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

Abstract

Candidiasis is an opportunistic fungal infection with Candida albicans being the most frequently isolated species. Treatment of these infections is challenging due to resistance that can develop during therapy, and the limited number of available antifungal compounds. Given this situation, the aim of this study was to evaluate the antifungal activity of four thiazolylhydrazone compounds against C. albicans. Thiazolylhydrazone compounds 1, 2, 3, and 4 were found to exert antifungal activity, with MICs of 0.125–16.0 μg/mL against C. albicans. The toxicity of the compounds was evaluated using human erythrocytes and yielded LC50 > 64 μg/mL. The compounds were further evaluated using the greater wax moth Galleria mellonella as an in vivo model. The compounds prolonged larval survival when tested between 5 and 15 mg/kg, performing as well as fluconazole. Compound 2 was evaluated in murine models of oral and systemic candidiasis. In the oral model, compound 2 reduced the fungal load on the mouse tongue; and in the systemic model it reduced the fungal burden found in the kidney when tested at 10 mg/kg. These results show that thiazolylhydrazones are an antifungal towards C. albicans with in vivo efficacy.

Galleria mellonella as a consolidated in vivo model hosts: New developments in antibacterial strategies and novel drug testing

“…Although these compounds showed antifungal activity, the authors observed an LD 50 < 10mg/kg. This low toxicity was confirmed by a hemolysis assay performed using human erythrocytes [98].…”

Galleria mellonella for the Evaluation of Antifungal Efficacy against Medically Important Fungi, a Narrative Review

“…The genus Candida has been extensively studied in the G. mellonella model especially for the evaluation of virulence and antifungal efficacy [10,71,72]. G. mellonella was used to test the efficacy of different antifungal compounds against Candida yeasts including conventional antifungal drugs [13][14][15][16][17][18][19][20][21][22][23], new drugs [25][26][27][30][31][32]34] or non-antifungal compounds in a repurposing perspective [24,28,29,33]. Antifungal combinations against Candida spp.…”

“…Several drugs, such as atorvastatin, a cholesterol-lowering agent [24], miltefosine, an anti-leishmanial drug [33], miramistin, an antiseptic [29], and pilocarpine, a muscarinic agonist [28] were evaluated in a repurposing perspective. In other instances, new synthetic compounds or natural products were tested in vivo in the model [25][26][27][30][31][32]34]. It must be noticed that in all cases, larvae were infected with C. albicans.…”

Advances in Biomaterials for the Prevention and Disruption of Candida Biofilms

“…Among these are newly synthesized imidazole derivatives, which have been found to prevent Candida biofilm formation and disrupt existing biofilms (Ribeiro et al, 2014;Gabriel et al, 2019). Thiazolylhydrazone derivatives have also recently emerged as effective antifungal compounds with low mammalian cell toxicity (Cruz et al, 2018).…”

“…Among these are newly synthesized imidazole derivatives, which have been found to prevent Candida biofilm formation and disrupt existing biofilms ( Ribeiro et al, 2014 ; Gabriel et al, 2019 ). Thiazolylhydrazone derivatives have also recently emerged as effective antifungal compounds with low mammalian cell toxicity ( Cruz et al, 2018 ). 2,6-Bis[(E)-(4-pyridyl)methylidene]cyclohexanone, an antiparasitic compound, was also found to exhibit antifungal properties including the inhibition of Candida filamentation, crucial in biofilm formation ( de Sá et al, 2018 ).…”