Abstract
Candida spp. is considered an important cause of healthcare-associated infections worldwide. Currently, the emergence and spread of resistant Candida isolates are being increasingly reported, making the development of new agents urgently needed. In this study, we showed the in vitro anti-Candida activity of seven synthetic 3-alkylpyridine alkaloid analogs. Among them, alkaloid 1 presented a potent antifungal effect, which was independent of its capacity of binding with the fungal membrane ergosterol or cell wall. Analog 1 showed fungistatic and fungicidal effects against C. albicans (MIC 7.8 μg/mL and MFC 62.5 μg/mL), C. glabrata, C. krusei (MIC and MFC 31.2 μg/mL), and C. tropicalis (MIC 31.2 μg/mL and MFC 125 μg/mL). The time kill-curve study showed that compound 1 has a potent fungicidal effect in vitro, eliminating C. albicans cells. Furthermore, an in vitro synergistic effect with ketoconazole was observed for compound 1. This compound also eliminated the yeast-to-hypha transition. However, it showed high cytotoxicity against mammalian cells. Taken together, these findings support the use of compound 1 as a prototype to develop new anti-Candida agents, but molecular modifications should be done to minimize the high cytotoxicity obtained.
Highlights
Candida albicans is the most prevalent fungal pathogen in humans; it is associated with severe fungal infections, accounting for more than 90% of cases of invasive fungal infection (Kauffman 2006, Zida et al 2016)
The antifungal potential of seven synthetic 3-alkylpyridine alkaloid (3-APA) analogs was evaluated against several Candida species frequently involved in invasive candidiasis (Table I)
Alkaloid 1 presented fungistatic and fungicidal activities against all Candida species evaluated (MIC ranging from 7.8 to 31.25 μg/mL and minimum fungicidal concentration (MFC) ranging from 31.25 to 125 μg/mL), revealing an extended spectrum of action that covers the most frequent species involved in candidiasis
Summary
Candida albicans is the most prevalent fungal pathogen in humans; it is associated with severe fungal infections, accounting for more than 90% of cases of invasive fungal infection (Kauffman 2006, Zida et al 2016). This fungus can assume several morphologies, including yeast, hypha, and pseudohypha (Kornitzer 2019). The increase of opportunistic fungal infections raises the need for the design and synthesis of new antifungal agents. In this context, alkaloid derivatives are an important source of novel compounds with pharmaceutical potentials, as they have been described to
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