Structure-activity relationship of cyclic thiacarbocyanine tau aggregation inhibitors

Macrocyclic bis-thiacarbocyanines are efficacious inhibitors of tau protein aggregation. To extend the structure-activity relationship of this inhibitor class, N,N'-alkylene bis-thiacarbocyanines linked by chains of three to eight methylene carbons were synthesized and examined for inhibitory activity against recombinant human tau aggregation in vitro. At 10 micromolar concentration, inhibitory activity varied with linker length, with four methylene units being most efficacious. On the basis of absorbance spectroscopy measurements, linker length also affected compound folding and aggregation propensity, with a linker length of four methylene units being optimal for preserving open monomer conformation. These data suggest that inhibitory potency can be optimized through control of linker length, and that a contributory mechanism involves modulation of compound folding and aggregation.