Synthesis, anticancer evaluation, and molecular docking study of novel 4‐hydroxybenzo[h][1,6]naphthyridine‐2,5‐dione derivatives

• Published in: Journal of physical organic chemistry 2023-02, Vol.36 (2), p.n/a
• Main Author: Mostafa, Mai A.
• Format: Article
• Language: English
• Subjects: anticancer activity; benzo[h][1,6]naphthyridine; lactone‐to‐lactam; molecular docking; Topo II enzyme
• ISSN: 0894-3230; 1099-1395
• DOI: 10.1002/poc.4429

An operationally efficient and affordable lactone‐to‐lactam transformation was designed from pyrano[3,2‐c]quinolinone 1 to obtain 4‐hydroxybenzo[h][1,6]naphthyridine‐2,5‐dione 2 utilizing ammonium acetate. The newly synthesized compound 2 was subjected to different electrophilic substitution reactions such as nitration, chlorination, bromination, and N‐acylation to obtain novel benzo[h][1,6]naphthyridine derivatives with different substituents at C‐3, C‐4, and NH. Structures of novel products were achieved by elemental analyses and spectroscopic techniques. The benzonapthyridine derivatives were screened for their antitumor activities against some cancer cell lines including HepG‐2, HCT‐116, and MCF‐7. All the examined compounds revealed strong, good, moderate to weak anticancer activity compared with 5‐fluorouracil as a reference standard. Compound (3, ‐3NO2) was the most cytotoxic one and exhibited a higher inhibitory activity than the standard drug against HCT‐116 and MCF‐7 with IC50 values of 20.7 ± 1.9 and 22.5 ± 2.1 μg/ml, respectively, and strong activity against HepG‐2 with IC50 = 15.3 ± 0.7 μg/ml. Moreover, a molecular docking study was carried out for the tested compounds against the crystallographic structure of the Topo II enzyme as a potential target to investigate their binding modes. Docking results showed that compound 6b fitted well into the active site of topoisomerase II (PDB ID: 1ZXM) with hydrogen bond interactions. 4‐Hydroxybenzo[h][1,6]naphthyridine‐2,5‐dione was subjected to different electrophilic substitution reactions to obtain novel benzonaphthyridine derivatives with different substituents at different positions. Antitumor activity and cytotoxicity of new compounds were evaluated toward some cancer cell lines. Molecular docking with the Topo II enzyme active site is performed.