Proflavine and zinc chloride “team chemistry”: combining antibacterial agents via solid-state interaction

Abstract

Co-crystallization of the antibacterial agent proflavine (PF) with the inorganic salt ZnCl₂ by mechanochemical and solution methods results in the formation of novel compounds ZnCl₃(HPF) (1) and [HPF]₂[ZnCl₄]·H₂O (2), both containing the proflavinium cation (HPF)⁺. Both compounds show a 50–125% enhanced antimicrobial activity with respect to a reference standard of AgNO₃, and a 25–50% enhancement to the behaviour of the separate components against pathogen indicator strains of Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli. In terms of crystal structure, both compounds ZnCl₃(HPF) and [HPF]₂[ZnCl₄]·H₂O are characterized by extensive π-stacking interactions between the proflavine moieties. The same interaction is predominant in the previously unknown crystal structures of neutral proflavine (PF), as well as in that of its dihydrated monochloride salt, [HPF]Cl·2H₂O, which are also described in this paper.