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Design, synthesis, and biodistribution studies of new analogues of marine alkaloids: Potent in vitro and in vivo fungicidal agents against Candida spp.

Abstract：

:Invasive candidiasis, such as intra-abdominal candidiasis (IAC), is a significant cause of morbidity and mortality worldwide. IAC is still poorly understood, and its treatment represents a challenge for public health. In this study, we showed the in vitro anti-Candida activity of four alkaloid synthetic derivatives and their antifungal potential in a murine model of IAC. The biological effects of alkaloids were evaluated against Candida spp. through the determination of the minimum inhibitory concentration (MIC). For the alkaloids that showed antifungal activity, the fungicidal concentration, time-kill curve, synergism with azoles and polyenes, phenotypic effects, and the effect against virulence factors were also determined. The most active alkaloids were selected for in vivo assays. The compounds 6a and 6b were active against C. albicans, C. glabrata, and C. tropicalis (MIC 7.8 μg/mL) and showed promising antifungal activity against C. krusei (MIC 3.9 μg/mL). The compound 6a presented a potent fungicidal effect in vitro, eliminating the yeast C. albicans after 8 h of incubation at MIC. An important in vitro synergistic effect with ketoconazole was observed for these two alkaloids. They also induced the lysis of fungal cells by binding to the ergosterol of the membrane. Besides that, 6a and 6b were able to reduce yeast-to-hyphal transition in C. albicans, as well as inhibit the biofilm formation of this pathogen. In the in vivo assay, the compound 6a did not show acute toxicity and was mainly absorbed by the liver, spleen, and lung after a parenteral administration. Also, this analogue significantly reduced the fungal load of C. albicans on the kidney and spleen of animals with IAC. Therefore, these results showed that the compound 6a is a potent anti-Candida agent in vitro and in vivo.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Andrade JT,Lima WG,Sousa JF,Saldanha AA,Nívea Pereira De Sá,Morais FB,Prates Silva MK,Ribeiro Viana GH,Johann S,Soares AC,Araújo LA,Antunes Fernandes SO,Cardoso VN,Siqueira Ferreira JM

doi

10.1016/j.ejmech.2020.113048

subject

Has Abstract

pub_date

2021-01-15 00:00:00

pages

113048

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(20)31020-5

journal_volume

210

pub_type

杂志文章

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Design, synthesis, and biodistribution studies of new analogues of marine alkaloids: Potent in vitro and in vivo fungicidal agents against Candida spp.