Cu(I)‐Catalyzed One‐Pot Synthesis of [1,2,3]Triazolo[5,1‐a] isoquinolin‐6(5H)‐one Derivatives as EGFR‐Targeting Anticancer Agents

Abstract

The CuI promoted one‐pot multi‐component synthesis of new fused [1,2,3]triazolo[5,1‐a]isoquinoline derivatives (4 a–4 h, 8 a–8 f & 9 a–9 f) without isolating unsafe azides and their in vitro cytotoxic activity against MCF‐7 & MDA‐MB‐231 (breast cancer cells) and A‐549 (alveolar carcinoma) was reported herein. Out of all, compounds 9‐chloro‐1‐(morpholinomethyl)‐[1,2,3]triazolo[5,1‐a]isoquinolin‐6(5H)‐one (8 d), 9‐fluoro‐1‐(morpholinomethyl)‐[1,2,3]triazolo[5,1‐a]isoquinolin‐6(5H)‐one (8 e), 9‐chloro‐1‐((1,1‐dioxidothiomorpholino)methyl)‐[1,2,3]triazolo[5,1‐a]isoquinolin‐6(5H)‐one (9 d), and 1‐((1,1‐dioxidothiomorpholino)methyl)‐9‐fluoro‐[1,2,3]triazolo[5,1‐a]isoquinolin‐6(5H)‐one (9 e) showed superior potency against all the cell lines than the standard drug erlotinib with IC50 values ranging from 2.45 to 7.19 μM. The most active compounds 8 d, 8 e, 9 d, and 9 e were also screened for their efficacy in inhibiting tyrosine kinase EGFR and results revealed that compound 9 d showed comparable activity with standard drug erlotinib, whereas, compounds 8 d, 8 e, and 9 e showed superior activity than the erlotinib. Molecular modeling studies for active compounds on EGFR (PDB‐ID‐4HJO) were also conducted and the obtained free energies were observed to be in agreement with the in vitro activity data. Finally, compounds 8 d, 8 e, 9 d, and 9 e didn't show AMES toxicity and followed the rules of Egan, Ghose, Veber, Lipinski, and Muegge rules without any deviation.

The anti‐breast cancer therapeutic potential of 1,2,3‐triazole‐containing hybrids

“…[1,2,3]Triazolo[5,1‐ a ]isoquinolin‐6(5 H )‐ones hybrids 85 (IC 50 : 2.45–24.67 µM, MTT assay) and 86 (IC 50 : 3.68–20.44 µM) showed considerable antiproliferative activity against MCF‐7 and MDA‐MB‐231 breast cancer cell lines, and the SAR illustrated that (1) heterocycle at C‐4 position of 1,2,3‐triazole moiety was critical for the high activity; (2) halogen atom at R position was favorable to the activity. [ 111 ] The representative hybrids 85a,b (IC 50 : 2.45–5.85 µM) and 86a,b (IC 50 : 3.68–6.32 µM) were superior to erlotinib (IC 50 : 4.15 and 7.21 µM) against MCF‐7 and MDA‐MB‐231 breast cancer cell lines and displayed relatively low cytotoxicity (IC 50 : 13.67–16.54 µM) toward normal MCF‐10A breast cells. In addition, hybrids 85a,b (IC 50 : 210 and 340 nM) and 86a,b (IC 50 : 416 and 469 nM) were comparable to erlotinib (IC 50 : 421 nM) in inhibition of EGFR.…”

“…[110] In particular, hybrids 84a-c (2) halogen atom at R position was favorable to the activity. [111] The 1.28 and 7.34 µM) against MCF-7 and MDA-MB-231 breast cancer cell lines. [112] In addition, hybrid 87 (IC 50 : 167.2 µM) also displayed lower cytotoxicity than cisplatin (IC 50 : 24.92 µM) toward normal MCF-10A breast cells.…”

Organocatalytic [3+2] Cycloaddition Reaction: Synthesis of Fully Decorated Sulfonyl 1,2,3‐Triazoles as Potent EGFR Targeting Anticancer Agents**

“…[5][6][7][8][9][10][11][12] Some sulfonyl 1,2,3-triazoles have also been shown to have effective anticancer properties. [13][14][15][16] Furthermore, imidazoles are a significant class of nitrogen-containing heterocyclic chemicals with numerous uses, particularly anticancer properties. [17,18] Naamidine A potent Epidermal Growth Factor Receptor targeting imidazole derivative reported by Brent et al in 1988 [19] and Topsentin, a potent anticancer agent containing imidazole derivative reported by Hwang et al in 2020.…”

“…Anticancer, antibacterial, antioxidant, anti‐HIV, and anti‐inflammatory characteristics are among the biological properties [5–12] . Some sulfonyl 1,2,3‐triazoles have also been shown to have effective anticancer properties [13–16] . Furthermore, imidazoles are a significant class of nitrogen‐containing heterocyclic chemicals with numerous uses, particularly anticancer properties [17,18] .…”

One‐pot synthesis and biological evaluation of novel 4‐[3‐fluoro‐4‐(morpholin‐4‐yl)]phenyl‐1H‐1,2,3‐triazole derivatives as potent antibacterial and anticancer agents

“…With this in mind, the research has begun to study biologically active properties, especially anticancer and antibacterial, by merging two units of pharmacophore, both an anticancer active 1,2,3‐triazole scaffold and an antibacterial active 4‐(2‐fluorophenyl) morpholine derived from linezolid, which are designed and synthesized (Figure ), a substituent at the fourth position of the 1,2,3‐triazole ring adapts the potency of anticancer and antibacterial activities.…”