Design and synthesis of 4-aminophenol-1,3,4-oxadiazole derivative potentiates apoptosis by targeting MAP kinase in triple negative breast cancer cells

Women below 40 years greatly suffer from triple negative breast cancers (TNBCs). Compared to other breast cancer cases, the poor prognosis and lower survival rate of TNBC patients make it an alarming task to save the human era from this dreadful disease. Therefore, identifying potential novel leads is urgently required to combat the TNBC. To discover a novel anticancer agent, we synthesized a series of novel 4-aminophenolbenzamide-1,3,4 oxadiazole hybrid analogues (7a-l). The structure of the compounds was confirmed by spectral methods (1H & 13C NMR, IR and MS). All the compounds were subjected to their in-silico and in-vitro antiproliferative studies against the TNBC cell lines MDA-MB-468 and MDA-MB-231. The investigations revealed that 7i has significantly promoted apoptosis against MDA-MB-468 and MDA-MB-231 cells with IC50 values of 16.89 and 19.43 mu M, respectively. Molecular docking of 7i, with MAPK has exhibited the highest binding score of -7.10 kcal/mol by interacting with crucial amino acids present at the active sites. Molecular docking is further validated with molecular dynamic studies with simulation for 100 ns, depicting various stable interactions with MAPK. Compound 7i, forms stable H-bonds and pi-pi stacking with amino acid residues. Molecular dynamic simulation (MDS) reveals that hydrophobic and water bridges were very prominent for 7i to bind, with the amino acid residues in close proximity to the active site of p38 MAPK. The investigations show that the In-vitro antiproliferative study of 7i agreed with the in-silico studies. Collectively, our investigations depict 7i as a potent novel lead for the inhibition of TNBCs by targeting p38 MAPK.Communicated by Ramaswamy H. Sarma A novel 4-aminophenolbenzamide-1,3,4 oxadiazole library of small molecules displayed potent antiproliferative activity.Compound 7i induces apoptosis significantly against triple-negative breast cancer cells.Compound 7i potentiates apoptosis by targeting p38 MAPK and altering mitochondrial membrane potential.Molecular docking and molecular dynamic simulation (MDSs) confirm the efficient binding of compound 7i with MAPK (Docking score of -7.10 kcal/mol).