ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Microwave-assisted synthesis of 2,5-dioxo-pyrano[3,2-c]quinoline-3-carboxylates and their investigation as antiproliferative agents targeting EGFR and/or BRAF^V600E

Ashraf A. Aly, Hisham A. Abd El-Naby, Essam Kh. Ahmed, Raafat M. Shaker, Sageda A. Gedamy, Bahaa G. M. Youssif, Hesham A. M. Gomaa, Olaf Fuhr, Alan B. Brown, Mahmoud A. A. Ibrahim, and Lamiaa E. Abd El-Haleem

Chemistry Department, Faculty of Science, Minia University, El-Minia, Egypt

E-mail: ashrafaly63@yahoo.com

Received: 20 January 2024  Accepted: 5 July 2024

Abstract:

Pyrano[3,2-c]quinoline-3-carboxylate derivatives 3a-j were synthesized efficiently by the microwave–irradiated condensation of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehydes 4a-j with ethyl cyanoacetate (2) in the presence of ethanol and a catalytic amount of piperidine. The structures of the products were confirmed by a combination of spectral techniques including infra-red (IR), nuclear magnetic resonance (NMR), mass spectrometry (MS) and elemental analyses in addition to X-ray structure analysis. The synthesized compounds 3a-j were tested for their in vitro antiproliferative activity against four human cancer cell lines using the MTT assay and doxorubicin as the reference drug: pancreas (Panc-1) cancer cell line, breast cancer (MCF-7) cell line, colon cancer (HT-29) cell line, and epithelial cancer (A-549) cell line. In comparison to the standard doxorubicin (GI₅₀= 1.10 µM), compounds 3a-j demonstrated promising antiproliferative action, with GI₅₀ values ranging from 1.30 to 5.90 µM. The most effective derivatives were compounds 3c, 3g, 3h, and 3i with GI₅₀ values ranging from 1.30 to 2.20 µM. The most potent antiproliferative derivative, compound 3c (R¹= OCH₃, R²= R³= H), was also the most potent EGFR inhibitor, with an IC₅₀ value of 105 ± 08 nM, 1.3-fold less potent than erlotinib (IC₅₀ = 80 ± 05 nM). Compounds 3g (R¹= Br, R²= R³= H) and 3h (R¹= Cl, R²= R³= H) were the second and third most active, with IC₅₀ values of 124 ± 10 nM and 195 ± 13 nM, respectively. Molecular docking calculations were conducted to inspect the docking scores and poses of the most promising compounds against EGFR and BRAF^V600E. Based on the docking computations, compounds 3c and 3g revealed promising docking scores against the EGFR and BRAF^V600E with values of − 7.9 and − 8.3 kcal/mol, respectively.

Graphical Abstract

Keywords: Pyrano[3,2-c]quinoline-3-carboxylates; Microwave; X-ray structure; Antiproliferative activity; EGFR; BRAF; Viability; Molecular modeling

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-024-03599-9

Chemical Papers 78 (12) 7187–7199 (2024)