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

  • J Med Chem. 2021 Dec 9;64(23):17468-17485. doi: 10.1021/acs.jmedchem.1c01674.
Ahmed H Tantawy  1  2  3 ,  Mohammed Farrag El-Behairy  4 ,  Walaa Hamada Abd-Allah  5 ,  Hong Jiang  2 ,  Man-Qun Wang  1 ,  Adel A Marzouk  6
Affiliations
  • 1. Hubei Insect Resources Utilization and Sustainable Pest Management Key Laboratory, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, People's Republic of China.
  • 2. Department of Chemistry, College of Science, Huazhong Agricultural University, Wuhan 430070, People's Republic of China.
  • 3. Department of Chemistry, College of Science, Benha University, Benha 13518, Egypt.
  • 4. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Menoufiya 32897, Egypt.
  • 5. Pharmaceutical Chemistry Department, Collage of Pharmaceutical Science and Drug Manufacturing, Misr University for Science and Technology, P.O. 77, 6th of October City, Giza 12568, Egypt.
  • 6. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
PMID: 34791873 DOI: 10.1021/acs.jmedchem.1c01674
Abstract

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.

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