Tetrahydrocarbazole as a Versatile Scaffold in Drug Discovery: A Cross-Target SAR Analysis and Design Paradigms

Tetrahydrocarbazole (THCz) is a privileged scaffold validated by clinically approved drugs such as ondansetron, frovatriptan, and ramatroban and exhibits diverse bioactivities including antimicrobial, antitumor, antidiabetic, and neuroprotective effects. Despite extensive structure-activity relationship (SAR) studies, a systematic integration of findings across different therapeutic targets has been lacking. This review provides a comprehensive SAR dissection of THCz derivatives across key targets (bacterial sliding clamp, BTK, HDAC, AMPK, etc.), analyzing how modifications at key positions of the core scaffold (N-9, C-1, and C-6) influence potency and selectivity. Notably, we highlight four emerging design paradigms: pharmacophore hybridization, conformational constraint, cross-target SAR decoding, and precision intervention. By consolidating fragmented knowledge into a practical cross-target SAR matrix, this review offers a strategic framework for the rational design of next-generation THCz-based therapeutics.