Synthesis and Influence of 3-Amino Benzoxaboroles Structure on Their Activity against Candida albicans

Abstract

Benzoxaboroles emerged recently as molecules of high medicinal potential with Kerydin® (Tavaborole) and Eucrisa® (Crisaborole) currently in clinical practice as antifungal and anti-inflammatory drugs, respectively. Over a dozen of 3-amino benzoxaboroles, including Tavaborole’s derivatives, have been synthetized and characterized in terms of their activity against Candida albicans as a model pathogenic fungus. The studied compounds broaden considerably the structural diversity of reported benzoxaboroles, enabling determination of the influence of the introduction of a heterocyclic amine, a fluorine substituent as well as the formyl group on antifungal activity of those compounds. The determined zones of the growth inhibition of examined microorganism indicate high diffusion of majority of the studied compounds within the applied media as well as their reasonable activity. The Minimum Inhibitory Concentration (MIC) values show that the introduction of an amine substituent in position “3” of the benzoxaborole heterocyclic ring results in a considerable drop in activity in comparison with Tavaborole (AN2690) as well as unsubstituted benzoxaborole (AN2679). In all studied cases the presence of a fluorine substituent at position para to the boron atom results in lower MIC values (higher activity). Interestingly, introduction of a fluorine substituent in the more distant piperazine phenyl ring does not influence MIC values. As determined by X-ray studies, introduction of a formyl group in proximity of the boron atom results in a considerable change of the boronic group geometry. The presence of a formyl group next to the benzoxaborole unit is also detrimental for activity against Candida albicans.

Merging Electron Deficient Boronic Centers with Electron-Withdrawing Fluorine Substituents Results in Unique Properties of Fluorinated Phenylboronic Compounds

“…However, it should be emphasized that the arrangement of the tested boronic ligands in the active center of the enzyme is, in most cases, different from that known for Tavaborole’s spiroester determined in structural studies [ 13 , 45 ]. This, in turn, may result in a reduced activity of the studied derivatives in comparison with the lead drug determined in in vitro studies of the activity against C. albicans [ 47 , 83 ]. Docking studies showed also that the hydrogen bond interactions with the active sites of the enzyme takes place in the AMP part of the spiroester and not in the benzoxaborole part ( Figure 7 ).…”

“…For substances exerting antimicrobial activity in preliminary well tests, the Minimal Inhibitory Concentration (MIC) values were determined [ 38 , 45 , 47 , 68 , 70 , 79 , 83 ]. Several structural elements that determine the antimicrobial activity of the tested compounds were indicated.…”

“…Tests of antifungal properties of fluoro-substituted benzoxaboroles show that the introduction of an amino substituent in the “3” position of the heterocyclic ring is associated with a reduced activity of those compounds towards C. albicans , compared to benzoxaboroles without these substituents [ 83 ].…”

“…The presence and position of the fluorine substituent also have a significant influence on the activity against C. albicans [ 83 ]. Compounds containing a fluorine atom in the benzoxaborole ring at a position analogous to that in Tavaborole usually display reasonably higher antifungal activity in comparison to those without fluorine substituents or with such a substituent at a different position [ 38 , 83 ].…”

“…The presence and position of the fluorine substituent also have a significant influence on the activity against C. albicans [ 83 ]. Compounds containing a fluorine atom in the benzoxaborole ring at a position analogous to that in Tavaborole usually display reasonably higher antifungal activity in comparison to those without fluorine substituents or with such a substituent at a different position [ 38 , 83 ]. The influence of Tavaborole, as well as other benzoxaboroles, on the growth and composition of photosynthetic pigments in cyanobacteria ( Chroococcidiopsis thermalis, Arthrospira platensis, A. fusiformis, A. maxima and Anabaena ) was also investigated.…”