Evaluation of N 10 -substituted acridone-based derivatives as AKT inhibitors against breast cancer cells: in vitro and molecular docking studies.

A series of N 10 -substituted acridone-2-carboxamide derivatives were synthesized and evaluated for their potent anti-cancer agents targeting AKT kinase. In vitro cytotoxicity activity of the target compounds was tested against breast cancer cell lines (MCF-7 and MDA-MB-231). Among the tested compounds, four compounds (7f, 8d, 8e, and 8f) exhibited promising anti-cancer activity against both cancer cell lines. Notably, compound 8f demonstrated the highest activity against MCF-7 and MDA-MB-231 at IC50 values of 4.72 and 5.53 µM, respectively. In vitro AKT kinase activity revealed that compounds 7f and 8f were the most potent AKT inhibitors with IC50 values of 5.38 and 6.90 µM, respectively. In addition, the quantitative ELISA method of testing confirmed that compound 8f effectively inhibited cell proliferation by suppressing the activation of p-AKT Ser473. Furthermore, molecular docking studies revealed that compound 8f can bind well to the active site of the AKT enzyme. The in silico ADME studies suggested that all synthesized molecules showed good oral bioavailability with a low-toxicity profile and can be used for further optimization as AKT kinase inhibitors in the treatment of breast cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03524-z.

Studies on ligand-based pharmacophore modeling approach in identifying potent future EGFR inhibitors.

Epidermal growth factor receptor (EGFR) is a validated drug target for cancer chemotherapy. Mutations in EGFR are directly linked with the development of drug resistance and this has led for the development of newer drugs in quest for more efficacious inhibitors. The current research is focused on identifying potential and safe molecules as EGFR inhibitors by using both structure and ligand based computational approaches. In quest for finding newer moieties, we have developed a pharmacophore model utilizing drugs like lazertinib, osimertinib, nazartinib, avitinib, afatininb, and talazoparib that are known to inhibit EGFR along with their downstream signaling. Ligand-based pharmacophore model have been developed to screen the ZINC database through ZINCPharmer webserver. The server has identified 9482 best possible ligands with high pharmacophoric similarity i.e., RMSD value less than 0.2 Å. The top 10 ligands with the criteria of dock score(s) and interactions were further subjected to in silico ADMET studies giving two plausible ligands that were further subjected to Molecular Dynamics and MM/PBSA free energy calculations to ensure stability to the target site. Results deduced by in silico work in the current study may be corroborated biologically in the future. The current work, therefore, provides ample opportunity for computational and medicinal chemists to work in allied areas to facilitate the design and development of novel and more efficacious EGFR inhibitors for future experimental studies.