New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum

Lis Lobo, Lília I.L. Cabral, Maria Inês Sena, Bruno Guerreiro, António Sebastião Rodrigues, Valter Ferreira De Andrade-Neto, Maria L.S. Cristiano, Fatima Nogueira

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: The emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy in Southeast Asia prompted the need to develop new endoperoxide-type drugs. Methods: A chemically diverse library of endoperoxides was designed and synthesized. The compounds were screened for in vitro and in vivo anti-malarial activity using, respectively, the SYBR Green I assay and a mouse model. Ring survival and mature stage survival assays were performed against artemisinin-resistant and artemisinin-sensitive P. falciparum strains. Cytotoxicity was evaluated against mammalian cell lines V79 and HepG2, using the MTT assay. Results: The synthesis and anti-malarial activity of 21 new endoperoxide-derived compounds is reported, where the peroxide pharmacophore is part of a trioxolane (ozonide) or a tetraoxane moiety, flanked by adamantane and a substituted cyclohexyl ring. Eight compounds exhibited sub-micromolar anti-malarial activity (IC50 0.3-71.1 nM), no cross-resistance with artemisinin or quinolone derivatives and negligible cytotoxicity towards mammalian cells. From these, six produced ring stage survival < 1% against the resistant strain IPC5202 and three of them totally suppressed Plasmodium berghei parasitaemia in mice after oral administration. Conclusion: The investigated, trioxolane-tetrazole conjugates LC131 and LC136 emerged as potential anti-malarial candidates; they show negligible toxicity towards mammalian cells, ability to kill intra-erythrocytic asexual stages of artemisinin-resistant P. falciparum and capacity to totally suppress P. berghei parasitaemia in mice.

Original languageEnglish
Article number145
JournalMalaria Journal
Volume17
Issue number1
DOIs
Publication statusPublished - 3 Apr 2018

Fingerprint

Plasmodium falciparum
Antimalarials
Plasmodium berghei
Parasitemia
Tetraoxanes
Adamantane
Southeastern Asia
Quinolones
Peroxides
Inhibitory Concentration 50
Libraries
Oral Administration
In Vitro Techniques
artemisinine
Cell Line
Pharmaceutical Preparations
Therapeutics

Keywords

  • Antimalarial drug resistance
  • In vivo antimalarial activity
  • Plasmodium falciparum
  • Tetraoxane-tetrazole conjugates
  • Trioxolane-tetrazole conjugates

Cite this

Lobo, Lis ; Cabral, Lília I.L. ; Sena, Maria Inês ; Guerreiro, Bruno ; Rodrigues, António Sebastião ; De Andrade-Neto, Valter Ferreira ; Cristiano, Maria L.S. ; Nogueira, Fatima. / New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum. In: Malaria Journal. 2018 ; Vol. 17, No. 1.
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abstract = "Background: The emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy in Southeast Asia prompted the need to develop new endoperoxide-type drugs. Methods: A chemically diverse library of endoperoxides was designed and synthesized. The compounds were screened for in vitro and in vivo anti-malarial activity using, respectively, the SYBR Green I assay and a mouse model. Ring survival and mature stage survival assays were performed against artemisinin-resistant and artemisinin-sensitive P. falciparum strains. Cytotoxicity was evaluated against mammalian cell lines V79 and HepG2, using the MTT assay. Results: The synthesis and anti-malarial activity of 21 new endoperoxide-derived compounds is reported, where the peroxide pharmacophore is part of a trioxolane (ozonide) or a tetraoxane moiety, flanked by adamantane and a substituted cyclohexyl ring. Eight compounds exhibited sub-micromolar anti-malarial activity (IC50 0.3-71.1 nM), no cross-resistance with artemisinin or quinolone derivatives and negligible cytotoxicity towards mammalian cells. From these, six produced ring stage survival < 1{\%} against the resistant strain IPC5202 and three of them totally suppressed Plasmodium berghei parasitaemia in mice after oral administration. Conclusion: The investigated, trioxolane-tetrazole conjugates LC131 and LC136 emerged as potential anti-malarial candidates; they show negligible toxicity towards mammalian cells, ability to kill intra-erythrocytic asexual stages of artemisinin-resistant P. falciparum and capacity to totally suppress P. berghei parasitaemia in mice.",
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New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum. / Lobo, Lis; Cabral, Lília I.L.; Sena, Maria Inês; Guerreiro, Bruno; Rodrigues, António Sebastião; De Andrade-Neto, Valter Ferreira; Cristiano, Maria L.S.; Nogueira, Fatima.

In: Malaria Journal, Vol. 17, No. 1, 145, 03.04.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum

AU - Lobo, Lis

AU - Cabral, Lília I.L.

AU - Sena, Maria Inês

AU - Guerreiro, Bruno

AU - Rodrigues, António Sebastião

AU - De Andrade-Neto, Valter Ferreira

AU - Cristiano, Maria L.S.

AU - Nogueira, Fatima

PY - 2018/4/3

Y1 - 2018/4/3

N2 - Background: The emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy in Southeast Asia prompted the need to develop new endoperoxide-type drugs. Methods: A chemically diverse library of endoperoxides was designed and synthesized. The compounds were screened for in vitro and in vivo anti-malarial activity using, respectively, the SYBR Green I assay and a mouse model. Ring survival and mature stage survival assays were performed against artemisinin-resistant and artemisinin-sensitive P. falciparum strains. Cytotoxicity was evaluated against mammalian cell lines V79 and HepG2, using the MTT assay. Results: The synthesis and anti-malarial activity of 21 new endoperoxide-derived compounds is reported, where the peroxide pharmacophore is part of a trioxolane (ozonide) or a tetraoxane moiety, flanked by adamantane and a substituted cyclohexyl ring. Eight compounds exhibited sub-micromolar anti-malarial activity (IC50 0.3-71.1 nM), no cross-resistance with artemisinin or quinolone derivatives and negligible cytotoxicity towards mammalian cells. From these, six produced ring stage survival < 1% against the resistant strain IPC5202 and three of them totally suppressed Plasmodium berghei parasitaemia in mice after oral administration. Conclusion: The investigated, trioxolane-tetrazole conjugates LC131 and LC136 emerged as potential anti-malarial candidates; they show negligible toxicity towards mammalian cells, ability to kill intra-erythrocytic asexual stages of artemisinin-resistant P. falciparum and capacity to totally suppress P. berghei parasitaemia in mice.

AB - Background: The emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy in Southeast Asia prompted the need to develop new endoperoxide-type drugs. Methods: A chemically diverse library of endoperoxides was designed and synthesized. The compounds were screened for in vitro and in vivo anti-malarial activity using, respectively, the SYBR Green I assay and a mouse model. Ring survival and mature stage survival assays were performed against artemisinin-resistant and artemisinin-sensitive P. falciparum strains. Cytotoxicity was evaluated against mammalian cell lines V79 and HepG2, using the MTT assay. Results: The synthesis and anti-malarial activity of 21 new endoperoxide-derived compounds is reported, where the peroxide pharmacophore is part of a trioxolane (ozonide) or a tetraoxane moiety, flanked by adamantane and a substituted cyclohexyl ring. Eight compounds exhibited sub-micromolar anti-malarial activity (IC50 0.3-71.1 nM), no cross-resistance with artemisinin or quinolone derivatives and negligible cytotoxicity towards mammalian cells. From these, six produced ring stage survival < 1% against the resistant strain IPC5202 and three of them totally suppressed Plasmodium berghei parasitaemia in mice after oral administration. Conclusion: The investigated, trioxolane-tetrazole conjugates LC131 and LC136 emerged as potential anti-malarial candidates; they show negligible toxicity towards mammalian cells, ability to kill intra-erythrocytic asexual stages of artemisinin-resistant P. falciparum and capacity to totally suppress P. berghei parasitaemia in mice.

KW - Antimalarial drug resistance

KW - In vivo antimalarial activity

KW - Plasmodium falciparum

KW - Tetraoxane-tetrazole conjugates

KW - Trioxolane-tetrazole conjugates

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U2 - 10.1186/s12936-018-2281-x

DO - 10.1186/s12936-018-2281-x

M3 - Article

VL - 17

JO - Malaria Journal

JF - Malaria Journal

SN - 1475-2875

IS - 1

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ER -