Synthesis and cytotoxic activity evaluation of novel dihydroartemisinin and zerumbone conjugates with 2-mercapto-1,3,4-oxadiazoles as potential EGFR inhibitors

Abstract

Sixteen conjugates of dihydroartemisinin and zerumbone with 2-mercapto-1,3,4-oxadiazoles were synthesized and structurally elucidated by 1D NMR, 2D NMR, and HRMS spectra. The cytotoxic screening results showed that all the conjugates of dihydroartemisinin with 2-mercapto-1,3,4-oxadiazoles (19a-h) exhibited cytotoxic activity against two human cancer cell lines, HepG2 and LU-1, with the IC 50 values ranging from 2.22 to 40.69 µM. Among dihydroartemisinin conjugates, conjugate 19b displayed the strongest activity against both HepG2 and LU-1 cell lines, with the IC 50 values of 3.49 and 2.22 μM, respectively. The zerumbone conjugates (20a-h) expressed their cytotoxic activity stronger than that of 19a-h series, with IC 50 values ranging from 1.54 to 2.00 µM. In addition, all 16 compounds exhibited an impressively inhibitory effect against EGFR tyrosine kinase with binding affinities ranging from −8.61 to −10.2 kcal/mol, higher than that of the erlotinib drug (−7.50 kcal/mol), a co-crystallized inhibitor of EGFR receptor. Both conjugates (19a and 20a) containing the 2-hydroxyphenyl-2mercapto-1,3,4-oxadiazole moiety had the best binding energies (−10.2 and −9.494 kcal/mol, respectively) on the EGFR tyrosine kinase. Furthermore, the potential interactions and binding patterns between the compounds and the relevant amino acid residues revealed the most significant contribution to amplifying their efficacy against this protein, according to docking studies, which identified both hydrogen bonds and hydrophobic contacts at the active site of the EGFR protein.