Design and development of benzyl piperazine linked 5-phenyl-1,2,4-triazole-3-thione conjugates as potential agents to combat Alzheimer’s disease
2023; Elsevier BV; Volume: 139; Linguagem: Inglês
10.1016/j.bioorg.2023.106749
ISSN1090-2120
AutoresPidugu Venkata Ravi Kiran, Digambar Kumar Waiker, Akash Verma, Poorvi Saraf, Bhagwati Bhardwaj, Hansal Kumar, Abhinav Singh, Pradeep Kumar, Namrata Singh, Saripella Srikrishna, Surendra Kumar Trigun, Sushant K. Shrivastava,
Tópico(s)Tryptophan and brain disorders
ResumoOur present work demonstrates the molecular hybridization-assisted design, synthesis, and biological evaluation of 22 benzylpiperazine-linked 1,2,4-triazole compounds (PD1-22) as AD modifying agents. All the compounds were tested for their in vitro hChEs, hBACE-1, and Aβ-aggregation inhibition properties. Among them, compound PD-08 and PD-22 demonstrated good hChE and hBACE-1 inhibition as compared to standards donepezil and rivastigmine. Both compounds displaced PI from PAS at 50 µM concentration which was comparable to donepezil and also demonstrated anti-Aβ aggregation properties in self- and AChE-induced thioflavin T assay. Both compounds have shown excellent BBB permeation via PAMPA-BBB assay and were found to be non-neurotoxic at 80 µM concentration against differentiated SH-SY5Y cell lines. Compound PD-22 demonstrated an increase in rescued eye phenotype in Aβ-phenotypic drosophila AD model and amelioration of behavioral deficits in the Aβ-induced rat model of AD. The in-silico docking studies of compound PD-22 revealed a good binding profile towards CAS and PAS residues of AChE and the catalytic dyad of the BACE-1. The 100 ns molecular dynamics simulation studies of compound PD-22 complexed with AChE and BACE-1 enzymes suggested stable ligand-protein complex throughout the simulation run. Based on our findings compound PD-22 could further be utilized as a lead to design a promising candidate for AD therapy
Referência(s)