADMET Analysis of Newly Bioactive Pyrazolophosphonate and Spiro-Pyrazole Derivatives

This study presents an efficient and simple method for synthesizing novel bioactive organophosphorus compounds 4 and 5 via a three-component condensation reaction of aminophenylpyrazolinone, an aromatic aldehyde, and triethyl phosphite, using L-proline as the organocatalyst. Furthermore, a series of spiro-pyrazolone derivatives was successfully obtained by a simple condensation reaction between aminophenylpyrazolinone and various aromatic aldehydes. In addition, molecular docking studies demonstrated that all compounds effectively interact with the target protein's active site, forming stable ligand–protein complexes. ADMET analysis against E. coli also reveals favorable pharmacokinetic properties for most compounds. However, compounds 6a, 6g, and 7j show potential toxicity, which may limit their applicability as drugs. 3-amino-1-phenyl-2-pyrazolin-5-one, aromatic aldehydes, and triethyl phosphite were used in condensation reactions and Kabachnik–Fields/Pudovik-type reactions to create the compounds. HRMS and NMR (1H, 13C, 2D) were used for characterization. Pharmacokinetic characteristics were predicted using pKCSM, and binding affinities were evaluated using molecular docking with the E. coli protein 1FJ4. The produced compounds showed stable docking conformations and strong binding affinities (-7.0 to -9.2 kcal/mol). The compounds with the best interaction profiles were 6d, 6e, 6f, and 7i. Compounds 6a, 6g, and 7j showed potential toxicity, but ADMET analysis indicated good intestinal absorption and acceptable metabolism. The synthetic method worked well and did not harm the environment. Several derivatives show promising pharmacological potential, as indicated by docking and ADMET results. This study introduces a simple synthesis of biologically active pyrazolophosphonate and spiro-pyrazole derivatives with promising antibacterial and pharmacokinetic profiles, highlighting compounds 6d, 6e, 6f, and 7i as potential drug candidates.

Integrated Synthetic, Pharmacological and In-Silico Evaluation of Novel Heterocyclic Compounds Targeting Cancer Pathways

The findings validate the medicinal-chemistry hypothesis that heterocyclic hybridization and rational substitution drive potency, binding affinity, and biological response across multiple pharmacological models.

3-substituted indole derivatives as potential drug candidates: Lipophilicity, solubility, drug-likeness, and VEGFR2 binding studies.

Improving key physicochemical and pharmacokinetic properties such as lipophilicity, water solubility, pharmacokinetics, and drug-likeness is crucial for evaluating a compound's absorption, distribution, metabolism, and excretion (ADME). Lipophilicity influences membrane permeability, while solubility affects bioavailability; both are vital for effective drug absorption and distribution. Pharmacokinetic properties and drug-likeness, which are shaped by factors like molecular weight and hydrogen bonding, are significant indicators of a compound's potential for clinical success. Indole derivatives demonstrate a broad spectrum of pharmacological activities, including anti-inflammatory and antimicrobial properties, highlighting the need for careful optimization of these characteristics to enhance their therapeutic effectiveness. In this study, a series of 3-substituted indole derivatives were synthesized and systematically characterized, including positional isomers with -NO₂ as well as substitutions like Br, hydroxy and phenyl groups. We conducted density functional theory (DFT) calculations on the synthesized indole derivatives at the B3LYP/6-311G(d,p) level using the G16W software package to investigate their thermochemical properties, physicochemical attributes, frontier molecular orbitals (FMOs) and molecular electrostatic potential (MEP) plots also estimated lipophilicity and water solubility to evaluate their dissolution behavior in octanol and water. Pharmacokinetic properties and drug-likeness profiles were further evaluated using in silico prediction tools. Moreover, a comprehensive molecular docking study was conducted on five rationally designed derivatives against the kinase domain of VEGFR2 to examine their potential binding interactions and therapeutic relevance. Overall, this study provides valuable molecular-level insights into how structural modifications influence physicochemical and biological properties, thereby offering strategic guidance for the rational design and development of indole-based drug candidates.

Green Synthesis, Molecular Modelling, and ADME Evaluation of Functionalized Pyridine Derivatives as Potential SARS-CoV-2 Inhibitors

Synthesis and In Vitro Anticancer Activity of New Acridone Derivatives: Computational DFT and Molecular Docking Studies

Cancer continuing to present a serious global health threat, creating an urgent demand for new and effective anticancer candidates. In this study, several novel acridone derivatives were synthesized and characterized by 1H NMR, 13C NMR, HRMS and FT‐IR, and their in vitro anticancer activity was evaluated combined with systematic theoretical calculations. Of these derivatives, 6a demonstrated antiproliferative activity against the HGC‐27 gastric cancer cell line (IC50 = 4.86 µM) in comparison with the HeLa cervical cancer cell line and the HCT116 colon carcinoma cell line. Furthermore, morphological assessment under an inverted microscope revealed that it induced apoptosis like morphological changes. Density functional theory calculations were employed to gain insight into the electronic structure and intramolecular interactions of these compounds. Molecular docking studies revealed that compound 6a binds to the gastric cancer target protein (4OUM) through hydrogen bonds with Arg1106 and Asn1057, which contribute to its enhanced binding affinity (−5.59 kcal/mol). This binding energy is consistent with its potent antiproliferative activity, establishing a correlation between the computational prediction and the experimental observation. Taken together, these results indicate that compound 6a represents a promising lead for the development of novel anticancer agents.