Development and molecular modeling studies of new thiadiazole piperazine urea derivatives as potential fatty acid amide hydrolase inhibitors

A series of novel piperazine urea derivatives with thiadiazole moieties were designed, synthesized, and investigated for their inhibition potential against human fatty acid amide hydrolase (hFAAH). The urea derivatives possessing p‐chlorophenylthiadiazole and benzylpiperazine fragments (19–22) were effective inhibitors of hFAAH. Notably, compounds with 4‐chlorobenzyl (19) and 4‐fluorobenzyl (20) tails at the piperazine side were identified as the most active inhibitors with IC50 values of 0.13 and 0.22 µM, respectively. The preincubation test of 19 was in agreement with the irreversible binding mechanism. Molecular docking was performed to explore the potential binding interactions with key amino acid residues at the FAAH active site. These newly identified inhibitors could serve as leads for the further development of potent and selective FAAH inhibitors for FAAH‐associated diseases. A series of novel piperazine urea derivatives with thiadiazole moieties were designed, synthesized, and investigated for their inhibition potential against human fatty acid amide hydrolase (hFAAH). Among them, compound 19 showed the most potent inhibitory activity (IC50 = 0.13 μM). Molecular docking was performed to explore the binding interactions with key amino acid residues at the FAAH active site.