Synthesis of Oxindole-Conjugated imidazo[2,1-b][1,3,4]thiadiazole as BCL-2 Inhibitors with Anticancer Activity

Abstract

The anti-apoptotic protein BCL-2 is overexpressed in a wide range of human malignancies and plays a pivotal role in tumor progression, therapeutic resistance, and evasion of programmed cell death. Consequently, selective inhibition of BCL-2 has emerged as an attractive strategy in anticancer drug discovery. Despite the clinical success of currently available BCL-2 inhibitors, many compounds still suffer from limitations, including off-target toxicity, resistance development, and adverse hematological effects, underscoring the need for safer, more effective therapeutic alternatives. This study aimed to synthesize oxindole-conjugated imidazo[2,1-b][1,3,4] thiadiazoles inspired by the structural framework of Disarib, a selective BCL-2 inhibitor known for its unique BH1-domain binding mode and minimal platelet toxicity. A molecular hybridization strategy was employed to combine imidazothiadiazole and oxindole pharmacophores into a single scaffold. The target compounds were synthesized via a multistep synthetic route that involved construction of the 1,3,4-thiadiazole core, cyclization to the imidazothiadiazole framework, Vilsmeier–Haack formylation, and final condensation with substituted oxindoles. Structural characterization was accomplished using ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry (HRMS). Three derivatives were successfully obtained in good yields (80–84%) and exhibited high structural stability. Spectroscopic analyses confirmed the successful formation of the desired molecular frameworks. Furthermore, the incorporation of chlorine, bromine, and methoxy substituents was expected to modulate electronic properties and enhance interactions with the BCL-2 binding site. These findings suggest that the synthesized compounds are promising candidates for the development of selective BCL-2-targeted anticancer agents and warrant further biological and pharmacological evaluation.