Design, synthesis and docking studies of novel 4-aminophenol-1,2,4-oxadiazole hybrids as apoptosis inducers against triple negative breast cancer cells targeting MAP kinase

Abstract

In our study, a series of novel 4-aminophenol benzamide-1,2,4-oxadiazole hybrid analogues have been designed and synthesized by condensing 4-hydroxyphenyl arylamides (3a–c) and 5-chloromethyl-3-aryl-1,2,4-oxadiazoles (6a–d). The structure of the synthesised compounds was verified by various spectroscopic techniques (¹H NMR, ¹³C NMR, IR and LC-MS). All the prepared compounds were subjected to in silico and in vitro antiproliferative study against TNBC cell lines MDA-MB-468 and MDA-MB-231. The investigations revealed that compound 7k significantly promoted apoptosis against MDA-MB-468 and MDA-MB-231 cells with IC₅₀ values of 22.31 µM and 26.27 µM, respectively. Compound 7k interacted with crucial active sites of MAPK and exhibited the highest docking score of −7.06 kcal/mol. Docking was validated with molecular dynamic studies with simulation for 100 ns, depicting various stable interactions with MAPK. Consequently, 7k forms stable H-Bonds and π-π stacking with amino acid residues along with π-cation. Our investigations reveal that the in vitro antiproliferative study of 7k was in good correlation with the in silico studies. Hence, 7k serves as a potential novel lead for the inhibition of TNBCs by downregulating MAPK P38.

Communicated by Ramaswamy H. Sarma

Highlights

• Novel 4-aminophenol benzamide-1,2,4 oxadiazole library of small molecules displayed potent antiproliferative activity.

• Compound 7k induces apoptosis significantly against triple-negative breast cancer cells.

• Compound 7k potentiates apoptosis by targeting MAPK P38 and altering mitochondrial membrane potential.

• Molecular docking and molecular dynamic simulations confirm the efficient binding of compound 7k with MAPK (Docking score of –7.06 kcal/mol).

Keywords:

• 4-Aminophenol
• 1,2,4-oxadiazole
• 4-aminophenolbenzamide
• anticancer
• triple negative breast cancer

Disclosure statement

The authors declare no conflict of interest.

Acknowledgments

The authors are thankful to Prof. Sathees C. Raghavan, IISc, for gifting HEK cell lines. SMS, VHK and SR thank Prof. Dr. M. A. Shekar, & Dr. M. G. Shivaramu, for their kind support. VSM thanks Prof. Dr. Siddhartha Kumar Mishra, Department of Biochemistry, University of Lucknow, for his valuable suggestion.

Additional information

Funding

VSM gratefully acknowledges Dayananda Sagar University, Bengaluru, India for providing financial support (seed grant) to carry out the research work. SMS, VHK and SR thank Adichunchanagiri University, Mandya, India for providing financial assistance from the University’s Internal funding scheme.