Biological evaluation and molecular docking of novel 1,3,4-thiadiazole-resorcinol conjugates as multifunctional cholinesterases inhibitors

Two series of novel 1,3,4-thiadiazole-resorcinol conjugates were efficiently synthesized and evaluated as cholinesterases inhibitors. N-Butyl- and N-chlorophenyl-5-amino-1,3,4-thiadiazol-2-yl)benzene-1,3-diols were identified as the most promising compounds of low nanomolar activity against AChE (IC50 = 29-76 nM) and moderate activity against BuChE. The inhibition mechanism studies proved that the compounds are mixed type inhibitors. The docking simulations showed great affinity of the compounds for both enzymes. The modelled amine derivatives exhibited a similar arrangement in the catalytic anionic site of AChE similar to that of tacrine. The thiadiazole ring interacted with Trp84 and the phenyl groups created pi-pi stacking interactions with the residue - Phe330. The compounds showed better inhibition of the in vitro self-induced A beta (1-42) aggregation than that compared with curcumin as well as antioxidant properties similar to those of quercetin. They exhibited metal ion chelating properties, acceptable cytotoxicity in vitro and favourable ADMET profile determined in silico.

Automated summary

Two series of novel 1,3,4-thiadiazole-resorcinol conjugates were efficiently synthesized and evaluated as cholinesterases inhibitors, showing potential as mixed type inhibitors with good affinity for both AChE and BuChE. These compounds exhibited better inhibition of Aβ aggregation and antioxidant properties compared to curcumin, with metal ion chelating properties and acceptable cytotoxicity in vitro.