Quinazoline‐tethered hydrazone: A versatile scaffold toward dual anti‐TB and EGFR inhibition activities in NSCLC
- 29 September 2021
- journal article
- research article
- Published by Wiley in Archiv der Pharmazie
- Vol. 354 (12), e2100281
- https://doi.org/10.1002/ardp.202100281
Abstract
Globally, lung cancer and tuberculosis are considered to be very serious and complex diseases. Evidence suggests that chronic infection with tuberculosis (TB) can often lead to lung tumors; therefore, developing drugs that target both diseases is of great clinical significance. In our study, we designed and synthesized a suite of 14 new quinazolinones (5a–n) and performed biological investigations of these compounds in Mycobacterium tuberculosis (MTB) and cancer cell lines. In addition, we conducted a molecular modeling study to determine the mechanism of action of these compounds at the molecular level. Compounds that showed anticancer activity in the preliminary screening were further evaluated in three cancer cell lines (A549, Calu-3, and BT-474 cells) and characterized in an epidermal growth factor receptor (EGFR) binding assay. Cytotoxicity in noncancerous lung fibroblast cells was also evaluated to obtain safety data. Our theoretical and experimental studies indicated that our compounds showed a mechanism of action similar to that of erlotinib by inhibiting the EGFR tyrosine kinase. In turn, the antituberculosis activity of these compounds would be produced by the inhibition of enoyl-ACP-reductase. From our findings, we were able to identify two potential lead compounds (5i and 5l) with dual activity and elevated safety toward noncancerous lung fibroblast cells. In addition, our data identified three compounds with excellent anti-TB activities (compounds 5i, 5l, and 5n).Keywords
This publication has 71 references indexed in Scilit:
- Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domainBiochemical Journal, 2012
- Characterization of Domain–Peptide Interaction Interface: Prediction of SH3 Domain-Mediated Protein–Protein Interaction Network in Yeast by Generic Structure-Based ModelsJournal of Proteome Research, 2012
- Strategies for overcoming resistance to EGFR family tyrosine kinase inhibitorsCancer Treatment Reviews, 2011
- A Slow, Tight Binding Inhibitor of InhA, the Enoyl-Acyl Carrier Protein Reductase from Mycobacterium tuberculosisOnline Journal of Public Health Informatics, 2010
- Improved side‐chain torsion potentials for the Amber ff99SB protein force fieldProteins, 2010
- AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibilityJournal of Computational Chemistry, 2009
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004
- Development and testing of a general amber force fieldJournal of Computational Chemistry, 2004
- Comparative Protein Modelling by Satisfaction of Spatial RestraintsJournal of Molecular Biology, 1993
- Comparison of simple potential functions for simulating liquid waterThe Journal of Chemical Physics, 1983