Novel furo[2,3-<i>d</i>]pyrimidine derivatives as PI3K/AKT dual inhibitors: design, synthesis, biological evaluation, and molecular dynamics simulation

The current study aimed to synthesize a series of innovative improved anticancer chemical entities by combining the unique advantages of 1,3,4-thiadiazole as an established anticancer pharmacophore with the furopyrimidine scaffold which is a key component of many reported cytotoxic agents. Sixteen furopyrimidine derivatives were designed and evaluated by several biological tests including antiproliferative activity against 60 human cancer cell lines, measurement of GI₅₀, TGI, and LC₅₀ values, MTT and selectivity index (SI) calculation, <i>in vitro</i> enzymatic PI3Kα/β and AKT inhibitory assay, cell cycle analysis and apoptosis evaluation. The results indicated that the designed compound 10b revealed potent anticancer activity with a mean GI of 108.32%, remarkable anticancer activity with GI₅₀ values ranging from 0.91 to 16.7 μM and strong cytostatic action (TGI range: 2.32-15.0 μM) against 38 cancer cell lines. It also exhibited a potent and selective antiproliferative activity against the breast cancer HS 578T cell line (GI₅₀ = 1.51 μM and TGI = 4.96 μM). Furthermore, compound 10b demonstrated the highest inhibitory activity against PI3Kα/β and AKT enzymes with IC₅₀ = 0.175 ± 0.007, 0.071 ± 0.003 and 0.411 ± 0.02 μM, respectively. Additionally, it could strongly induce cell cycle arrest in breast cancer HS 578T cells at the G0-G1 phase and trigger apoptosis. Molecular docking and dynamics were also performed in this study which revealed that compound 10b provided an improved binding pattern with the key amino acids in the PI3K and AKT-1 binding sites. According to the findings, the designed compound 10b has potent antiproliferative and apoptotic activities with a wide therapeutic index particularly against breast cancer.