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 (-) and its cyclic analogues hydrazineylidenethiazolidine (-), 2-aminothiadiazole (-), and 2-hydrazineylidenethiazolidin-4-one (-) were synthesized, and their cytotoxic activity was assayed against 60 tumor cell lines. Compounds , , and displayed the most potent activity with lower toxic effects on MCF-10a. phosphatidylinositol 3-kinase (PI3K) enzyme inhibition was performed. Compound displayed half-maximal inhibitory concentration (IC, μM) values of 5.8, 2.3, and 7.9; compound displayed IC values of 19.4, 30.7, and 73.7; and compound displayed IC 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 and and at G1/S for compound , while apoptosis was induced. studies; molecular docking; physicochemical parameters; and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis were performed. The results showed that compound 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.