Abstract
To minimize the intrinsic toxicity of the antibacterial agent hydrazinyloxadiazole 1, the hydrazine moiety was replaced with ethylenediamine (compound 7). This replacement generated a potent antifungal agent with no antibacterial activity. Notably, use of a 1,2-diaminocyclohexane moiety, as a conformationally-restricted isostere for ethylenediamine, potentiated the antifungal activity in both the cis and trans forms of N-(5-(2-([1,1’-biphenyl]-4-yl)-4-methylthiazol-5-yl)-1,3,4-oxadiazol-2-yl)cyclohexane-1,2-diamine (compounds 16 and 17). Both compounds 16 and 17 were void of any antibacterial activity; nonetheless, they showed equipotent antifungal activity in vitro to that of the most potent approved antifungal agent, amphotericin B. The promising antifungal effects of compounds 16 and 17 were maintained when assessed against an additional panel of 26 yeast and mold clinical isolates, including the Candida auris and C. krusei. Furthermore, compound 17 showed superior activity to amphotericin B in vitro against Candida glabrata and Cryptococcus gattii. Additionally, neither compound inhibited the normal human microbiota, and both possessed excellent safety profiles and were 16 times more tolerable than amphotericin B.
Highlights
More than 1.6 million patients die annually as a result of fungal infections
Bisphenylthiazoles for multidrug-resistant fungal infections infections is highly compromised by the increasing resistance to the current antifungal agents, such as fluconazole [3]
The chemical structures of compounds 10 and 15 were found to be joined by an oxadiazole ring via the pyrrolidine/piperidine nitrogen rather than the terminal primary amine-based on their spectral data
Summary
More than 1.6 million patients die annually as a result of fungal infections. This crisis has positioned fungi at the same level of threat as tuberculosis, and the threat is 3-fold more serious than that of malaria [1]. Aspergillus, and Cryptococcus are the principal fungal pathogens responsible for human morbidity and mortality [2]. Bisphenylthiazoles for multidrug-resistant fungal infections infections is highly compromised by the increasing resistance to the current antifungal agents, such as fluconazole [3]. The isolation of panazole-resistant strains of Aspergillus fumigatus has been reported at an increasing frequency, thereby complicating disease management. Its treatment options are limited due to the increased resistance and inadequacy of the current antifungal therapeutics [7]. The low number of available antifungals and the increasing resistance to them require the development of new classes of effective antifungals
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