Combined in silico and in vitro cytotoxic profiling of novel quinazoline derivatives targeting anaplastic lymphoma kinase for lung cancer therapy

Lung Cancer is one of the most common cancers globally, and targeting specific molecular pathways, such as the anaplastic lymphoma kinase (ALK), has shown great potential in developing effective treatments. From the X-ray crystal structure analysis of ALK, its binding interactions have highlighted the critical role of the pyrimidine moiety in ALK inhibition. Building on this insight, a series of novel N,4-diaryl-5,6-dihydrobenzo[h]quinazolin-2-amines was designed by incorporating 2-aminopyrimidine and tetralin frameworks via a hybridisation strategy. The library of eleven novel N,4-diaryl-5,6-dihydrobenzo[h]quinazolin-2-amines has been synthesised through the optimised Buchwald-Hartwig reaction. The synthesised compounds were evaluated for in vitro antiproliferative activity against lung Cancer cell lines Karpas 299, H2228, A549, and gastric adenocarcinoma cell line AGS. And its ALK-selective inhibition was analyzed experimentally using an enzyme inhibition assay. Parallelly, molecular docking studies and molecular mechanics/generalized Born surface area (MM/GBSA) calculations have been conducted to assess their binding affinities with Anaplastic Lymphoma Kinase (ALK). Both the biological assay and computational studies revealed that the synthesised compounds exhibited significant cytotoxic activity. In particular, compound 8c, featuring a 4-methoxybenzene moiety, showed significant potency, emphasizing the therapeutic potential of pyrimidine-based scaffolds in the development of novel anti-lung Cancer agents.

Anaplastic lymphoma kinase (ALK); Buchwald-Hartwig reaction; In silico studies; Lung cancer; Novel Quinazolines.