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Journal of Chemistry
Volume 2019, Article ID 4785756, 12 pages
https://doi.org/10.1155/2019/4785756
Research Article

Design, Antileishmanial Activity, and QSAR Studies of a Series of Piplartine Analogues

1Laboratory of Pharmaceutical Chemistry, Universidade Federal da Paraíba, 58051-900 João Pessoa, PB, Brazil
2Department of Cellular and Molecular Biology, Universidade Federal da Paraíba, 58051-900 João Pessoa, PB, Brazil
3Department of Pharmacy, Federal University of Sergipe, 49100-000 São Cristóvão, SE, Brazil
4Escuela de Ciencias Físicas y Matemáticas, Universidad de Las Américas, Quito, Ecuador
5Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia 40296-710, Brazil

Correspondence should be addressed to Damião P. de Sousa; rb.moc.oohay@asuosed_oaimad

Received 14 October 2018; Accepted 17 December 2018; Published 8 January 2019

Academic Editor: Andrea Trabocchi

Copyright © 2019 Flávio R. Nóbrega et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Piplartine is an alkamide found in different Piper species and possesses several biological activities, including antiparasitic properties. Thus, the aim of the present study was to evaluate a series of 32 synthetic piplartine analogues against the Leishmania amazonensis promastigote forms and establish the structure-activity relationship and 3D-QSAR of these compounds. The antileishmanial effect of the compounds was determined using the MTT method. Most compounds were found to be active against L. amazonensis. Among 32 assayed derivatives, compound (E)-(−)-bornyl 3-(3,4,5-trimethoxyphenyl)-acrylate exhibited the most potent antileishmanial activity (IC50 = 0.007 ± 0.008 μM, SI > 10), followed by benzyl 3,4,5-trimethoxybenzoate (IC50 = 0.025 ± 0.009 μM, SI > 3.205) and (E)-furfuryl 3-(3,4,5-trimethoxyphenyl)-acrylate (IC50 = 0.029 ± 0.007 μM, SI > 2.688). It was found that the rigid substituents contribute to increasing antiparasitic activity against L. amazonensis promastigotes. The presence of the unsaturated heterocyclic substituent in the phenylpropanoid chemical structure (furfuryl group) resulted in a bioactive derivative. Molecular simplification of benzyl 3,4,5-trimethoxybenzoate by omitting the spacer group contributed to the bioactivity of this compound. Furthermore, bornyl radical appears to be important for antileishmanial activity, since (E)-(−)-bornyl 3-(3,4,5-trimethoxyphenyl)-acrylate exhibited the most potent antileishmanial activity. These results show that some derivatives studied would be useful as prototype molecules for the planning of new derivatives with profile of antileishmanial drugs.