Antifungal Properties of Hydrazine Derivatives and Metal Complexes

Abstract

Hydrazine derivatives and their metal complexes have attracted considerable attention from the medicinal chemists because of their wide-range biological activities including antifungal properties. These complexes contain the hydrazine (–NH–NH2) moiety with sites for functionalization and chelation with different metal ions. Owing to their structural flexibility, Many hydrazine derivatives can be easily synthesized and several proved to have potential antifungal activity such as hydrazones, thiosemicarbazones and Schiff bases. When formed with copper, cobalt, zinc, nickel and iron, these molecules have a pronounced antifungal activity. The metal complexation increases not only the stability of the ligand scaffold, but also lipophilicity and bioavailability of the compounds and, consequently, increased their potential therapeutic properties. It was recently reported that hydrazine-metal complexes exert their antifungal activity through various kind of actions such as disruption of membrane potential, inhibition on the biosynthesis of ergosterol, intercalation into DNA, and production of reactive oxygen species (ROS). These mechanisms of action are critical in defeating resistance to fungi. For instance, hydrazone ligands have been demonstrated to form complexes with Cu(II), Zn(II) or Co(II) ions that are potent against clinical strains of Candida albicans, Aspergillus niger and Fusarium oxysporum[12. In addition, comparisons of several kinds of metal complex have demonstrated the attachments of central metal ions on the antifungal efficacy. The pharmacokinetic improvements mediated by the metal-hydrazine complexes are also remarkable. Such advantages extend from better permeation through the membrane, to lower toxicity and in vivo systemic availability, to a more prolonged therapeutic effectiveness of the controlled release of the metal ion. In addition, metal-binding could shield hydrazine derivatives from rapid metabolic clearance, improving their potential clinical utility. Nevertheless, it has many attractive properties; however, the problems with such potential cytotoxicity to human cells, low water solubility, and poor in vivo and clinical efficacy. This review summarizes the synthetic method, structural parameters, antifungal mechanisms, comparative effectiveness and the pharmacokinetic properties of hydrazine-metal complexes. It also considers the problems that need to be overcome to support the clinical development of these agents. The future prospects of research are discussed, which involve study on biocompatible metal ions as new gene carriers, targeted systems for delivery, and synthesis through green chemistry approaches. Given the escalating pattern of fungal resistance to current antifungal drugs, the metal complexes of hydrazine derivatives appear to be one of the most promising sources for the development of new antifungal drugs, which may be particularly useful to fill the existing gap with the current antifungal agents.