Novel α-Aminophosphonates and α-Aminophosphonic Acids: Synthesis, Molecular Docking and Evaluation of Antifungal Activity against Scedosporium Species

Abstract

The Scedosporium genus is an emerging pathogen with worldwide prevalence and high mortality rates that gives multidrug resistance to antifungals; therefore, pharmacological alternatives must be sought for the treatment of diseases caused by this fungus. In the present project, six new α-aminophosphates were synthesized by the Kabachnik–Fields multicomponent reaction by vortex agitation, and six new monohydrolyzed α-aminophosphonic acids were synthesized by an alkaline hydrolysis reaction. Antifungal activity was evaluated using the agar diffusion method as an initial screening to determine the most active compound compared to voriconazole; then it was evaluated against 23 strains of the genus Scedosporium following the M38-A2 protocol from CLSI (activity range: 648.76–700 µg/mL). Results showed that compound 5f exhibited the highest antifungal activity according to the agar diffusion method (≤1 mg/mL). Cytotoxicity against healthy COS-7 cells was also evaluated by the MTT assay and it was shown that compound 5f exhibits a lower toxicity in comparison to voriconazole at the same concentration (1000 µM). A docking study was conducted afterwards, showing that the possible mechanism of action of the compound is through the inhibition of allosteric 14-α-demethylase. Taking these results as a basis, 5f is presented as a compound with attractive properties for further studies.

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

“…For this reason, it was necessary to synthesize the aminophosphonates 6 and 14 through another methodology. Therefore, the KF reaction was carried out between 4-dimethylaminocinnamaldehyde 2d , diphenyl phosphite 4 and the corresponding amines 3b , c using vortex mixing ( Scheme 3 ) [ 35 ]. Remarkably, there was an increase in the yields of compounds 6 and 14 from 11% and 29%, to 87% and 81%, respectively.…”

“…The methodology for the validation of the active site of the lanosterol-14α-demethylase protein (PDB ID: 5HS1) was performed and described in a previous work by Cordero-Díaz et al [ 35 ] where validation was performed with the native co-crystallized ligand Voriconazole, with an RMSD of less than 2.5 Å. The Autodock-Vina program ( ; accessed on 15 January 2023) was used to predict molecular docking [ 42 , 43 ], using 1000 modes, 1000 exhaustiveness and 10 replicates for each one, selecting the lowest energy value [ 35 , 44 ]. All figures were visualized with Pymol (Schrödinger, San Diego, CA, USA; ; accessed on 15 December 2022) and Discovery Studio Visualizer 4.5 software.…”

“…It is important to point out some specific coupling It is noteworthy that the hydrolysis reaction proceeded by selectively hydrolyzing one of the -O-phenyl substituents on the phosphonate group, which was confirmed by 1 H NMR and 13 C NMR, where the observed signals agreed with the expected ones for compounds 17-28 (Table 1). Potassium carbonate and water reacted to form a catalytic number of hydroxide ions, which are the species responsible for promoting the specific monohydrolysis reaction [35]. All the spectra of synthesized aminophosphonic acids are supplied in the Supplementary Materials.…”

“…In a previous work reported by our research group [ 35 ], a series of α-aminophosphonates and monohydrolyzed α-aminophosphonic acids was evaluated against different strains of the multi-resistant fungi Scedosporium spp. Compound 1 was the most active compound of the series, showing activity in the range of 648.76–700 μg/mL, in comparison to voriconazole, which presented an activity range of 0.44–2.64 μg/mL; it was less active but exhibited lower cytotoxicity.…”

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] …”