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

Autor: Harold Hilarion Fokoue, Guilherme Matos Passarini, Christian Collins Kuehn, Massuo J. Kato, Marcia Paranho Veloso, Ana Paula de Azevedo dos Santos, Leandro do Nascimento Martinez, Kassius de Souza Reis, Carolina Bioni Garcia Teles, Minelly Azevedo da Silva
Rok vydání: 2020
Předmět:
Zdroj: Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual)
Universidade de São Paulo (USP)
instacron:USP
ISSN: 1432-1955
0932-0113
DOI: 10.1007/s00436-020-06681-9
Popis: 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.
Databáze: OpenAIRE
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