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In silico evaluation and in vitro growth inhibition of Plasmodium falciparum by natural amides and synthetic analogs

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Abstract

Malaria, caused by protozoa of the genus Plasmodium, is a disease that infects hundreds of millions of people annually, causing an enormous social burden in many developing countries. Since current antimalarial drugs are starting to face resistance by the parasite, the development of new therapeutic options has been prompted. The enzyme Plasmodium falciparum enoyl-ACP reductase (PfENR) has a determinant role in the fatty acid biosynthesis of this parasite and is absent in humans, making it an ideal target for new antimalarial drugs. In this sense, the present study aimed at evaluating the in silico binding affinity of natural and synthetic amides through molecular docking, in addition to their in vitro activity against P. falciparum by means of the SYBR Green Fluorescence Assay. The in vitro results revealed that the natural amide piplartine (1a) presented partial antiplasmodial activity (20.54 μM), whereas its synthetic derivatives (1m—IC50 104.45 μM), (1b, 1g, 1k, and 14f) and the natural amide piperine (18a) were shown to be inactive (IC50 > 200 μM). The in silico physicochemical analyses demonstrated that compounds 1m and 14f violated the Lipinski's rule of five. The in silico analyses showed that 14f presented the best binding affinity (− 13.047 kcal/mol) to PfENR and was also superior to the reference inhibitor triclosan (− 7.806 kcal/mol). In conclusion, we found that the structural modifications in 1a caused a significant decrease in antiplasmodial activity. Therefore, new modifications are encouraged in order to improve the activity observed.

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  • 21 May 2020

    The original version of the article above contained an error in the text.

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Acknowledgments

We are thankful to the Instituto Federal de Rondônia, campus of Porto Velho – Calama; Plataforma de Bioensaios de Malária e Leishmaniose – FIOCRUZ-RO; Institute of Chemistry of the Federal University of São Paulo – USP; the Instituto Nacional de Ciência e Tecnologia em Fármacos e Medicamentos (INCT-INOFAR), Rede Mineira de Química (RQ-MG), FAPEMIG and CNPq; and Programa de Pós-Graduação em Biologia Experimental – PGBIOEXP/UNIR.

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Authors and Affiliations

  1. Programa de Pós graduação em Biologia Experimental, PGBIOEXP, Porto Velho, Brazil

    Minelly Azevedo da Silva, Guilherme de Matos Passarini, Ana Paula de Azevedo dos Santos, Leandro do Nascimento Martinez, Carolina Bioni Garcia Teles & Christian Collins Kuehn

  2. Instituto Federal de Rondônia, IFRO, Porto Velho / Rondônia, Brazil

    Minelly Azevedo da Silva

  3. Universidade Federal de Rondônia –UNIR, Porto Velho, Brazil

    Minelly Azevedo da Silva, Guilherme de Matos Passarini, Ana Paula de Azevedo dos Santos, Leandro do Nascimento Martinez, Carolina Bioni Garcia Teles & Christian Collins Kuehn

  4. Laboratório de Avaliação e de Síntese de Substâncias Bioativas, Alfenas - MG, Brazil

    Márcia Paranho Veloso & Kassius de Souza Reis

  5. Universidade Federal de Alfenas, Alfenas - MG, Brazil

    Márcia Paranho Veloso & Kassius de Souza Reis

  6. Fundação Oswaldo Cruz, Rondônia (FIOCRUZ –RO) / EpiAmO, Porto Velho, Brazil

    Guilherme de Matos Passarini, Ana Paula de Azevedo dos Santos, Leandro do Nascimento Martinez & Carolina Bioni Garcia Teles

  7. Instituto de Química da Universidade de São Paulo, IQ-USP, São Paulo, Brazil

    Harold Hilarion Fokoue & Massuo Jorge Kato

  8. Centro Universitário São Lucas, UniSL, Porto Velho, Brazil

    Carolina Bioni Garcia Teles

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  1. Minelly Azevedo da Silva
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  2. Márcia Paranho Veloso
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  3. Kassius de Souza Reis
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Correspondence to Minelly Azevedo da Silva.

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da Silva, M.A., Veloso, M.P., de Souza Reis, K. et al. In silico evaluation and in vitro growth inhibition of Plasmodium falciparum by natural amides and synthetic analogs. Parasitol Res 119, 1879–1887 (2020). https://doi.org/10.1007/s00436-020-06681-9

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