Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Fluorinated Candidates as PI3K Inhibitors: Targeting Fluorophilic Binding Sites

Highly fluorinated candidates containing anticancer pharmacophores like thiosemicarbazone (5a–e) and its cyclic analogues hydrazineylidenethiazolidine (6a–e), 2-aminothiadiazole (7a–e), and 2-hydrazineylidenethiazolidin-4-one (8a–e) were synthesized, and their cytotoxic activity was assayed against 60 tumor cell lines. Compounds 6c, 7b, and 8b displayed the most potent activity with lower toxic effects on MCF-10a. In vitro phosphatidylinositol 3-kinase (PI3K) enzyme inhibition was performed. Compound 6c displayed half-maximal inhibitory concentration (IC₅₀, μM) values of 5.8, 2.3, and 7.9; compound 7b displayed IC₅₀ values of 19.4, 30.7, and 73.7; and compound 8b displayed IC₅₀ values of 77.5, 53.5, and 121.3 for PI3Kα, β, and δ, respectively. Moreover, cell cycle progression caused cell cycle arrest at the S phase for compounds 6c and 8b and at G1/S for compound 7b, while apoptosis was induced. In silico studies; molecular docking; physicochemical parameters; and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis were performed. The results showed that compound 6c is the most potent one with a selectivity index (SI) of 39 and is considered as a latent lead for further optimization of anticancer agents.