Design, synthesis and chemoinformatic studies of new thiazolopyrimidine derivatives as potent anticancer agents via phosphodiesterase-5 inhibition and apoptotic inducing activity

Inhibition of phosphodiesterase-5 (PDE5) has been validated as possible new therapeutic approach for cancer. To further explore this concept, three series of thiazolopyrimidine containing compounds has been designed and synthesized as PDE5 inhibitors. All the compounds were evaluated against PDE5 inhibitory effect in addition to their antiproliferative activities against three different cancer cell lines (colorectal carcinoma colon cancer; HCT-116, mammary gland breast cancer; MCF-7 and human prostate cancer; PC3) in addition to normal cell line (human lung fibroblast; WI38). Among the synthesized compounds, three compounds (3c, 4a and 5a) significantly inhibit PDE5 with IC50 0.046 nM, 0.323 nM, and 0.546 nM, respectively in comparison to sildenafil (IC50 0.689 nM). Moreover, compounds 3a, 3c, 3f, 3g, 3h were found to have potent cytotoxic activities against MCF-7 cancer cell line with IC50 ranging from 5.47 +/- 0.4 to 9.92 +/- 0.9 mu M. Apoptosis cytometric assay showed that compound 5a induced pronounced increase in the total percent of apoptotic HCT116 cells (15.87%) compared to 3c (12.43%), mainly during late stage. Additionally, compounds 3c and 5a were evaluated against proapoptotic Bax, and anti-apoptotic Bcl-2 expression levels that revealed that both compounds expressively enhanced Bax 7.68 and 5.42 folds, respectively compared to untreated control. Also, both compounds 3c and 5a down regulate Bcl-2 with 2.94 and 2.354 ng/mL, respectively. From the docking study, it was concluded that compounds 3c and 5a interact in a similar pattern to sildenafil in the binding site of PDE5. Finally, logP and in silico ADMET assessment were calculated to determine the lipohpilcity metric and ADMET properties for these candidates. (c) 2022 Elsevier B.V. All rights reserved.