Convenient method for the synthesis of some novel chiral methyl 2‐(2‐oxo‐2H‐benzo[e][1,3]oxazin‐3(4H)‐yl)propanoate derivatives and biological evaluation of their antioxidant, cytotoxic, and molecular docking properties

Abstract

AbstractTen chiral methyl 2‐(2‐oxo‐2H‐benzo[e][1,3]oxazin‐3(4H)‐yl)propanoate derivatives 6a‐6j have been synthesized from optically pure amino methyl phenol 5 and 4‐nitrophenyl chloroformate. These derivatives 6a‐6j are characterized by 1H NMR, 13C NMR, FT‐IR, and HRMS spectral techniques. Optical purity of these derivatives was confirmed by chiral HPLC method. Ten synthesized ester derivatives 6a‐6j were screened for their in vitro antioxidant activity. Among the compounds 6b‐d and 6h‐j have exhibited comparable antioxidant activity with ascorbic acid as a standard. Compounds 6a and 6e‐g have shown moderate antioxidant activity. Further, the in vitro cytotoxicity of these compounds were studied through MTT cell proliferation assay in addition the effect on LDH leakage and NO release. Among the derivatives, 6j showed extremely best activity and the IC50 value (12.54 ± 0.71 μM) is very close to doxorubicin (7.2 ± 0.58 μM) as a standard. Compounds 6b, 6h, and 6i showed better inhibition next to compound 6j on the viability of HepG2 cells with an IC50 value (μM) of 56.02 ± 1.4, 41.76 ± 0.58, and 38.17 ± 0.34, respectively. Also, molecular docking studies have been carried out with STAT‐3 (PDB ID: 1BG1) and BCL‐2 (PDB ID: 4AQ3) proteins against the four active compounds 6b, 6h, 6i, and 6j. The binding energies of the tested compounds were in the range of −7.76 to −8.41 kcal/mol, which is very close to doxorubicin (−8.53 kcal/mol) as a standard. These molecular docking results are in good agreement with the in vitro studies.