Furan α-acetoxy methylphosphonates: Design and synthesis, in vitro antibacterial and antifungal activities, DFT, topology exploration (ELF , LOL, RDG) and molecular docking

The addition of a furan moiety to methylphosphonate can lead to molecules possessing strongest antibacterial and antifungal properties. In this work, novel furan alpha-acetoxy methylphosphonate derivatives were designed and successfully synthesized in two steps using alpha-hydroxyphosphonates as intermediates. The desired products were obtained with excellent yields (up to 80 %), and their chemical structures were confirmed by IR, UV-vis, NMR (1H, 13C, 31P), as well as HRMS analyses. The antibacterial and antifungal activities of these molecules were assessed against ten Gram-negative bacteria, such as Escherichia coli (ATCC 25,922, ertapenem-resistant, and ciprofloxacin-resistant strains), Klebsiella pneumoniae (KPC), Pseudomonas aeruginosa (ATCC 27,853, VIM-2- producing, and imipenem-resistant strains), and Acinetobacter baumannii (ESBL, OXA-23, and carbapenemaseproducing strains); four Gram-positive bacteria, including Staphylococcus aureus (ATCC 25,923, 29,213, and ATCC 43,300) and Bacillus cereus; and two fungi, including Candida albicans and Saccharomyces cerevisiae. The results showed that all compounds exhibited high antibacterial and antifungal activities. DFT calculations were carried out using the CAM-B3LYP/6-31 G (d,p) basis set to study the stability and reactivity of the compounds through the HOMO and LUMO energy values. Additionally, topology analyses (ELF, LOL, and RDG) were performed using Multiwfn software to further elucidate the reactivity of the molecules. Molecular docking studies revealed strong interactions between the synthesized compounds and target proteins. Overall, the results demonstrate the promising antibacterial and antifungal potential of the studied compounds.