Nanoparticles of a Pyrazolo-Pyridazine Derivative as Potential EGFR and CDK-2 Inhibitors: Design, Structure Determination, Anticancer Evaluation and In Silico Studies

Abstract

The strategic planning of this study is based upon using the nanoformulation method to prepare nanoparticles 4-SLNs and 4-LPHNPs of the previously prepared 4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-amine (4) after confirming its structure with single crystal X-ray analysis. These nanoparticles exhibited promising cytotoxic activity against HepG-2, HCT-116 and MCF-7 cancer cell lines in comparison with the reference doxorubicin and the original derivative 4. Moreover, their inhibitory assessment against EGFR and CDK-2/cyclin A2 displayed improved and more favorable impact than the parent 4 and the references. Detection of their influence upon cancer biomarkers revealed upregulation of Bax, p53 and caspase-3 levels and downregulation of Bcl-2 levels. The docking simulation demonstrated that the presence of the pyrazolo[3,4-c]pyridazin-3-amine scaffold is amenable to enclosure and binding well within EGFR and CDK-2 receptors through different hydrophilic interactions. The pharmacokinetic and physicochemical properties of target 4 were also assessed with ADME investigation, and the outcome indicated good drug-like characteristics.

Synthesis, in silico ADMET prediction analysis, and pharmacological evaluation of sulfonamide derivatives tethered with pyrazole or pyridine as anti-diabetic and anti-Alzheimer's agents

“… The biological effects of pyrazole, pyridine, and sulfonamide derivatives. Nitrogenous compounds with multiple biological activities, such as antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic agents ( Zahoor et al, 2023 , Hammouda et al, 2023 , Zhang et al, 2024 , Abdel-Aziz et al, 2015 , Hashem et al, 2023 ). In addition to our previous studies that highlight the development of various compounds and evaluation of their biological effects as potential drug candidates ( Mukhtar et al, 2021 , Hassan et al, 2015 , Morsy et al, 2021 ).…”

“…Nitrogenous compounds with multiple biological activities, such as antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic agents ( Zahoor et al, 2023 , Hammouda et al, 2023 , Zhang et al, 2024 , Abdel-Aziz et al, 2015 , Hashem et al, 2023 ).…”