Current Enzyme Inhibition - Online First

Heterocyclic compounds containing oxygen, nitrogen, and/or sulfur atoms are of significant importance in drug discovery and development. Pyrazole moieties, in particular, have broad applications across various fields, including herbicides, corrosion inhibitors, electron transport materials, polymers, and luminescent materials. This underscores the growing need in medicinal chemistry to design new anticancer agents that improve therapeutic efficacy and safety.

A series of novel pyrazole-naphthalene derivatives were synthesized from chalcones, which were obtained through an aldol condensation between benzaldehyde and acetophenone, followed by a Claisen-condensation reaction. All the synthesized compounds were characterized by NMR and IR spectrum examinations, as well as C, H, and N analyses. The synthesized compounds were screened for biological activity against the breast cancer cell line (MCF-7 strain) using an MTT assay. Furthermore, a molecular docking study was performed to elucidate the binding modes of synthesized ligands in the active pockets of the three-dimensional crystallographic structure of CDK2 in complex with inhibitor RC-1-148 (PDB ID: 3QTR) for further predicting the mechanism of action.

Molecules R5, R8, and R9 were found to be the most active compounds in the series, exhibiting sensitivity of up to 5.0 μg/ml. Additionally, compounds R8, R13, and R10 demonstrated activity against cancer cells, with sensitivity reaching up to 3.2 μg/ml.

This study presents a promising class of pyrazole-naphthalene derivatives with significant anticancer activity, particularly against the MCF-7 breast cancer cell line. The combined biological screening and molecular docking suggest that these compounds could serve as potential lead candidates for further development in anticancer drug discovery.

The current study highlights the unique structural characteristics and significant biological activity of the synthesized compounds. In the pursuit of novel anticancer molecules, these compounds could prove beneficial to society.

Breast cancer is the most prevalent cancer among women globally, characterized by the uncontrolled growth of breast cells, and remains a leading cause of cancer-related morbidity and mortality. It can occur in both men and women, though it is significantly rarer in men. The multifactorial nature of breast cancer involves genetic mutations, hormonal influences, and complex cellular signalling pathways. The disease is typically classified into different subtypes based on hormone receptor status, which influences treatment decisions. Early detection through regular screening, such as mammograms, and awareness of symptoms significantly improve prognosis. Treatment options vary based on the stage and type of breast cancer and may include surgery, radiation therapy, chemotherapy, hormone therapy, and targeted therapy. We aimed to design novel compounds based on reported active pharmacophoric features and validate them through molecular modelling. These designed compounds were then synthesized and characterized. Finally, a biological evaluation of the synthesized compounds was performed to assess their efficacy.

Thirty compounds were designed based on a literature survey. Out of these compounds, twelve compounds were found good on the docking studies, and these twelve new derivatives (RD 01-12) were synthesized and subjected to in silico, in vitro (EGFR assay), and ADMET profiling to identify the most potent compound.

All 12 compounds were synthesised and characterised. Out of 12 compounds, RD-09 emerged as the most potent enzymatic assay with an IC50 value of 1.21 ± 0.03 µM, confirmed by docking studies; it possessed a docking score of -7.302 against the EGFR receptor. These compounds were further characterized using IR, ¹H NMR, and mass spectrometry.

Based on pharmacophoric features, twelve triazine-4-thiazolidinone derivatives (RD 01-12) were designed, synthesized, and evaluated for their potential as EGFR-2 inhibitors, specifically targeting triple-negative breast cancer (TNBC). Among 12 synthesised compounds, compound RD-09 demonstrated the most significant activity with an IC50 value of 1.21 ± 0.03 µM. Docking studies further supported its binding interaction with the catalytic domain of the EGFR receptor. The combined results from in vitro, in silico, and ADMET profiling suggest that RD-09 holds promise as a leading compound for further development in the treatment of TNBC.