A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling Using <i>Leishmania donovani</i>
Metals have been used in medicine since ancient times for the treatment of different ailments with various elements such as iron, gold and arsenic. Metal complexes have also been reported to show antibiotic and antiparasitic activity. In this context, we tested the antiparasitic potential of 10 orga...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
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MDPI AG
2022-11-01
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| Series: | Pathogens |
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| author | Obaid Hayat Nazif Ullah Muhammad Sirajuddin Miriam A. Giardini Jennifer V. Nguyen Karol R. Francisco Lawrence J. Liu Yujie Uli Sun Svetlana Maurya Dominic McGrosso David J. Gonzalez Conor R. Caffrey Anjan Debnath Jair L. Siqueira-Neto |
| author_facet | Obaid Hayat Nazif Ullah Muhammad Sirajuddin Miriam A. Giardini Jennifer V. Nguyen Karol R. Francisco Lawrence J. Liu Yujie Uli Sun Svetlana Maurya Dominic McGrosso David J. Gonzalez Conor R. Caffrey Anjan Debnath Jair L. Siqueira-Neto |
| author_sort | Obaid Hayat |
| collection | DOAJ |
| description | Metals have been used in medicine since ancient times for the treatment of different ailments with various elements such as iron, gold and arsenic. Metal complexes have also been reported to show antibiotic and antiparasitic activity. In this context, we tested the antiparasitic potential of 10 organotin (IV) derivatives from 4-(4-methoxyphenylamino)-4 oxobutanoic acid (MS26) against seven eukaryotic pathogens of medical importance: <i>Leishmania donovani</i>, <i>Trypanosoma cruzi</i>, <i>Trypanosoma brucei</i>, <i>Entamoeba histolytica</i>, <i>Giardia lamblia</i>, <i>Naegleria fowleri</i> and <i>Schistosoma mansoni</i>. Among the compounds with and without antiparasitic activity, compound MS26Et3 stood out with a 50% effective concentration (EC<sub>50</sub>) of 0.21 and 0.19 µM against promastigotes and intracellular amastigotes of <i>L. donovani,</i> respectively, 0.24 µM against intracellular amastigotes of <i>T. cruzi</i>, 0.09 µM against <i>T. brucei,</i> 1.4 µM against <i>N. fowleri</i> and impaired adult <i>S. mansoni</i> viability at 1.25 µM. In terms of host/pathogen selectivity, MS26Et3 demonstrated relatively mild cytotoxicity toward host cells with a 50% viability concentration of 4.87 µM against B10R cells (mouse monocyte cell line), 2.79 µM against C2C12 cells (mouse myoblast cell line) and 1.24 µM against HEK923 cells (human embryonic kidney cell line). The selectivity index supports this molecule as a therapeutic starting point for a broad spectrum antiparasitic alternative. Proteomic analysis of host cells infected with <i>L. donovani</i> after exposure to MS26Et3 showed a reduced expression of Rab7, which may affect the fusion of the endosome with the lysosome, and, consequently, impairing the differentiation of <i>L. donovani</i> to the amastigote form. Future studies to investigate the molecular target(s) and mechanism of action of MS26Et3 will support its chemical optimization. |
| first_indexed | 2024-03-09T15:59:10Z |
| format | Article |
| id | doaj.art-3a11b00416ca4f92923dce5b3db08fed |
| institution | Directory Open Access Journal |
| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-03-09T15:59:10Z |
| publishDate | 2022-11-01 |
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| series | Pathogens |
| spelling | doaj.art-3a11b00416ca4f92923dce5b3db08fed2023-11-24T17:12:28ZengMDPI AGPathogens2076-08172022-11-011112142410.3390/pathogens11121424A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling Using <i>Leishmania donovani</i>Obaid Hayat0Nazif Ullah1Muhammad Sirajuddin2Miriam A. Giardini3Jennifer V. Nguyen4Karol R. Francisco5Lawrence J. Liu6Yujie Uli Sun7Svetlana Maurya8Dominic McGrosso9David J. Gonzalez10Conor R. Caffrey11Anjan Debnath12Jair L. Siqueira-Neto13Department of Biotechnology, Faculty of Chemical and Life Sciences, Abdul Wali Khan University, Mardan 23200, PakistanDepartment of Biotechnology, Faculty of Chemical and Life Sciences, Abdul Wali Khan University, Mardan 23200, PakistanDepartment of Chemistry, University of Science and Technology, Bannu 28100, PakistanCenter for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USACenter for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USACenter for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USACenter for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USACenter for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USADepartment of Pharmacology, University of California San Diego, La Jolla, CA 92093, USADepartment of Pharmacology, University of California San Diego, La Jolla, CA 92093, USACenter for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USACenter for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USACenter for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USACenter for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USAMetals have been used in medicine since ancient times for the treatment of different ailments with various elements such as iron, gold and arsenic. Metal complexes have also been reported to show antibiotic and antiparasitic activity. In this context, we tested the antiparasitic potential of 10 organotin (IV) derivatives from 4-(4-methoxyphenylamino)-4 oxobutanoic acid (MS26) against seven eukaryotic pathogens of medical importance: <i>Leishmania donovani</i>, <i>Trypanosoma cruzi</i>, <i>Trypanosoma brucei</i>, <i>Entamoeba histolytica</i>, <i>Giardia lamblia</i>, <i>Naegleria fowleri</i> and <i>Schistosoma mansoni</i>. Among the compounds with and without antiparasitic activity, compound MS26Et3 stood out with a 50% effective concentration (EC<sub>50</sub>) of 0.21 and 0.19 µM against promastigotes and intracellular amastigotes of <i>L. donovani,</i> respectively, 0.24 µM against intracellular amastigotes of <i>T. cruzi</i>, 0.09 µM against <i>T. brucei,</i> 1.4 µM against <i>N. fowleri</i> and impaired adult <i>S. mansoni</i> viability at 1.25 µM. In terms of host/pathogen selectivity, MS26Et3 demonstrated relatively mild cytotoxicity toward host cells with a 50% viability concentration of 4.87 µM against B10R cells (mouse monocyte cell line), 2.79 µM against C2C12 cells (mouse myoblast cell line) and 1.24 µM against HEK923 cells (human embryonic kidney cell line). The selectivity index supports this molecule as a therapeutic starting point for a broad spectrum antiparasitic alternative. Proteomic analysis of host cells infected with <i>L. donovani</i> after exposure to MS26Et3 showed a reduced expression of Rab7, which may affect the fusion of the endosome with the lysosome, and, consequently, impairing the differentiation of <i>L. donovani</i> to the amastigote form. Future studies to investigate the molecular target(s) and mechanism of action of MS26Et3 will support its chemical optimization.https://www.mdpi.com/2076-0817/11/12/1424organotin (IV) compoundsantiparasitic activityneglected tropical diseasesdrug discovery |
| spellingShingle | Obaid Hayat Nazif Ullah Muhammad Sirajuddin Miriam A. Giardini Jennifer V. Nguyen Karol R. Francisco Lawrence J. Liu Yujie Uli Sun Svetlana Maurya Dominic McGrosso David J. Gonzalez Conor R. Caffrey Anjan Debnath Jair L. Siqueira-Neto A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling Using <i>Leishmania donovani</i> Pathogens organotin (IV) compounds antiparasitic activity neglected tropical diseases drug discovery |
| title | A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling Using <i>Leishmania donovani</i> |
| title_full | A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling Using <i>Leishmania donovani</i> |
| title_fullStr | A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling Using <i>Leishmania donovani</i> |
| title_full_unstemmed | A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling Using <i>Leishmania donovani</i> |
| title_short | A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling Using <i>Leishmania donovani</i> |
| title_sort | broad spectrum antiparasitic activity of organotin iv derivatives and its untargeted proteomic profiling using i leishmania donovani i |
| topic | organotin (IV) compounds antiparasitic activity neglected tropical diseases drug discovery |
| url | https://www.mdpi.com/2076-0817/11/12/1424 |
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