Background: Cancer is one of the major health and social-economic problems despite considerable
progress in its early diagnosis and treatment. Owing to the emergence and increase of multidrug resistance to
various conventional drugs, and the continuing importance of health-care expenditure, many researchers have
focused on developing novel and effective anticancer compounds.
Objective: Chemical repositories provide a good platform to evaluate and exploit known chemical entities for
the identification of other biological activities. In the present study, we have selected an in-house library of
synthesized compounds based on two different pharmacophoric scaffolds to evaluate their cytotoxic potency on
various cancer cell lines and mechanisms of action.
Methods: A series of in-house synthesized quinazoline and quinazolino-benzothiadiazine derivatives were investigated
for their anticancer efficacy against a panel of five cancer (DU145, MCF7, HepG2, SKOV3 and
MDA-MB-231) and one normal (MRC5) cell lines. Furthermore, the active compound of the study was investigated
to elucidate the mechanism of cytotoxicity by performing series of experiments such as cell cycle analysis,
inhibition of tubulin polymerization, alteration of mitochondrial membrane potential, determination of endocytic
pathway for drug uptake pathway and combination drug treatment.
Results: Among all the tested compounds, fifteen of them exhibited promising growth-inhibitory effect (0.15-
5.0μM) and induced cell cycle arrest in the G2/M phase. In addition, the selected compounds inhibited the microtubule
assembly; altered mitochondrial membrane potential and enhanced the levels of caspase-9 in MCF-7
cells. Furthermore, the active compound with a combination of drugs showed a synergistic effect at lower concentrations,
and the drug uptake was mediated through clathrin-mediated endocytic pathway.
Conclusion: Our results indicated that quinazoline and quinazolino-benzothiadiazine conjugates could serve as
potential leads in the development of new anticancer agents.