Effect of substituents in novel bioactive tavaborole derivatives on the intermolecular interaction hierarchy

Abstract

Tavaborole, a molecule based on the benzoxaborole scaffold, is an effective antifungal drug marketed under the Kerydin® trademark. New tavaborole biologically active derivatives, namely 5-fluoro-3-morpholin-4-yl-2,1-benzoxaborol-1(3H)-ol and 5-fluoro-3-thiomorpholin-4-yl-2,1-benzoxaborol-1(3H)-ol have been synthesized and their crystal structures are discussed in comparison to the parent tavaborole and nonfluorinated benzoxaborole analogs. Our aim is to find the structural differences caused by the substitution with the fluorine atom, the introduction of a substituent at position 3, and its modification at a peripheral site. For this purpose, we have employed state-of-art tools using knowledge-based and quantum crystallography algorithms. Our study revealed that the presence of the fluorine atom reduces both the molecular dipole moment and the hydrogen bond acceptor abilities of a ring oxygen atom, hence affecting the structure of the main hydrogen-bonded motif. The analysis shows that in the new thiomorpholine derivative, the observed motif is not optimal, and thus other polymorphs might be sought. Hierarchical analysis of weak intermolecular interactions and elucidation of large supramolecular synthons allowed us to find similarities in the networks formed by 3-substituted derivatives and their different arrangement compared to unsubstituted benzoxaboroles. This approach gives an insight into weak interaction cooperativity and their exchange upon different substitutions. The results may serve as a basis for future search for new polymorphic forms and benzoxaborole derivative multicomponent crystals.