Cargando…
Antimalarial activity assay of artesunate-3-chloro-4(4-chlorophenoxy) aniline in vitro and in mice models
The global spread of multi-drug resistant P. falciparum, P. vivax, and P. malariae strains and absence of long-term effective vaccine makes chemotherapy the mainstay of malaria control strategies in endemic settings. The Mossman’s assay and the Organization for Economic Co-operation and Development...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977633/ https://www.ncbi.nlm.nih.gov/pubmed/36859621 http://dx.doi.org/10.1007/s00436-023-07801-x |
_version_ | 1784899336821276672 |
---|---|
author | Waithera, Milka Wambui Sifuna, Martin Wekesa Kariuki, Daniel Wainaina Kinyua, Johnson Kang’ethe Kimani, Francis Thuo Ng’ang’a, Joseph Kang’ethe Takei, Masahiro |
author_facet | Waithera, Milka Wambui Sifuna, Martin Wekesa Kariuki, Daniel Wainaina Kinyua, Johnson Kang’ethe Kimani, Francis Thuo Ng’ang’a, Joseph Kang’ethe Takei, Masahiro |
author_sort | Waithera, Milka Wambui |
collection | PubMed |
description | The global spread of multi-drug resistant P. falciparum, P. vivax, and P. malariae strains and absence of long-term effective vaccine makes chemotherapy the mainstay of malaria control strategies in endemic settings. The Mossman’s assay and the Organization for Economic Co-operation and Development (OECD), 2001 guideline 423, were used to determine the cytotoxicity and acute oral toxicity of a novel hybrid drug, artesunate-3-Chloro-4(4-chlorophenoxy) aniline (ATSA), in vitro and in vivo, respectively. A modified Desjardins method was used to screen for antiplasmodial activity using P. falciparum (3D(7) and W(2)) strains in vitro. The Peter’s 4-day suppressive tests (4DTs) was used to evaluate the in vivo antimalaria activity using P. berghei ANKA strain, lumefantrine resistant (LuR), and piperaquine resistant (PQR) P. berghei lines. In silico prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles was assayed using PreADMET online prediction tool. The reference drug in all experiments was artesunate (ATS). Statistical significance between ATSA’s activities in treated and control mice was evaluated by one-way analysis of variance (ANOVA). Results show that inhibitory concentrations-50 (IC(50)) of ATSA is 11.47 ± 1.3 (3D(7)) and 1.45 ± 0.26 (W(2)) against 4.66 ± 0.93 (3D(7)) and 0.60 ± 0.15 (W(2)) ng/ml of ATS with a selective index of 2180.91(3D(7)) and a therapeutic index (TI) of > 71). No mortalities were observed in acute oral toxicity assays and mean weight differences for test and controls were statistically insignificant (P > 0.05). The in vivo activity of ATSA was above 40% with effective dosage-50 (ED(50)) of 4.211, 2.601, and 3.875 mg/kg body weight against P. berghei ANKA, LuR, and PQR lines, respectively. The difference between treated and control mice was statistically significant (P < 0.05). ATSA has high intestinal absorption (HIA) > 95% and has medium human ether-a-go-go related gene (hERG) K(+) channel inhibition risks. Preclinical and clinical studies on ATSA are recommended to evaluate its value in developing novel drugs for future management of multi-drug resistant malaria parasites. |
format | Online Article Text |
id | pubmed-9977633 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-99776332023-03-02 Antimalarial activity assay of artesunate-3-chloro-4(4-chlorophenoxy) aniline in vitro and in mice models Waithera, Milka Wambui Sifuna, Martin Wekesa Kariuki, Daniel Wainaina Kinyua, Johnson Kang’ethe Kimani, Francis Thuo Ng’ang’a, Joseph Kang’ethe Takei, Masahiro Parasitol Res Research The global spread of multi-drug resistant P. falciparum, P. vivax, and P. malariae strains and absence of long-term effective vaccine makes chemotherapy the mainstay of malaria control strategies in endemic settings. The Mossman’s assay and the Organization for Economic Co-operation and Development (OECD), 2001 guideline 423, were used to determine the cytotoxicity and acute oral toxicity of a novel hybrid drug, artesunate-3-Chloro-4(4-chlorophenoxy) aniline (ATSA), in vitro and in vivo, respectively. A modified Desjardins method was used to screen for antiplasmodial activity using P. falciparum (3D(7) and W(2)) strains in vitro. The Peter’s 4-day suppressive tests (4DTs) was used to evaluate the in vivo antimalaria activity using P. berghei ANKA strain, lumefantrine resistant (LuR), and piperaquine resistant (PQR) P. berghei lines. In silico prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles was assayed using PreADMET online prediction tool. The reference drug in all experiments was artesunate (ATS). Statistical significance between ATSA’s activities in treated and control mice was evaluated by one-way analysis of variance (ANOVA). Results show that inhibitory concentrations-50 (IC(50)) of ATSA is 11.47 ± 1.3 (3D(7)) and 1.45 ± 0.26 (W(2)) against 4.66 ± 0.93 (3D(7)) and 0.60 ± 0.15 (W(2)) ng/ml of ATS with a selective index of 2180.91(3D(7)) and a therapeutic index (TI) of > 71). No mortalities were observed in acute oral toxicity assays and mean weight differences for test and controls were statistically insignificant (P > 0.05). The in vivo activity of ATSA was above 40% with effective dosage-50 (ED(50)) of 4.211, 2.601, and 3.875 mg/kg body weight against P. berghei ANKA, LuR, and PQR lines, respectively. The difference between treated and control mice was statistically significant (P < 0.05). ATSA has high intestinal absorption (HIA) > 95% and has medium human ether-a-go-go related gene (hERG) K(+) channel inhibition risks. Preclinical and clinical studies on ATSA are recommended to evaluate its value in developing novel drugs for future management of multi-drug resistant malaria parasites. Springer Berlin Heidelberg 2023-03-02 2023 /pmc/articles/PMC9977633/ /pubmed/36859621 http://dx.doi.org/10.1007/s00436-023-07801-x Text en © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. |
spellingShingle | Research Waithera, Milka Wambui Sifuna, Martin Wekesa Kariuki, Daniel Wainaina Kinyua, Johnson Kang’ethe Kimani, Francis Thuo Ng’ang’a, Joseph Kang’ethe Takei, Masahiro Antimalarial activity assay of artesunate-3-chloro-4(4-chlorophenoxy) aniline in vitro and in mice models |
title | Antimalarial activity assay of artesunate-3-chloro-4(4-chlorophenoxy) aniline in vitro and in mice models |
title_full | Antimalarial activity assay of artesunate-3-chloro-4(4-chlorophenoxy) aniline in vitro and in mice models |
title_fullStr | Antimalarial activity assay of artesunate-3-chloro-4(4-chlorophenoxy) aniline in vitro and in mice models |
title_full_unstemmed | Antimalarial activity assay of artesunate-3-chloro-4(4-chlorophenoxy) aniline in vitro and in mice models |
title_short | Antimalarial activity assay of artesunate-3-chloro-4(4-chlorophenoxy) aniline in vitro and in mice models |
title_sort | antimalarial activity assay of artesunate-3-chloro-4(4-chlorophenoxy) aniline in vitro and in mice models |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977633/ https://www.ncbi.nlm.nih.gov/pubmed/36859621 http://dx.doi.org/10.1007/s00436-023-07801-x |
work_keys_str_mv | AT waitheramilkawambui antimalarialactivityassayofartesunate3chloro44chlorophenoxyanilineinvitroandinmicemodels AT sifunamartinwekesa antimalarialactivityassayofartesunate3chloro44chlorophenoxyanilineinvitroandinmicemodels AT kariukidanielwainaina antimalarialactivityassayofartesunate3chloro44chlorophenoxyanilineinvitroandinmicemodels AT kinyuajohnsonkangethe antimalarialactivityassayofartesunate3chloro44chlorophenoxyanilineinvitroandinmicemodels AT kimanifrancisthuo antimalarialactivityassayofartesunate3chloro44chlorophenoxyanilineinvitroandinmicemodels AT ngangajosephkangethe antimalarialactivityassayofartesunate3chloro44chlorophenoxyanilineinvitroandinmicemodels AT takeimasahiro antimalarialactivityassayofartesunate3chloro44chlorophenoxyanilineinvitroandinmicemodels |