Heterocycle Thiazole Compounds Exhibit Antifungal Activity through Increase in the Production of Reactive Oxygen Species in the Cryptococcus neoformans-Cryptococcus gattii Species Complex

Abstract

Human cryptococcosis can occur as a primary or opportunistic infection and develops as an acute, subacute, or chronic systemic infection involving different organs of the host. Given the limited therapeutic options and the occasional resistance to fluconazole, there is a need to develop novel drugs for the treatment of cryptococcosis. In this report, we describe promising thiazole compounds 1, 2, 3, and 4 and explore their possible modes of action against Cryptococcus. To this end, we show evidence of interference in the Cryptococcus antioxidant system. The tested compounds exhibited MICs ranging from 0.25 to 2 g/ml against Cryptococcus neoformans strains H99 and KN99␣. Interestingly, the knockout strains for Cu oxidase and sarcosine oxidase were resistant to thiazoles. MIC values of thiazole compounds 1, 2, and 4 against these mutants were higher than for the parental strain. After the treatment of C. neoformans ATCC 24067 (or C. deneoformans) and C. gattii strain L27/01 (or C. deuterogattii) with thiazoles, we verified an increase in intracellular reactive oxygen species (ROS). Also, we verified the synergistic interactions among thiazoles and menadione, which generates superoxides, with fractional inhibitory concentrations (FICs) equal to 0.1874, 0.3024, 0.25, and 0.25 for the thiazole compounds 1, 2, 3, and 4, respectively. In addition, thiazoles exhibited antagonistic interactions with parasulphonatephenyl porphyrinato ferrate III (FeTPPS). Thus, in this work, we showed that the action of these thiazoles is related to an interference with the antioxidant system. These findings suggest that oxidative stress may be primarily related to the accumulation of superoxide radicals.

Anti-Candida albicans Activity of Thiazolylhydrazone Derivatives in Invertebrate and Murine Models

“…In contrast, the positive control, Triton X-100, caused hemolysis at all concentrations. These findings are consistent with previous studies showing that thiazoles heterocyclic compounds do not cause damage to mammalian blood cells [20,21].…”

A Phenylthiazole Derivative Demonstrates Efficacy On Treatment of the Cryptococcosis & Candidiasis in Animal Models

“…Sá et al . [ 27 ] showed evidence that CHT target action is related to interference in antioxidant fungal system and here in this work we show that in addition to this CHT is also capable of inhibiting C. albicans adhesion in HBEC and shows an indication in reducing of biofilms.…”

“…In a previous work [ 16 ] we had demonstrated that there was no toxicity to mammalian cells, and recently we verified that CHT is nontoxic to human erythrocytes [ 27 ]. These findings indicate that CHT has potential in a murine model, which is considered the gold standard for studying pathogenesis, quantifying virulence, and analyzing the efficacy of antifungal drugs [ 30 ].…”

A New Antifungal Agent (4-phenyl-1, 3-thiazol-2-yl) Hydrazine Induces Oxidative Damage in Candida albicans

“…On the one hand, the antifungal effects of many compounds were confirmed to be related to the elevated endogenous ROS. Compounds with different scaffolds, such as shikonin, heterocycle thiazole compounds, clerodane type diterpene, and SM21, exhibited antifungal activity through increasing the production of ROS in fungi (Miao et al, 2012;Bhattacharya et al, 2015;de Sa et al, 2017;Truong et al, 2018). On the other hand, the induction of elevated endogenous ROS is the mechanism of many antifungal synergists.…”