In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives

De Sena Pereira, Valeska Santana, Da Silva Emery, Flávio, Lobo, Lis Tavares Coelho, F Nogueira, Oliveira, Jonas I.N., Fulco, Umberto L., Albuquerque, Eudenílson Lins De, Katzin, Alejandro Miguel, Valter Ferreira De Andrade-Neto

Research output: Contribution to journalArticle

Abstract

BACKGROUND:
Plasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones.

RESULTS:
The two hydroxy-naphthoquinones derivatives have been tested against P. falciparum in vitro, using strains of parasites chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2), causing 50% inhibition of parasite growth with concentrations that varied from 7 to 44.5 μM. The cell viability in vitro against RAW Cell Line displayed IC50 = 483.5 and 714.9 μM, whereas, in primary culture tests using murine macrophages, IC50 were 315.8 and 532.6 μM for the two selected compounds, causing no haemolysis at the doses tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioural toxicity up to 300 mg/kg. It is suggested that this drug seems to inhibit the biosynthesis of isoprenic compounds, particularly the menaquinone and tocopherol.

CONCLUSIONS:
These derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host.
Original languageEnglish
Article number482
Pages (from-to)482-493
Number of pages11
JournalMalaria Journal
VolumeVol. 17
Issue numbern.º 1
DOIs
Publication statusPublished - 19 Dec 2018

Fingerprint

Naphthoquinones
Terpenes
Pharmacokinetics
Chloroquine
Antimalarials
Plasmodium falciparum
Inhibitory Concentration 50
Parasites
Pharmaceutical Preparations
Vitamin K 2
Tocopherols
Multiple Drug Resistance
Hemolysis
Metabolic Networks and Pathways
Cell Survival
Macrophages
Safety
Cell Line
aniline
In Vitro Techniques

Keywords

  • ADME predictions
  • Antimalarial drugs
  • Hydroxy-naphthoquinones
  • Isoprenoid pathway
  • Plasmodium falciparum

Cite this

Valeska Santana, D. S. P., Flávio, D. S. E., Lis Tavares Coelho, L., Nogueira, F., Jonas I.N., O., Umberto L., F., ... De Andrade-Neto, V. F. (2018). In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives. Malaria Journal, Vol. 17(n.º 1), 482-493. [482]. https://doi.org/10.1186/s12936-018-2615-8
Valeska Santana, De Sena Pereira, ; Flávio, Da Silva Emery, ; Lis Tavares Coelho, Lobo, ; Nogueira, F ; Jonas I.N., Oliveira, ; Umberto L., Fulco, ; Eudenílson Lins De, Albuquerque, ; Alejandro Miguel, Katzin, ; De Andrade-Neto, Valter Ferreira. / In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives. In: Malaria Journal. 2018 ; Vol. Vol. 17, No. n.º 1. pp. 482-493.
@article{920c41e5bbf8417f9d04b67c07643887,
title = "In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives",
abstract = "BACKGROUND:Plasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones.RESULTS:The two hydroxy-naphthoquinones derivatives have been tested against P. falciparum in vitro, using strains of parasites chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2), causing 50{\%} inhibition of parasite growth with concentrations that varied from 7 to 44.5 μM. The cell viability in vitro against RAW Cell Line displayed IC50 = 483.5 and 714.9 μM, whereas, in primary culture tests using murine macrophages, IC50 were 315.8 and 532.6 μM for the two selected compounds, causing no haemolysis at the doses tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioural toxicity up to 300 mg/kg. It is suggested that this drug seems to inhibit the biosynthesis of isoprenic compounds, particularly the menaquinone and tocopherol.CONCLUSIONS:These derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host.",
keywords = "ADME predictions, Antimalarial drugs, Hydroxy-naphthoquinones, Isoprenoid pathway, Plasmodium falciparum",
author = "{Valeska Santana}, {De Sena Pereira,} and Fl{\'a}vio, {Da Silva Emery,} and {Lis Tavares Coelho}, Lobo, and F Nogueira and {Jonas I.N.}, Oliveira, and {Umberto L.}, Fulco, and {Euden{\'i}lson Lins De}, Albuquerque, and {Alejandro Miguel}, Katzin, and {De Andrade-Neto}, {Valter Ferreira}",
year = "2018",
month = "12",
day = "19",
doi = "10.1186/s12936-018-2615-8",
language = "English",
volume = "Vol. 17",
pages = "482--493",
journal = "Malaria Journal",
issn = "1475-2875",
publisher = "Springer Verlag",
number = "n.º 1",

}

Valeska Santana, DSP, Flávio, DSE, Lis Tavares Coelho, L, Nogueira, F, Jonas I.N., O, Umberto L., F, Eudenílson Lins De, A, Alejandro Miguel, K & De Andrade-Neto, VF 2018, 'In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives', Malaria Journal, vol. Vol. 17, no. n.º 1, 482, pp. 482-493. https://doi.org/10.1186/s12936-018-2615-8

In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives. / Valeska Santana, De Sena Pereira,; Flávio, Da Silva Emery, ; Lis Tavares Coelho, Lobo, ; Nogueira, F; Jonas I.N., Oliveira, ; Umberto L., Fulco, ; Eudenílson Lins De, Albuquerque, ; Alejandro Miguel, Katzin, ; De Andrade-Neto, Valter Ferreira.

In: Malaria Journal, Vol. Vol. 17, No. n.º 1, 482, 19.12.2018, p. 482-493.

Research output: Contribution to journalArticle

TY - JOUR

T1 - In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives

AU - Valeska Santana, De Sena Pereira,

AU - Flávio, Da Silva Emery,

AU - Lis Tavares Coelho, Lobo,

AU - Nogueira, F

AU - Jonas I.N., Oliveira,

AU - Umberto L., Fulco,

AU - Eudenílson Lins De, Albuquerque,

AU - Alejandro Miguel, Katzin,

AU - De Andrade-Neto, Valter Ferreira

PY - 2018/12/19

Y1 - 2018/12/19

N2 - BACKGROUND:Plasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones.RESULTS:The two hydroxy-naphthoquinones derivatives have been tested against P. falciparum in vitro, using strains of parasites chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2), causing 50% inhibition of parasite growth with concentrations that varied from 7 to 44.5 μM. The cell viability in vitro against RAW Cell Line displayed IC50 = 483.5 and 714.9 μM, whereas, in primary culture tests using murine macrophages, IC50 were 315.8 and 532.6 μM for the two selected compounds, causing no haemolysis at the doses tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioural toxicity up to 300 mg/kg. It is suggested that this drug seems to inhibit the biosynthesis of isoprenic compounds, particularly the menaquinone and tocopherol.CONCLUSIONS:These derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host.

AB - BACKGROUND:Plasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones.RESULTS:The two hydroxy-naphthoquinones derivatives have been tested against P. falciparum in vitro, using strains of parasites chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2), causing 50% inhibition of parasite growth with concentrations that varied from 7 to 44.5 μM. The cell viability in vitro against RAW Cell Line displayed IC50 = 483.5 and 714.9 μM, whereas, in primary culture tests using murine macrophages, IC50 were 315.8 and 532.6 μM for the two selected compounds, causing no haemolysis at the doses tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioural toxicity up to 300 mg/kg. It is suggested that this drug seems to inhibit the biosynthesis of isoprenic compounds, particularly the menaquinone and tocopherol.CONCLUSIONS:These derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host.

KW - ADME predictions

KW - Antimalarial drugs

KW - Hydroxy-naphthoquinones

KW - Isoprenoid pathway

KW - Plasmodium falciparum

UR - https://malariajournal.biomedcentral.com/track/pdf/10.1186/s12936-018-2615-8

U2 - 10.1186/s12936-018-2615-8

DO - 10.1186/s12936-018-2615-8

M3 - Article

VL - Vol. 17

SP - 482

EP - 493

JO - Malaria Journal

JF - Malaria Journal

SN - 1475-2875

IS - n.º 1

M1 - 482

ER -