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

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 Feb 16:268:116235. doi: 10.1016/j.ejmech.2024.116235.
Khadija El Gadali 1,  Meriem Rafya 2,  Az-Eddine El Mansouri 3,  Mohamed Maatallah 4,  Arie Vanderlee 5,  Ahmad Mehdi 6,  Johan Neyts 7,  Dirk Jochmans 7,  Steven De Jonghe 7,  Fatiha Benkhalti 2,  Yogesh S Sanghvi 8,  Moha Taourirte 9,  Hassan B Lazrek 10
Affiliations

Affiliations

  • 1 Laboratoire de Recherche en Développement Durable et Santé, Faculty of Sciences and Technology Gueliz (FSTG), BP549, Marrakech 40000, Morocco; Laboratory of Molecular Chemistry, Department of Chemistry, Faculty of Sciences Semlalia, Marrakech 40000, Morocco.
  • 2 Laboratoire de Recherche en Développement Durable et Santé, Faculty of Sciences and Technology Gueliz (FSTG), BP549, Marrakech 40000, Morocco.
  • 3 University of the Free State Faculty of Natural and Agricultural Sciences Chemistry Department 205 Nelson Mandela, Bloemfontein, 9301, South Africa.
  • 4 Laboratory of Molecular Chemistry, Department of Chemistry, Faculty of Sciences Semlalia, Marrakech 40000, Morocco.
  • 5 Institut Européen des Membranes, IEM, UMR 5635, Univ. Montpellier, CNRS, ENSCM, 34095 Montpellier, France.
  • 6 ICGM, UMR5253 1919, Route de Mende 34293 Montpellier cedex 5, France.
  • 7 KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, Box 1043, B-3000 Leuven, Belgium.
  • 8 Rasayan Inc, 2802 Crystal Ridge Road, Encinitas, CA 92024-6615, USA.
  • 9 Laboratoire de Recherche en Développement Durable et Santé, Faculty of Sciences and Technology Gueliz (FSTG), BP549, Marrakech 40000, Morocco. Electronic address: taourirte@uca.ac.ma.
  • 10 Laboratory of Molecular Chemistry, Department of Chemistry, Faculty of Sciences Semlalia, Marrakech 40000, Morocco. Electronic address: hblazrek50@gmail.com.
PMID: 38377828 DOI: 10.1016/j.ejmech.2024.116235
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.

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