Synthesis, In Silico Docking Study, and Biological Evaluation of S-Alkylated 1,3,4-Oxadiazole Hybrids

A library of 3-(5-[(substituted benzyl)sulfanyl]-1,3,4-oxadiazol-2-yl)-N-substituted pyridine-2-amines and 2-[(5-{2-[(substituted phenyl)amino]pyridin-3-yl}-2,3-dihydro-1,3,4-oxadiazol-2-yl)sulfanyl]-N-substituted phenylacetamides were synthesized by the multistage procedure, starting from 2-chloronicotinic acid. The newly synthesized compounds were tested for in vitro cytotoxicity against the MCF-7 breast cancer cell line. Significant cell death rates were demonstrated by all the test compounds in a concentration-dependent manner. The active compounds N-(4-fluorophenyl)-3-{5-[(4-nitrobenzyl)sulfanyl]-1,3,4-oxadiazol-2-yl}pyridin-2-amine and 2-[(5-{2-[(3-chloro-4-fluorophenyl)amino]pyridin-3-yl}-1,3,4-oxadiazol-2-yl)sulfanyl]-N-(2,4-dichlorophenyl)-acetamide were further subjected to DAPI staining to assess their effect on nuclear fragmentation. Additionally, the synthesized compounds were screened for anti-inflammatory and antioxidant activities, yielding promising results. A molecular docking study was conducted to assess the binding affinities of the synthesized compounds to PDB 3ERT (human estrogen receptor-α in complex with 4-hydroxytamoxifen). For all the compounds, good binding energies with the target protein were predicted. An ADME screening showed that the majority of the synthesized compounds have good pharmacokinetic profiles.