Design, synthesis, and molecular modeling studies of novel 2-quinolone-1,2,3-triazole-α-aminophosphonates hybrids as dual antiviral and antibacterial agents

Eur J Med Chem. 2024 Mar 15:268:116235. doi: 10.1016/j.ejmech.2024.116235. Epub 2024 Feb 16.

Abstract

With the aim to identify new antiviral agents with antibacterial properties, a series of 2-quinolone-1,2,3-triazole derivatives bearing α-aminophosphonates was synthesized and characterized by 1H NMR, 13C NMR, 31P NMR, single crystal XRD and HRMS analyses. These compounds were examined against five RNA viruses (YFV, ZIKV, CHIKV, EV71 and HRV) from three distinct families (Picornaviridae, Togaviridae and Flaviviridae) and four bacterial strains (S. aureus, E. feacalis, E. coli and P. aeruginosa). The α-aminophosphonates 4f, 4i, 4j, 4k, 4p and 4q recorded low IC50 values of 6.8-10.91 μM, along with elevated selectivity indices ranging from 2 to more than 3, particularly against YFV, CHIKV and HRV-B14. Besides, the synthesized compounds were generally more sensitive toward Gram-positive bacteria, with the majority of them displaying significant potency against E. feacalis. Specifically, an excellent anti-enterococcus activity was obtained by compound 4q with MIC and MBC values of 0.03 μmol/mL, which were 8.7 and 10 times greater than those of the reference drugs ampicillin and rifampicin, respectively. Also, compounds 4f, 4p and 4q showed potent anti-staphylococcal activity with MIC values varying between 0.11 and 0.13 μmol/mL, compared to 0.27 μmol/mL for ampicillin. The results from DFT and molecular docking simulations were in agreement with the biological assays, proving the binding capability of hybrids 4f, 4i, 4j, 4k, 4p and 4q with viral and bacterial target enzymes through hydrogen bonds and other non-covalent interactions. The in silico ADME/Tox prediction revealed that these molecules possess moderate to good drug-likeness and pharmacokinetic properties, with a minimal chance of causing liver toxicity or carcinogenic effects.

Keywords: 1,2,3-Triazole; 2-Quinolone; Antibacterial activity; Antiviral activity; In silico simulation; α-aminophosphonates.

Publication types

  • Review

MeSH terms

  • Ampicillin / pharmacology
  • Anti-Bacterial Agents / chemistry
  • Antiviral Agents / pharmacology
  • Escherichia coli
  • Humans
  • Hydroxyquinolines*
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Molecular Structure
  • Quinolones*
  • Staphylococcus aureus
  • Structure-Activity Relationship
  • Triazoles / pharmacology
  • Zika Virus Infection*
  • Zika Virus*

Substances

  • Anti-Bacterial Agents
  • carbostyril
  • Triazoles
  • Ampicillin
  • Antiviral Agents
  • Hydroxyquinolines
  • Quinolones