An insight into the synthesis, structure-activity relationships, and bioactivity of synthetic small molecule ligands targeting toll-like receptor 4.

Toll-like receptor 4 (TLR4), and its co-receptor myeloid differentiation protein 2 (MD-2), form a critical part of the pattern recognition receptor family, playing a central role in innate immune activation, inflammation, and tissue injury responses. Aberrant activation of TLR4 is associated with cytokine storms syndrome and the progression of numerous inflammatory and autoimmune diseases. Conversely, controlled stimulation of TLR4 can enhance adaptive immunity, particularly in the context of vaccine efficacy. These dual roles underscore the therapeutic potential of small molecules that modulate TLR4 signalling. This review provides a comprehensive overview of the synthetic approaches, structure-activity relationships (SAR), and biological activities of small-molecule TLR4 modulators-both agonists and antagonists-that target TLR4, MD-2, or the TLR4/MD-2 complex. The aim is to guide future design and development of selective, potent TLR4-targeted agents with clinical relevance.