Synthesis and Biological Evaluation of Benzo[d] thiazolyl‐Sulfonyl‐Benzo[4,5]isothiazolo [2,3‐c][1,2,3] triazole Derivatives as EGFR Targeting Anticancer Agents

Abstract

A one‐step procedure for the synthesis of new fused Benzo[d]thiazolo‐1,2,3‐triazoles (3 a–3 h and 4 a–4 h) in good yields using sulfonylazides (2) and iodoalkyne (1) through from the 5‐iodo 1,2,3‐triazole generated in situ was developed. Among all, compounds 5‐chloro‐3‐(((1,1‐dioxidobenzo[d]thiazol‐2‐yl)sulfonyl)methyl)benzo[4,5]isothiazolo[2,3‐c] [1,2,3]triazole 8,8‐dioxide (3 e), 3‐(((1,1‐dioxidobenzo[d]thiazol‐2‐yl)sulfonyl)methyl)‐5‐fluorobenzo[4,5]isothiazolo [2,3‐c][1,2,3]triazole 8,8‐dioxide (3 f), 5‐bromo‐3‐(((5‐bromo‐1,1‐dioxidobenzo[d]thiazol‐2‐yl)sulfonyl)methyl)benzo [4,5]isothiazolo[2,3‐c][1,2,3]triazole 8,8‐dioxide (4 d), 3‐(((5‐bromo‐1,1‐dioxidobenzo[d]thiazol‐2‐yl)sulfonyl)methyl)‐5‐chlorobenzo [4,5]isothiazolo[2,3‐c][1,2,3]triazole 8,8‐dioxide (4 e) and 3‐(((5‐bromo‐1,1‐dioxidobenzo[d]thiazol‐2‐yl)sulfonyl)methyl)‐5‐fluorobenzo [4,5] isothiazolo[2,3‐c][1,2,3]triazole 8,8‐dioxide (4 f) showed superior activity against A‐549 and good activity against the MCF‐7. Later, in vitro EGFR results revealed that compounds 4 e and 4 f indicated promising potency with IC50 values of 0.316±0.07 and 0.211±0.09 μM respectively. In silico studies of five potent compounds were also carried out to identify interactions against EGFR receptors and found that the energy calculations were consistent with the IC50 values obtained. In silico pharmacokinetic profile was predicted for potent compounds 3 e, 3 f, 4 d, 4 e, and 4 f using SWISS/ADME and pkCSM, where, all the compounds followed the Lipinski rule without any deviation.

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

“…Similarly, carboxyamidotriazole (CAI), a clinical trial phase II anticancer agent [22] . and also our research group previously reported sulfonyl‐1,2,3‐triazoles (A and B) as potent EGFR‐targeting anticancer agents, as shown in Figure 1 [13,15] …”

“…[22] and also our research group previously reported sulfonyl-1,2,3triazoles (A and B) as potent EGFR-targeting anticancer agents, as shown in Figure 1. [13,15] To begin with, Meldal and Sharpless revealed the Cu and Ru-catalysed cycloaddition routes to create regioselective 1,4and 1,5-disubstituted 1,2,3-triazoles, [23,24] which were confined to terminal alkynes. However, the effective building of the ring structure of 1,2,3-triazole without the use of transition metal catalysts and terminal alkynes is also an important issue in pharmaceutical synthesis and organic molecule bioconjugation.…”

“…[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] .…”

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

“…Benzo [4,5]isothiazolo [2,3- c] [1,2,3] triazole-benzo[d]thiazole hybrid 13 (IC 50 : 4.47 µM, MTT assay) was comparable to erlotinib (IC 50 : 4.15 µM) against MCF-7 breast cancer cells and merited further investigations. [33] 1,2,3-Triazole-thiazolidine-2,4-dione hybrids 14 (IC 50 : 0.33-1.64 µM, MTT assay) exhibited potent antiproliferative activity against MCF-7 breast cancer cells, and hybrids 14a-c (IC 50 :330-560 nM) were not inferior to CA-4 (IC 50 : 180 nM). [34] Hybrids 15 (IC 50 : 17.61-26.04 µM, MTT assay) possessed moderate activity against MCF-7 breast cancer cells, and the SAR indicated that substituent on the para-position of phenyl ring reduced the activity.…”