Design, nanogel synthesis, anti-proliferative activity and <i>in silico</i> ADMET profile of pyrazoles and pyrimidines as topo-II inhibitors and DNA intercalators

Pyrazole derivatives 2 and 3, pyrimidine derivative 4, and their nanogels as drug delivery systems were synthesized, and their cytotoxicity against MCF-7, HCT-116, HepG2 and A549 cells was evaluated. Herein, we focused on the characterization and synthesis of chitosan/polyvinyl alcohol (Cs/PVA) nanogels loaded with derivatives 2, 3 and 4. The stability of the prepared nanogels 2, 3 and 4 was elucidated by zeta potential measurements, which possessed negative values of -9.7, -1.3 and -1.6 mV, respectively. Our compounds and their nanogels were evaluated as topo-II inhibitors and DNA intercalators. The nanogel delivery system enhanced the cytotoxicity of compound 2 against the A549, HCT116, HepG2 and MCF-7 cancer cell lines by 32.06%, 28.96%, 44.32% and 50.00%, respectively. Moreover, the nanogel of compound 3 exhibited enhanced cytotoxicity against the A549, HCT116, HepG2 and MCF-7 cancer cell lines by 33.61%, 30.64%, 44.69% and 47.86%, respectively. Furthermore, the nanogel of compound 4 showed enhanced cytotoxicity against the A549, HCT116, HepG2 and MCF-7 cancer cell lines by 31.82%, 40.12%, 50.00% and 52.61%, respectively. Moreover, derivatives 2, 2 (nanogel), 3, 3 (nanogel), 4 and 4 (nanogel) exhibited good selectivity against cancer cells and reduced toxicity to VERO cells with IC₅₀ values in the range of 48.29-59.70 μM. Furthermore, our derivatives displayed remarkable <i>in silico</i> predicted ADMET profiles.