Microwave-Assisted Synthesis of Aminophosphonic Derivatives and Their Antifungal Evaluation against Lomentospora prolificans

Abstract

Lomentospora prolificans is a pathogenic and multidrug-resistant fungus that can infect both immunocompetent and immunocompromised patients, with mortality rates up to 87%. The World Health Organization (WHO) included this fungal species in its first list of 19 priority fungal pathogens, which focused on fungal pathogens that can cause invasive acute and subacute systemic fungal infections. Therefore, there is a growing interest in finding new therapeutic alternatives. In this work, the synthesis of twelve α-aminophosphonates by the microwave-assisted Kabachnik–Fields reaction and twelve α-aminophosphonic acids by a monohydrolysis reaction is reported. All compounds were evaluated by the agar diffusion method as a preliminary screening in comparison with voriconazole, showing inhibition halos for compounds 7, 11, 13, 22 and 27. The five active compounds in the preliminary tests were evaluated against five strains of L. prolificans following protocol M38-A2 from CLSI. The results showed that these compounds exhibit antifungal activity in the concentration range of 900->900 μg/mL. Cytotoxicity against healthy COS-7 cells was also evaluated by the MTT assay, and it was shown that compound 22 was the least cytotoxic, with a viability of 67.91%, comparable to the viability exhibited by voriconazole (68.55%). Docking studies showed that the possible mechanism of action of the active compounds could be through the inhibition of the enzyme lanosterol-14-alpha-demethylase in an allosteric hydrophobic cavity.

SB‐2 cationic resin: an efficient and reusable organocatalyst for the synthesis of α‐aminophosphonates, DFT calculations and, computer aided design in antifungal activity

“…Due to the ongoing emergence of azole‐resistant strains, the understanding of the resistance mechanisms of CYP51 is important for the discovery of new CYP51 inhibitors [31] . The α ‐aminophosphonates were previously evaluated against various multidrug‐resistant fungi; such as: Scedosporium Species , [32] Lomentosporaprolificans , [33] Phomopsisasparagi, Fusariumoxysporum and Botrytis cinerea [34] . The α‐ aminophosphonates hold a prominent place in chemical synthesis, they have described various synthetic methods via multicomponents Kabachnik‐Fields reaction, [35–36] using various catalysts [37–42] …”