Sulfur-fluoride exchange (SuFEx)-enabled lead discovery of AChE inhibitors by fragment linking strategies

SuFEx click chemistry has been a method for the rapid synthesis of functional molecules with desirable prop-erties. Here, we demonstrated a workflow that allows for in situ synthesis of sulfonamide inhibitors based on SuFEx reaction for high-throughput testing of their cholinesterase activity. According to fragment-based drug discovery (FBDD), sulfonyl fluorides [R-SO2F] with moderate activity were identified as fragment hits, rapidly diversified into 102 analogs in SuFEx reactions, and the sulfonamides were directly screened to yield drug-like inhibitors with 70-fold higher potency (IC50 = 94 nM). Moreover, the improved molecule J8-A34 can ameliorate cognitive function in A beta 1_ 42-induced mouse model. Since this SuFEx linkage reaction succeeds on picomole scale for direct screening, this methodology can accelerate the development of robust biological probes and drug candidates.

Automated summary

SuFEx click chemistry has been demonstrated as a powerful method for the rapid synthesis of sulfonamide inhibitors for high-throughput testing of cholinesterase activity. By applying this methodology, a diverse library of sulfonamides was synthesized and directly screened to yield drug-like inhibitors with significantly enhanced potency. The improved molecule J8-A34 showed effectiveness in improving cognitive function in a mouse model. This study highlights the potential of SuFEx click chemistry for accelerating the development of biological probes and drug candidates.