Synthesis of a dehydrodieugenol B derivative as a lead compound for visceral leishmaniasis-mechanism of action and in vivo pharmacokinetic studies

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Amaral, Maiara ; Romanelli, Maiara M. ; Asiki, Hannah ; Bicker, Joana ; Lage, Daniela P. ; Freitas, Camila S. ; Taniwaki, Noemi N. ; Lago, Joao Henrique G. ; Coelho, Eduardo A. F. ; Falcao, Amilcar ; Fortuna, Ana ; Anderson, Edward A. ; Tempone, Andre G.

• Tipo de documento: Artigo Científico
• Fonte: Antimicrobial Agents and Chemotherapy; v. 68, n. 11, p. 20-pg., 2024-10-09.

Resumo

Leishmaniasis is a parasitic neglected tropical disease, affecting 12 million people. Available treatments present several limitations, with an increasing number of resistance cases. In the search for new chemotherapies, the natural product dehydrodieugenol B was used as a scaffold for the synthesis of a series of derivatives, resulting in the discovery of the promising analog [4-(4-(5-allyl-3-methoxy-2-((4-methoxybenzyl)oxy)phenoxy)-3-methoxybenzyl)morpholine, 1]. In this work, we investigated the effect of compound 1 on cell signaling in Leishmania (L.) infantum, culminating in cell death, as well as its immunomodulatory effect in the host cell. Additionally, we performed a pharmacokinetic profile study in an animal model. After treatment, compound 1 induced the alkalinization of acidocalcisomes and concomitant Ca2+ release in the parasite. These events may induce depolarization of the mitochondrial potential, with successive collapse of the bioenergetic system, leading to a reduction of ATP and reactive oxygen species (ROS) levels. The analysis of total proteins and protein profile by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/MS) demonstrated that compound 1 also altered the parasite proteins after treatment. Transmission electron microscopy studies revealed ultrastructural damage to mitochondria; together, these data suggest that compound 1 may promote autophagic cell death. Additionally, compound 1 also induced an immunomodulatory effect in host cells, with a reduction of Th1 and Th2 cytokine response, characterizing an anti-inflammatory compound. The obtained pharmacokinetic profile in rats enhances the potential of the compound, with a mean plasma half-life (T-1/2) of 21 h. These data reinforce the potential of compound 1 as a new lead for future efficacy studies. (AU)

• Processo FAPESP: 21/04464-8 - Protótipos microbianos e vegetais como candidatos a fármacos para protozooses negligenciadas e bactérias multirresistentes
• Beneficiário: André Gustavo Tempone Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular