Design and synthesis of 4-aminophenol-1,3,4-oxadiazole derivative potentiates apoptosis by targeting MAP kinase in triple negative breast cancer cells
Creators: name: Dhanalakshmi, Boregowda
name: Kumar, Belagal Motatis Anil
name: Srinivasa, Sudhanva Muddenahalli
name: Vivek, Hamse Kameshwar
name: Sennappan, Madhappan
name: Rangappa, Shobith
name: Murthy, Venkatappan Srinivasa
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biophysics
subject: Biochemistry
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Immunology
subject: FOS: Clinical medicine
subject: Biological Sciences not elsewhere classified
subject: Information Systems not elsewhere classified
subject: Cancer

description: 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 (<b>7a–l).</b> The structure of the compounds was confirmed by spectral methods <sup>(1</sup>H &amp; <sup>13</sup>C NMR, IR and MS). All the compounds were subjected to their <i>in-silico</i> and <i>in-vitro</i> antiproliferative studies against the TNBC cell lines MDA-MB-468 and MDA-MB-231. The investigations revealed that <b>7i</b> has significantly promoted apoptosis against MDA-MB-468 and MDA-MB-231 cells with IC<sub>50</sub> values of 16.89 and 19.43 µM, respectively. Molecular docking of <b>7i</b>, 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 <b>7i,</b> forms stable H-bonds and π–π stacking with amino acid residues. Molecular dynamic simulation (MDS) reveals that hydrophobic and water bridges were very prominent for <b>7i</b> to bind, with the amino acid residues in close proximity to the active site of p38 MAPK. The investigations show that the <i>In-vitro</i> antiproliferative study of <b>7i</b> agreed with the <i>in-silico studies</i>. Collectively, our investigations depict <b>7i</b> 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 <b>7i</b> induces apoptosis significantly against triple-negative breast cancer cells.Compound <b>7i</b> potentiates apoptosis by targeting p38 MAPK and altering mitochondrial membrane potential.Molecular docking and molecular dynamic simulation (MDSs) confirm the efficient binding of compound <b>7i</b> with MAPK (Docking score of −7.10 kcal/mol). A novel 4-aminophenolbenzamide-1,3,4 oxadiazole library of small molecules displayed potent antiproliferative activity. Compound <b>7i</b> induces apoptosis significantly against triple-negative breast cancer cells. Compound <b>7i</b> potentiates apoptosis by targeting p38 MAPK and altering mitochondrial membrane potential. Molecular docking and molecular dynamic simulation (MDSs) confirm the efficient binding of compound <b>7i</b> with MAPK (Docking score of −7.10 kcal/mol).