One-Pot Synthesis and Biological Evaluation of Piperidinium-3,3'-(arylmethylene) bis-lawsone derivatives by targeting caspase-7

Caspase-7, an effector enzyme activated by the initiator caspase-1, plays a crucial role in triggering apoptosis. It is also a significant factor in neurodegenerative conditions like Alzheimer's and Huntington's diseases. While both peptide and nonpeptide caspase inhibitors have shown promise in preclinical research, peptide inhibitors face challenges such as poor cell permeability, brief half-life, limited efficacy, and complex structures that are difficult to optimize. Additionally, they encounter bioavailability issues. Consequently, the development of nonpeptide-based caspase inhibitors remains an area of interest for researchers. Using a multicomponent reaction, eight lawsone derivatives, specifically piperidinium-3,3'-(arylmethylene) bis-lawsone, were successfully synthesized. This group included five novel compounds (2, 3, 4, 7, 8) and three previously known ones (1, 5, 6). The products were analyzed using Nuclear Magnetic Resonance (NMR) 1-2D spectroscopy and High Resolution Mass Spectrometry (HRMS), followed by an evaluation of their inhibitory activity against caspase-7. Notably, this study marks the first instance of piperidinium-3,3'-(arylmethylene) bis-lawsone being investigated for its potential to target the caspase-7 enzyme. Among the eight compounds, compound 8 demonstrated the most promising results, exhibiting an inhibitory activity of approximately 29.80% against caspase-7. This finding suggests that compound 8 could serve as a valuable fragment molecule for future development of caspase-7 inhibitors.