Anti-breast cancer activity of 6-bromo 2,3-disubstituted quinazolinone analogues as active dual EGFR and VEGFR2 inhibitors

Vandetanib is a quinazoline containing dual EGFR-VEGFR2 inhibitor. Based on its structure, novel inhibitors having quinazolinone moiety
(3a-k)
were designed. The IC
50
value of compounds
3j
was found to be 0.055
µ
M, comparable to erlotinib (0.048
µ
M) in EGFR kinase assay. While, in VEGFR2 kinase assay, lowest IC
50
value was found to be for the compound 3k (0.132
µ
M) as compared to sorafenib (0.114
µ
M). Both the compounds,
3j
and
3k
were found to be active in 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) cytotoxicity assay as compared to staurosporine against MCF7, T47D and MDA-MB-231 breast cancer cell lines. The high potency of compounds
3j
and
3k
is attributed to their low IC
50
values for EGFR and VEGFR2 kinases. Glide XP docking revealed good to excellent binding affinity of the compounds with both the targets EGFR and VEGFR2. The general properties like logD, logP and logS of the synthesized compounds were not excellent but found to be within acceptable limits. The compounds were predicted to be orally bioavailable with good intestinal absorption. In terms of toxicity, all the compounds were found to be non-mutagenic and non-carcinogenic. However, all the compounds were predicted hepatotoxic. So, the designed compounds (
3a-k
) can be used further modified as EGFR-VEGFR2 inhibitors for anti-cancer drug development.