Synthesis, DFT analysis, and molecular docking of pyrazole derivatives as targeted inhibitors of PI3K/AKT and JAK/STAT pathways in lung cancer cells

Abstract

Cancer is one of the most prevalent causes of death. Lung cancer is the primary cause of cancer-related mortality worldwide. Chemotherapy is one of the cornerstones of cancer treatment. Among the adverse effects of many anticancer drugs currently available on the market are decreased targetability and drug resistance. Therefore, we urgently need to create novel, focused anticancer medications. Because pyrazoles have several sites for alteration, they offer the flexibility to design and construct structural analogs of biomedical interest. In this study, pyrazole-based analogs 3a-b, 5a-b, 7a-b, 9a-b, 10a-b, 12a-b, 13a-b, 14a-b, 15a-b and 17a-b were synthesized and characterized through various spectrum analyses. The MTT technique evaluated all produced compounds using the human lung cancer cell line (A549). Compounds 7a and 14a showed the highest cytotoxicity against A549 cells, recording IC₅₀ values equal to 8.557 μg/mL and 8.656 μg/mL, respectively, versus Ruxolitinib (Ruxo) (IC₅₀ = 11.875 μg/mL).

Additionally, DFT calculations revealed smaller energy gaps (ΔE), enhanced electrophilicity (ω), and greater softness (σ) for 7a and 14a compared to the reference drug, which is consistent with their increased reactivity and better interaction with biological targets. Also, compounds 17a, 17b, and 15a showed high cytotoxicity against A549 cells. The lack of selectivity of chemotherapeutic medications is one of their primary drawbacks, as it may negatively impact healthy cells. Finding chemotherapy that is unique to tumors and has the potential to target cancer cells is therefore necessary. Pyrazole derivatives 7a, 14a, 15a, 17a, and 17b were the least cytotoxic to normal WI38 lung cells out of all the chemicals studied. It's fascinating to note that compounds 7a and 17a had little effect on normal WI-38 cells while particularly blocking the PI3K/AKT and JAK/STAT pathways in A549 cells. Compounds 7a and 17a induced lung cancer cell death by upregulating Bax and Caspase 3, which supported blocking these pathways. Moreover, a molecular docking investigation focused on the JAK/STAT and PI3K/AKT pathways was performed.