Design, synthesis, and biodistribution studies of new analogues of marine alkaloids: Potent in vitro and in vivo fungicidal agents against Candida spp. J  essica Tauany Andrade a , William Gustavo Lima a, e , Jaqueline França Sousa b , Aline Aparecida Saldanha c , Nívea Pereira De S  a d , Fernanda Barbara Morais a , Mayra Karla Prates Silva a , Gustavo Henrique Ribeiro Viana b , Susana Johann d , Adriana Cristina Soares c , Leonardo Allan Araújo f , Simone Odília Antunes Fernandes e , Valbert Nascimento Cardoso e , Jaqueline Maria Siqueira Ferreira a, * a Laborat orio de Microbiologia M edica, Campus Universidade Federal de S~ ao Jo~ ao Del-Rei (UFSJ), Centro-Oeste Dona Lindu, Divin opolis, Minas Gerais, Brazil b Laborat orio de Compostos Bioativos e Catalíticos, Campus Universidade Federal de S~ ao Jo~ ao Del-Rei (UFSJ), Centro-Oeste Dona Lindu, Divin opolis, Minas Gerais, Brazil c Laborat orio de Farmacologia da Dor e Inflamaç~ ao, Campus Universidade Federal de S~ ao Jo~ ao Del-Rei (UFSJ), Centro-Oeste Dona Lindu, Divin opolis, Minas Gerais, Brazil d Departamento de Microbiologia, Instituto de Ci^ encias Biol ogicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil e Laborat orio de Radiois otopos, Departamento de An alises Clinicas e Toxicol ogicas, Faculdade de Farm acia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil f Serviço de Recursos Vegetais e Opoter apicos (SRVO), Diretoria de Pesquisa (DPD), Fundaç~ ao Ezequiel Dias (FUNED), Belo Horizonte, MG, Brazil article info Article history: Received 17 March 2020 Received in revised form 26 June 2020 Accepted 23 November 2020 Available online 3 December 2020 Keywords: Antifungal activity Candida albicans Alkaloids Biofilm 99m Tc radiolabeled alkaloids Intra-abdominal candidiasis 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 mg/mL) and showed promising antifungal activity against C. krusei (MIC 3.9 mg/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 yeasteto-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. © 2020 Elsevier Masson SAS. All rights reserved. * Corresponding author. Laborat orio de Microbiologia M edica, Campus Centro Oeste Dona Lindu/ Universidade Federal de S~ ao Jo~ ao Del-Rei, Rua Sebasti~ ao Gonçalves Coelho, 400, Chanadour, Divin opolis, Minas Gerais, CEP: 35501-293, Brazil E-mail address: jackmaria4@gmail.com (J.M. Siqueira Ferreira). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech https://doi.org/10.1016/j.ejmech.2020.113048 0223-5234/© 2020 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 210 (2021) 113048