Structure-Activity Relationship of Piplartine and Synthetic Analogues against Schistosoma mansoni and Cytotoxicity to Mammalian Cells

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Campelo, Yuri ; Ombredane, Alicia ; Vasconcelos, Andreanne G. ; Albuquerque, Lucas ; Moreira, Daniel C. ; Placido, Alexandra ; Rocha, Jefferson ; Fokoue, Harold Hilarion ; Yamaguchi, Lydia ; Mafud, Ana ; Mascarenhas, Yvonne P. ; Delerue-Matos, Cristina ; Borges, Tatiana ; Joanitti, Graziella A. ; Arcanjo, Daniel D. R. ; Kato, Massuo J. ; Kuckelhaus, Selma A. S. ; Silva, Marcos P. N. ; de Moraes, Josue ; Leite, Jose Roberto S. A.

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 19, n. 6, p. 17-pg., 2018-06-01.

Abstract

Schistosomiasis, caused by helminth flatworms of the genus Schistosoma, is an infectious disease mainly associated with poverty that affects millions of people worldwide. Since treatment for this disease relies only on the use of praziquantel, there is an urgent need to identify new antischistosomal drugs. Piplartine is an amide alkaloid found in several Piper species (Piperaceae) that exhibits antischistosomal properties. The aim of this study was to evaluate the structure-function relationship between piplartine and its five synthetic analogues (19A, 1G, 1M, 14B and 6B) against Schistosoma mansoni adult worms, as well as its cytotoxicity to mammalian cells using murine fibroblast (NIH-3T3) and BALB/cN macrophage (J774A.1) cell lines. In addition, density functional theory calculations and in silico analysis were used to predict physicochemical and toxicity parameters. Bioassays revealed that piplartine is active against S. mansoni at low concentrations (5-10 mu M), but its analogues did not. In contrast, based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, piplartine exhibited toxicity in mammalian cells at 785 mu M, while its analogues 19A and 6B did not reduce cell viability at the same concentrations. This study demonstrated that piplartine analogues showed less activity against S. mansoni but presented lower toxicity than piplartine. (AU)

• FAPESP's process: 16/22488-3 - Drug repositioning for neglected diseases: identification of novel anthelmintic agents
• Grantee: Josué de Moraes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/50316-7 - Dimensions US-Biota São Paulo: Chemically mediated multi-trophic interaction diversity across tropical gradients
• Grantee: Massuo Jorge Kato
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 14/02282-6 - Structure-activity relationship studies about of Pilocarpus microphyllus (Rutaceae) alkaloid derivatives against Schistosoma mansoni
• Grantee: Ana Carolina Mafud
• Support Opportunities: Scholarships in Brazil - Post-Doctoral