Design and Synthesis of Potent Anticancer Agents Using Coumarin‐Quinazolinone Based Scaffolds: Exploration of ADME Properties and Molecular Docking Studies

• Published in: ChemistrySelect (Weinheim) 2024-05, Vol.9 (17), p.n/a
• Main Authors: Babagond, Vardhaman, Katagi, Kariyappa, Akki, Mahesh, Reddy, Dinesh S., Shanavaz, Hamzad, Jaggal, Ashwini, D K, Soumyashree
• Format: Article
• Language: English
• Subjects: Anticancer; Coumarin; Cytotoxicity; Molecular docking; Quinazolinones
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202400435

Cancer remains a complex global threat causing widespread deaths. Developing effective anticancer agents despite advancements still remained challenging. In this work it is designed and synthesised therapeutically active anticancer agents based on coumarin‐quinazolinone 5(a–j) through nucleophilic substitution reaction of 4‐bromomethyl coumarin derivatives with 6,7‐bis(2‐methoxyethoxy)quinazolin‐4(3H)‐one and characterised by using FTIR, 1HNMR, 13C NMR and LCMS analysis. The compounds 5(a–j) were screened for in vitro anticancer activity against A‐549 lung cancer cell lines and MDA‐MB‐231 cell lines. Compound 5i emerged as the most promising antiproliferative candidate demonstrating an IC50 value of 7.11 μM against A‐549 cell lines. Meanwhile compound 5g found as a hit candidate in the case of MDA‐MB‐231, exhibiting an IC50 of 5.12 μM, surpassing the potency of the standard drug doxorubicin (IC50 5.89 μM). Further, the safety profile of coumarin‐quinazolinone scafolds (5a–j) were examined for their cytotoxicity towards human embryonic kidney cell lines (HEK293). It was found that the most active compounds exhibited good safety profile towards human embryonic cell lines. Additionally, molecular docking investigations confirmed that compounds 5(a–j) exhibited elevated docking scores and demonstrated favourable interactions with the HER2 (PDB:3PP0) and VEGFR2 (PDB:4ASE). Furthermore, we investigated the ADME properties using the SwissADME tool. We designed active anticancer agents (3 a–j) based on coumarin‐quinazolinone. In testing on A‐549 and MDA‐MB‐231 cell lines, 3 i excelled against A‐549 (IC50 7.11 μM), and 3 g outperformed doxorubicin in MDA‐MB‐231 (IC50 5.12 μM). HEK293 cytotoxicity confirmed safety. Molecular docking showed favorable interactions with Topo IIα ATPase/AMP‐PNP. SwissADME assessed ADME properties.