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

• Published in: ChemistrySelect (Weinheim) Vol. 8; no. 34
• Main Authors: Reddy Dodlapati, Venkat, Madhukar Reddy, Tatipelly, Azam, Mohammad, Min, Kim, Narsimha, Sirassu
• Format: Journal Article
• Language: English
• Published: 13-09-2023
• Subjects: Anticancer activity; EGFR; Imidazole; Ramachary OrgAKC; Sulfonyl 1,2,3-triazole
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202301834

A general strategy was developed for the synthesis of new fully decorated sulfonyl1,2,3‐triazolyl imidazoles from β‐ketosulfones and several aryl sulfonyl azides using the ramachary organocatalytic cycloaddition method. Organocatalytic [3+2] cycloaddition reaction of β‐ketosulfone acts as an internal alkyne, as reported for the synthesis of sulfonyl‐1,2,3‐triazolyl imidazoles at 80 °C in good to excellent yields of products in the presence of catalytic amounts of pyrrolidine (10 mol %). In vitro anticancer activity of all these derivatives revealed that four compounds like 4‐((5‐(4‐methoxyphenyl)‐4‐((1‐methyl‐1H‐imidazol‐2‐yl) sulfonyl)‐1H‐1,2,3‐triazol‐1‐yl)sulfonyl) benzonitrile, 5‐(4‐methoxyphenyl)‐4‐((1‐methyl‐1H‐imidazol‐2‐yl)sulfonyl)‐1‐((4‐nitro phenyl) sulfonyl)‐1H‐1,2,3‐triazole,4‐((4‐((1‐methyl‐1H‐imidazol‐2‐yl) sulfonyl)‐5‐(4‐nitrophenyl)‐1H‐1,2,3‐triazol‐1‐yl)sulfonyl)benzonitrile, and 1‐((4‐chlorophenyl)sulfonyl)‐4‐((1‐methyl‐1H‐imidazol‐2‐yl) sulfonyl)‐5‐(4‐nitrophenyl)‐1H‐1,2,3‐triazole was active against three human cancer cell lines: MCF‐7, MDA‐MB‐231, and A‐549. Later, the results of the inhibitory assay of potent compounds against the tyrosine kinase epidermal growth factor receptor revealed that compounds 1‐((4‐chlorophenyl)sulfonyl)‐5‐(4‐methoxyphenyl)‐4‐((1‐methyl‐1H‐imidazol‐2‐yl)sulfonyl)‐1H‐1,2,3‐triazole and 1‐((4‐chlorophenyl) sulfonyl)‐4‐((1‐methyl‐1H‐imidazol‐2‐yl) sulfonyl)‐5‐(4‐nitrophenyl)‐1H‐1,2,3‐triazole showed more potency than the reference drug erlotinib.
The design and synthesis of fully decorated sulfonyl1,2,3‐triazolyl imidazoles (5 a–5 g and 6 a–6 g) from β‐ketosulfones (4 a, b) and several aryl sulfonyl azides using ramachary organocatalytic cycloaddition method. Among them, 5 d, 5 f, 6 d, and 6 f showed superior potency against tested cell lines than erlotinib. In vitro EGFR inhibiting activity results shows that 5 f and 6 f showed superior activity than the erlotinib.