Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation and destruction, leading to significant pain and disability. Adenosine deaminase (ADA) is identified as a biomarker for RA’s inflammatory process. This study aims to investigate the potential of flavonoids and phenolic acids to inhibit ADA activity (in silico) and evaluate their anti-inflammatory effects in a RA model (in vivo). Methods: The molecular docking study was conducted using YASARA Structure 19.12.14. software following the Auto Dock 4.2 protocol. A rat model with pristane-induced arthritis was used to test the anti-inflammatory effect of selected polyphenols. The consistency of the development of the rat model was evaluated through the following indicators artistic score, paw volume, and body weight. Quercetin was administered intragastrically at doses of 150 and 400 mg/kg over 15 days. The C-reactive protein (CRP) level in serum was measured with an automatic biochemical analyzer. Statistical analyses were performed using SPSS 29.0.2.0. Results: Molecular docking simulations showed flavonoids inhibited ADA activity with inhibition constants ranging from 0.012 mM to 0.190 mM. In the in vivo RA model, quercetin significantly reduced joint inflammation and serum CRP levels at a higher dose of 400 mg/kg. Conclusion: Quercetin shows promise as an anti-inflammatory agent for RA by targeting ADA, suggesting that flavonoid-rich plant extracts could enhance RA treatment.

The pyrimidine heterocycle plays an important role in anticancer research. In particular, the pyrimidine derivative families of uracil show promise as structural scaffolds relevant to cervical cancer. This group of chemicals lacks data-driven machine learning quantitative structure-activity relationships (QSARs) that allow for generalization and predictive capabilities in the search for new active compounds. To achieve this, a dataset of pyrimidine and uracil compounds from ChEMBL were collected and curated. A workflow was developed for data-driven machine learning QSAR using an intuitive dataset design and forwards selection of molecular descriptors. The model was thoroughly externally validated against available data. Blind validation was also performed by synthesis and antiproliferative evaluation of new synthesized uracil-based and pyrimidine derivatives. The most active compound among new synthesized derivatives, 2,4,5-trisubstituted pyrimidine was predicted with the QSAR model with differences of 0.02 compared to experimentally tested activity.

Xanthene derivatives are an important class of heterocyclic compounds with a wide spectrum of pharmacological activities. In our previous investigations, we found the good antiproliferative activity of two xanthene derivatives, with minimal toxicity investigated by in vitro tests. In this study, we tested the interaction of compound 1 (powerful potent antiproliferative compound) with calf thymus DNA (CT-DNA) under physiological conditions by spectrophotometric titration. The probable prediction of binding and the type of interaction forces involved in the arrangement between xanthene derivatives and CT-DNA were explored also through molecular docking studies. The results indicated that compound 1 interacts with CT-DNA by grove binding. The binding constant was found to be 2.5 ∙ 10 4 M −1 indicating the non-covalent binding of compound 1 to CT-DNA. Docking study results proposed possible binding modes, with binding energies of −9.39 and −8.65 kcal mol −1 for compounds 1 and 2, respectively, which supported previously obtained in vitro results for antiproliferative activity. In addition to experimental investigation, density functional theory (DFT) calculation with B3LYP/6-31G*, B3LYP/6-31G**, and B3LYP/6-31+G* levels of theories was performed on compounds 1 and 2 to obtain optimised geometry, spectroscopic and electronic properties. These studies could help in understanding the mechanisms of toxicity, resistance, side effects of xanthene derivatives, and their binding action mechanism to DNA

Two copper(II) complexes of 4-chloro- and 4-dimethylaminobenzaldehyde nicotinic acid hydrazones were prepared and characterized by elemental analysis, mass spectrometry, infrared and electron spectroscopy and conductometry. These rare examples of bis(hydrazonato)copper(II) complexes are neutral complex species with copper(II) center coordinated with two monoanionic bidentate O,N-donor hydrazone ligands coordinated in enol-imine form. The interaction of hydrazone ligands and corresponding copper(II) complexes with CT DNA and BSA was investigated. Copper(II) complexes are slightly effective in binding the DNA than pristine hydrazones. The results indicate groove binding or moderate intercalation which are not significantly affected by the nature of substituent at hydrazone ligands. On contrary, affinities of two copper(II) complexes toward BSA significantly differs and depends on the nature of the substituent, however in absence of thermodynamic data difference in nature of binding forces cannot be excluded. The complex bearing electron-withdrawing 4-chloro substituent has larger affinity toward BSA compared to 4-dimethyamino analogue. These findings were theoretically supported by molecular docking study.

Chronic myeloid leukemia (CML) is a myeloproliferative haematological malignancy characterized by constitutive activation of BCR-ABL1 tyrosine kinase in the majority of patients. BCR-ABL1 expression activates signaling pathways involved in cell proliferation and survival. Current treatment options for CML include tyrosine kinase inhibitors (TKI) with resistance as a major issue. Various treatment options for overcoming resistance are being investigated. Among them, phytochemical curcumin could play an important role. Curcumin has been found to exhibit anti-cancerous effects in various models, including CML, through regulation of multiple molecular signaling pathways contributing to tumorigenesis. We have evaluated curcumin’s effects on imatinib-sensitive LAMA84S and K562, as well as imatinib-resistant LAMA84R cell lines. Our results indicate a significant dose-dependent decrease in cell viability and proliferation of imatinib-sensitive and imatinib-resistant cell lines after curcumin treatment. Suppression of key signaling molecules regulating metabolic and proliferative events, such as Akt, P70S6K and NF-kB, was observed. Increased expression of caspase-3 suggests the potential pro-apoptotic effect of curcumin in the imatinib-resistant CML model. Additional in silico molecular docking studies revealed binding modes and affinities of curcumin with different targets and the results are in accordance with in vitro findings. Altogether, these results indicate the potential role of curcumin in the treatment of CML.

Two tetraketone derivatives, one previously reported and one novel, were synthesized, whose structures have been confirmed by elemental analyses, NMR, HPLC-MS, and IR spectroscopy. The crystal structures of synthesized tetraketones were determined using X-ray single-crystal diffraction. To analyze the molecular geometry and compare with experimentally obtained X-ray crystal data of synthesized compounds 1 (2,2'-((4-nitrophenyl)methylene)bis(5,5-dimethylcyclohexane-1,3-dione)) and 2 (2,2'-((4-hydroxy-3-methoxy-5-nitrophenyl)methylene)bis(5,5-dimethylcyclohexane-1,3-dione)), DFT calculations were performed with the standard 6-31G*(d), 6-31G**, and 6-31+G* basis sets. The calculated HOMO-LUMO energy gap for compound 1 was 4.60 eV and this value indicated that compound 1 is chemically more stable compared to compound 2 whose energy gap was 3.73 eV. Both compounds' calculated bond lengths and bond angles were in very good accordance to experimental values determined by X-ray single-crystal diffraction.

The aim of the present study is to improve the solubility and antimicrobial activity of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin by formulating its inclusion complexes with 2-hydroxypropyl-β-cyclodextrin in solution and in solid state. The phase solubility study was used to investigate the interactions between 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin and 2-hydroxypropyl-β-cyclodextrin and to estimate the molar ratio between them. The structural characterization of binary systems (prepared by physical mixing, kneading and solvent evaporation methods) was analysed using the FTIR-ATM spectroscopy. The antimicrobial activity of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin and inclusion complexes prepared by solvent evaporation method was tested by the diffusion and dilution methods on various strains of microorganisms. The results of phase solubility studies showed that 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin formed the inclusion complexes with 2-hydroxypropyl-β-cyclodextrin of AP type. The solubility of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin was increased 64.05-fold with 50% w/w of 2-hydroxypropyl-β-cyclodextrin at 37 o C. The inclusion complexes in solid state, prepared by the solvent evaporation method, showed higher solubility in purified water and in phosphate buffer solutions in comparison with 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin alone. The inclusion complexes prepared by solvent evaporation method showed higher activity on Bacillus subtilis and Staphylococcus aureus compared to uncomplexed 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin due to improved aqueous solubility, thus increasing the amount of available 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin that crosses the bacterial membrane.