Design, molecular modelling and synthesis of novel benzothiazole derivatives as BCL-2 inhibitors

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• Apoptosis, a programmed cell death process, is vital in cancer development and resistance to therapies.
• The BCL-2 protein family, comprising anti-apoptotic and pro-apoptotic members, critically regulates apoptosis.
• Dysregulation of the BCL-2 family's balance contributes to cancer pathogenesis.

Purpose of the Study:

• To design and synthesize novel benzothiazole-based molecules as inhibitors of BCL-2.
• To evaluate the BCL-2 inhibitory potential of these newly synthesized compounds.
• To explore structure-activity relationships for optimizing BCL-2 inhibition.

Main Methods:

• Synthesis of 33 novel benzothiazole derivatives utilizing a scaffold hopping strategy.
• In vitro testing of synthesized compounds for BCL-2 inhibitory activity.
• Molecular docking studies to assess binding interactions with BCL-2.
• Structure-activity relationship (SAR) analysis.

Main Results:

• Compounds 13c and 13d exhibited significant BCL-2 inhibitory activity with IC50 values of 0.471 µM and 0.363 µM, respectively.
• Molecular docking simulations indicated favorable binding interactions of the synthesized compounds with the BCL-2 target.
• SAR studies provided insights into how structural modifications influence BCL-2 inhibitory potency.

Conclusions:

• The synthesized benzothiazole derivatives show promise as BCL-2 inhibitors.
• Compounds 13c and 13d represent lead candidates for further development in anti-cancer drug discovery.
• The study highlights the potential of benzothiazole scaffolds in targeting BCL-2 for cancer therapy.