Design, Synthesis, and Anti-Inflammatory Evaluation of Novel Derivatives of 9-(Phenyl)-3-Methyl-1,3-Thiazolo[3,2-a]Indole from 3-Aryl Oxindoles

A concise and transition-metal-free synthetic strategy has been established for the efficient construction of highly functionalized 3-aryl thiazolo[3,2-a]indole architectures from readily available 3-aryl oxindole scaffolds. The protocol involves sequential thionation of oxindole precursors followed by regioselective annulative cyclization with ethyl 2-chloroacetoacetate and 4-cyanophenacyl bromide in an alcoholic medium, followed by hydrolysis and amidation to form corresponding ester (5a-g), acid (6a-f), 4-cyanophenyl (7a-f), and amide (8a-d) derivatives in consistently high yields. The protocol offers operational simplicity, mild reaction conditions, broad substrate tolerance, and avoids transition metal catalysts and chromatographically demanding purification, providing a practical approach to sulfur-fused polycyclic heteroaromatic scaffolds. A plausible mechanistic pathway involving the in situ generation of 3-aryl indoline-2-thiol intermediates, followed by intramolecular cyclocondensation, was proposed for the formation of the fused thiazolo[3,2-a]indole nucleus. Importantly, the protocol provides a direct and scalable route to densely functionalized heterocycles of potential in medicinal, pharmaceutical, and polycyclic aromatic chemistry. Structural elucidation of all synthesized compounds was accomplished using 1H NMR,13C NMR, IR, and mass spectrometric analyses. The synthesized derivatives were screened against cyclooxygenase-2 (COX-2) activity. It observed that the functionalized 3-aryl thiazolo[3,2-a]indole is found promising scaffold for the possible design of COX-2 inhibitors.