From Design to in Vivo Active Organometallic-Containing Antimycotic Agents

Abstract

Fungal infections are an alarming global problem, most importantly for immunocompromised patients in a hospital environment. The appearance of multidrug resistance in several fungal species is a strong indication that alternative treatments are required. Azoles represent the mainstay of antifungal drugs, and their mode of action involves the binding mode of these molecules to the fungal lanosterol 14α-demethylase target enzyme. In this work, by rational design, we have prepared and characterized four novel organometallic derivatives of the frontline antifungal drug fluconazole (<b>1a-4a</b>). All compounds showed excellent <i>in vitro</i> activity against the yeast <i>C. robusta</i>, clearly surpassing the progenitor organic drug fluconazole. As anticipated, due to the presence of the ferrocenyl moiety in <b>1a-4a</b>, a modest increase in ROS generation was observed on <i>C. robusta</i> upon treatment. Very importantly, enzyme inhibition and chemogenetic profiling demonstrated that lanosterol 14α-demethylase was the main target of the most active compound of the series, (<i>N</i>-(ferrocenylmethyl)-2-(2,4-difluorophenyl)-2-hydroxy-N-methyl-3-(1H-1,2,4-triazol-1-yl)propan-1-aminium chloride, <b>2a</b>). Transmission electron microscopy (TEM) studies suggested that <b>2a</b> induced a loss in wall integrity as well as intracellular features ascribable to late apoptosis or necrosis. The impressive activity of <b>2a</b> was further confirmed on clinical isolates, where antimycotic potency up to 400 times higher than fluconazole was observed. Also, <b>2a </b>showed activity towards azole-resistant strains. This finding is very interesting since the target of <b>2a</b> is primarily the same as that of fluconazole, emphasizing the role played by the organometallic moiety. <i>In vivo</i> experiments conducted with <b>2a</b> at a dose of 10 mg/Kg in mice model of <i>Candida</i> infections, while not decreasing fungal burden in the kidney, reduced distal distribution to liver and brain and greatly improved the inflammatory pathology in the kidney and colon, compared to untreated mice.<br>

Nontoxic Cobalt(III) Schiff Base Complexes with Broad‐Spectrum Antifungal Activity

“…Treatment of mice bearing a Candida infection with 10 mg kg À1 of Fe2 did not decrease fungal burden in the kidney.H owever,t he treatment seemed to significantly im-prove the inflammatory pathology in the kidney and colon relative to untreated mice. [12] In other work, Efimov et al describedaseries of half-sandwich cobalt(III) and iron(III) complexes and found that only compounds bearing am etal-iodine bond (e.g., Co1)s howed significant activity against ap anel of six phytopathogenic fungi at 30 mgmL À1 .H owever,n oa ctivity at lower concentrations or other toxicityd ata were reported.N evertheless, these compounds represent an ew class of half sandwich complexes and warrantfurther investigations. [13] Gałczyń ska et al reported as eries of copper(II) and cobalt(II) complexes with the ligands imidazole-4-acetate(iaa) and 1-allylimidazole and found that the Co II -iaa compound (Co2) showedasignificant decrease ( % 5l og)i nc olony forming units (CFU) against Candida albicans at 60 mMi nvitro, while not displaying any cytotoxicity at the same concentration.…”