Bio-computational modeling, POM analysis and molecular dynamic simulation for novel synthetic quinolone and benzo[d][1,3]oxazine candidates as antimicrobial inhibitors

Abstract

The current study offers a metal-free, direct, and successful synthesis technique for a new series of quinolinone and benzo[d][1,3]oxazine, along with an assessment of their biological activities. Heteroannulation of anthranilic acid with carbonyl-containing chemicals (aroyl pyruvate, ethyl acetoacetatete, maleic anhydride, and ethyl cyanoacetate) resulted in the desired quinolones and benzo[d][1,3]oxazines. This technique introduces a number of fundamental breakthroughs in organic synthesis, including metal-free catalysts, smart reaction conditions with column purification, and a wide functional scope. Furthermore, the structure of the newly synthesized chemical series was investigated and validated using spectroscopic techniques. The synthesized series were evaluated for antibacterial (against gram-positive and gram-negative bacterial strains) and antifungal activity. The quinolone and benzo[d][1,3]oxazine candidates had remarkable antibacterial action. Furthermore, molecular docking investigations corroborated the biological studies using the Molecular Operating Environment and Petro Osiris Molinspiration (POM) experiments, which confirmed the activity of compounds 8, 15, and 17. Our studies on the cytotoxic activity of various chemicals have demonstrated that these compounds exhibit minimal toxicity. Specifically, when comparing the cytotoxic effects on human lung fibroblast (WI38) cells to those of Doxorubicin, a well-known chemotherapy agent, compounds 8, 15, and 17 showed weak cytotoxic effects on the normal WI38 cells. This indicates that these compounds may possess some level of selectivity and reduced toxicity towards normal cells, suggesting potential for further exploration as antibacterial agents with a safer profile for normal cells.

Keywords: Antimicrobial; Bio-computational modeling; Molecular dynamic simulation; POM analysis; Quinolone.

Fig. 1

Rational of the work.

Fig. 2

Synthetic approach to quinolinones 5, 7 and 8.

Fig. 3

The plausible mechanism for the synthesis of 3-(4-Methoxybenzoyl)quinoline-4(3 H)-one (5).

Fig. 4

Synthetic approach quinolinones 11 and 14.

Fig. 5

Synthetic approach benzoxazine 15 and 17.

Fig. 6

OSIRIS Calculation of molecular proporties of copounds 8, 15 and 17.

Fig. 7

2D and 3D receptor interactions of the reference ligand V13(2,3,5,6-tetrafluoro-4-[(2-hydroxyethyl)sulfonyl]benzenesulfonamide).

Fig. 8

2D and 3D receptor interactions of the promising synthetized compounds.

Fig. 9

Molecular dynamics simulation results of the newly synthesized compounds in complexes with the protein carbonic anhydrase CAXII compared to the reference molecule (V13). (A) Root mean square deviation (RMSD) analysis. (B) Root mean square fluctuation (RMSF) analysis. (C) Radius of gyration (RG) analysis. (D) Solvent accessible surface area (SASA) analysis.

Fig. 10

The total number of hydrogen bonds formed between the compounds and the target protein carbonic anhydrase CAXII throughout the simulation time.

Fig. 11

The Inhibition % of the tested compounds as anti-fungal and anti-bacterial.

Fig. 12

Average of relative viability of samples cells (%) for WI38 cell line.