Among the all possible isomers of triazolopyrimidines, 1,2,4-triazolo[1,5-a]pyrimidines are the most important
isomers owing to their vast activities in agriculture and medicinal chemistry. Herein, we present an overview of
the most used synthetic pathways of this scaffold to assist researchers design new drug molecules with expected
pharmacological activities

Two new series of quinazoline‐chalcone hybrids were designed, synthesized as histone deacetylase (HDAC)/epidermal growth factor receptor (EGFR) dual inhibitors, and screened in vitro against the NCI 60 human cancer cell line panel. The most potent derivative, compound 5e bearing a 3,4,5‐trimethoxyphenyl chalcone moiety, showed the most effective growth inhibition value against the panel of NCI 60 human cancer
cell lines. Thus, it was selected for further investigation for NCI 5 log doses. Interestingly, this trimethoxy‐substituted analog inhibited the proliferation of Roswell Park Memorial Institute (RPMI)‐8226 cells by 96%, at 10 μMwith IC50 = 9.09 ± 0.34μM and selectivity index = 7.19 against normal blood cells. To confirm the selectivity of this compound, it was evaluated against a panel of tyrosine kinase enzymes. Mechanistically, it successfully and selectively inhibited HDAC6, HDAC8, and EGFR with IC50=0.41±0.015, 0.61 ± 0.027, and 0.09 ± 0.004 μM, respectively. Furthermore, the selected derivative induced apoptosis via the mitochondrial apoptotic pathway by raising the Bax/Bcl‐2 ratio and activating caspases 3, 7, and 9. Also, the flow cytometry analysis of RPMI‐8226 cells showed that the trimethoxy‐substituted analog produced cell cycle arrest in the G1 and S phases at 55.82%. Finally, an in silico study was performed to explore the binding interaction of the most active compound within the zinc‐containing binding site of HDAC6 and HDAC8.

Novel 3-(4-methylsulfonylphenyl) pyrazole derivatives with different substitutions at position four were
designed, synthesized, characterized by spectroscopic techniques, and investigated as potential anticancer agents via inhibition of cyclin-dependent kinase 2 and cyclooxygenase-2 enzymes. All the synthesized compounds were screened against three cancer cell line panels, hepatocellular carcinoma (HepG-2), mammary gland breast cancer (MCF-7), and colorectal carcinoma (HCT-116), to determine their antiproliferative properties by MTT assay. Compounds 5a, 6a, 6c, and 10c exhibited a considerable antiproliferative effect on HepG-2 cell line with IC50 value of 2.88 to 8.57 μM, on HCT-116 cell line with IC50 value of 6.34 to 17.84 μM, and on MCF-7 cell line with IC50 value of 1.75 to 9.58 μM. Compounds 5a, 6a, 6c, and 10c had weak toxicity towards normal HEK-293T, especially 10c displayed the highest IC50 with a value of 101.21 μM against normal cells. Furthermore, mechanistic studies for the antiproliferative activity were performed on the most active compounds 5a, 6a, 6c, and 10c. Compound 6c exhibited significant inhibitory activity against CDK2 enzyme with IC50 value of 0.614 μM compared to R-roscovitine (IC50 = 0.533 μM) as a reference drug. Additionally, compounds 5a, 6a, 6c, and 10c have significant potency and selectivity for the COX-2 enzyme (IC50 = 0.058 – 0.089 μM) over COX-1 enzyme (IC50 = 9.7 – 11.6 μM) compared to celecoxib and indomethacin. Accordingly, compounds 5a and 6c showed potent COX-2 inhibitory activity with IC50 values of 0.058 and 0.075 μM with a selectivity index of 198.27 and 154.66, respectively, in comparison to celecoxib and indomethacin with COX-2 IC50 value of 0.046 and 0.079 μM and a selectivity index of 315.21 and 1.25. compound 6c, with the potent CDK2 and COX-2 inhibitory activity, demonstrated apoptotic activity on HepG-2 cancer cells by inducing a strong G1 phase cell cycle arrest. Also, compound 6c significantly elevated the Bax/Bcl-2 ratio by 14.54 folds compared to the untreated control, which is clearly correlated with its sensitivity to apoptosis. Molecular docking and dynamics simulations were conducted to illustrate the binding modes inside the active sites. Finally, the hit compound 6c was discovered to
have antiproliferative activity against HepG-2, MCF-7, and HCT-116 cancer cell lines by inhibiting CDK2 and
COX-2 enzymes as proposal mechanisms.