Design, Synthesis, Antitumour Evaluation, and In Silico Studies of Pyrazolo-[1,5-c]quinazolinone Derivatives Targeting Potential Cyclin-Dependent Kinases

Abstract

An efficient, straightforward, and metal-free methodology to rapidly access functionalised pyrazolo-[1,5-c]quinazolinones via a [3 + 2] dipolar cycloaddition and regioselective ring expansion process was developed. The synthesised compounds were characterised by methods such as NMR, HRMS, and HPLC. The in vitro antiproliferative activity against A549 cells (non-small cell lung cancer) was significant for compounds 4i, 4m, and 4n with IC50 values of 17.0, 14.2, and 18.1 μM, respectively. In particular, compounds 4t and 4n showed inhibitory activity against CDK9/2. Predicted biological target and molecular modelling studies suggest that the compound 4t may target CDKs for antitumour effects. The synthesised derivatives were considered to have moderate drug-likeness and sufficient safety in silico. In summary, a series of pyrazolo-[1,5-c]quinazolinone derivatives with antitumour activity is reported for the first time. We provide not only a simple and efficient synthetic method but also helpful lead compounds for the further development of novel cyclin-dependent kinase (CDK) inhibitors.

Leveraging in situ N-tosylhydrazones as diazo surrogates for efficient access to pyrazolo-[1,5-c]quinazolinone derivatives

“…The Xu group described similar structures with significant antitumor properties and inhibitory activity against cyclin-dependent kinases CDK9 and CDK2. 16 More recently, the photophysical properties of pyrazolo-[1,5- c ]quinazolines have been scrutinized by Sutherland et al 17 These platforms appeared to be interesting chromophores with high fluorescence quantum yields, paving the way for possible bioimaging applications.…”