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

• Published in: Parasitology research (1987) Vol. 119; no. 6; pp. 1879 - 1887
• Main Authors: da Silva, Minelly Azevedo, Veloso, Márcia Paranho, de Souza Reis, Kassius, de Matos Passarini, Guilherme, dos Santos, Ana Paula de Azevedo, do Nascimento Martinez, Leandro, Fokoue, Harold Hilarion, Kato, Massuo Jorge, Teles, Carolina Bioni Garcia, Kuehn, Christian Collins
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-06-2020; Springer; Springer Nature B.V
• Subjects: Affinity; Amides; Amides - chemistry; Amides - pharmacology; Animals; Antimalarial agents; Antimalarials; Antimalarials - pharmacology; Antiprotozoal agents; Biomedical and Life Sciences; Biomedicine; Care and treatment; Chlorocebus aethiops; Computer Simulation; Developing countries; Drug development; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - antagonists & inhibitors; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - metabolism; Enzymes; Fatty acids; Health aspects; Hep G2 Cells; Humans; Immunology; LDCs; Malaria; Malaria, Falciparum; Medical Microbiology; Microbiology; Molecular Docking Simulation; Physiological aspects; Piper nigrum; Piperine; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Protozoa; Protozoology - Original Paper; Reductase; Triclosan; Triclosan - pharmacology; Vero Cells; Brazil; New York; Malaria; Piperidine alkaloids; Fatty acids; Plasmodium falciparum enoyl-ACP reductase
• ISSN: 0932-0113; 1432-1955
• DOI: 10.1007/s00436-020-06681-9

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 (P
f
ENR) 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
—IC
50
104.45 μM), (
1b
,
1g
,
1k
, and
14f
) and the natural amide piperine (
18a
) were shown to be inactive (IC
50
 > 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 P
f
ENR 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.