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Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation
A novel class of phthalimides functionalized with privileged scaffolds was designed, synthesized and evaluated as potential inhibitors of plasmepsin 2 (K(i): 0.99 ± 0.1 μM for 6u) and plasmepsin 4 (K(i): 3.3 ± 0.3 μM for 6t), enzymes found in the digestive vacuole of the plasmodium parasite and cons...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621027/ https://www.ncbi.nlm.nih.gov/pubmed/26502278 http://dx.doi.org/10.1371/journal.pone.0139347 |
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author | Singh, Anil K. Rathore, Sumit Tang, Yan Goldfarb, Nathan E. Dunn, Ben M. Rajendran, Vinoth Ghosh, Prahlad C. Singh, Neelu Latha, N. Singh, Brajendra K. Rawat, Manmeet Rathi, Brijesh |
author_facet | Singh, Anil K. Rathore, Sumit Tang, Yan Goldfarb, Nathan E. Dunn, Ben M. Rajendran, Vinoth Ghosh, Prahlad C. Singh, Neelu Latha, N. Singh, Brajendra K. Rawat, Manmeet Rathi, Brijesh |
author_sort | Singh, Anil K. |
collection | PubMed |
description | A novel class of phthalimides functionalized with privileged scaffolds was designed, synthesized and evaluated as potential inhibitors of plasmepsin 2 (K(i): 0.99 ± 0.1 μM for 6u) and plasmepsin 4 (K(i): 3.3 ± 0.3 μM for 6t), enzymes found in the digestive vacuole of the plasmodium parasite and considered as crucial drug targets. Three compounds were identified as potential candidates for further development. The listed compounds were also assayed for their antimalarial efficacy against chloroquine (CQ) sensitive strain (3D7) of Plasmodium falciparum. Assay of twenty seven hydroxyethylamine derivatives revealed four (5e, 6j, 6o and 6s) as strongly active, which were further evaluated against CQ resistant strain (7GB) of P. falciparum. Compound 5e possessing the piperidinopiperidine moiety exhibited promising antimalarial activity with an IC(50) of 1.16 ± 0.04 μM. Further, compounds 5e, 6j, 6o and 6s exhibited low cytotoxic effect on MCF-7 cell line. Compound 6s possessing C (2) symmetry was identified as the least cytotoxic with significant antimalarial activity (IC(50): 1.30 ± 0.03 μM). The combined presence of hydroxyethylamine and cyclic amines (piperazines and piperidines) was observed as crucial for the activity. The current studies suggest that hydroxyethylamine based molecules act as potent antimalarial agent and may be helpful in drug development. |
format | Online Article Text |
id | pubmed-4621027 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-46210272015-10-29 Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation Singh, Anil K. Rathore, Sumit Tang, Yan Goldfarb, Nathan E. Dunn, Ben M. Rajendran, Vinoth Ghosh, Prahlad C. Singh, Neelu Latha, N. Singh, Brajendra K. Rawat, Manmeet Rathi, Brijesh PLoS One Research Article A novel class of phthalimides functionalized with privileged scaffolds was designed, synthesized and evaluated as potential inhibitors of plasmepsin 2 (K(i): 0.99 ± 0.1 μM for 6u) and plasmepsin 4 (K(i): 3.3 ± 0.3 μM for 6t), enzymes found in the digestive vacuole of the plasmodium parasite and considered as crucial drug targets. Three compounds were identified as potential candidates for further development. The listed compounds were also assayed for their antimalarial efficacy against chloroquine (CQ) sensitive strain (3D7) of Plasmodium falciparum. Assay of twenty seven hydroxyethylamine derivatives revealed four (5e, 6j, 6o and 6s) as strongly active, which were further evaluated against CQ resistant strain (7GB) of P. falciparum. Compound 5e possessing the piperidinopiperidine moiety exhibited promising antimalarial activity with an IC(50) of 1.16 ± 0.04 μM. Further, compounds 5e, 6j, 6o and 6s exhibited low cytotoxic effect on MCF-7 cell line. Compound 6s possessing C (2) symmetry was identified as the least cytotoxic with significant antimalarial activity (IC(50): 1.30 ± 0.03 μM). The combined presence of hydroxyethylamine and cyclic amines (piperazines and piperidines) was observed as crucial for the activity. The current studies suggest that hydroxyethylamine based molecules act as potent antimalarial agent and may be helpful in drug development. Public Library of Science 2015-10-26 /pmc/articles/PMC4621027/ /pubmed/26502278 http://dx.doi.org/10.1371/journal.pone.0139347 Text en © 2015 Singh et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Singh, Anil K. Rathore, Sumit Tang, Yan Goldfarb, Nathan E. Dunn, Ben M. Rajendran, Vinoth Ghosh, Prahlad C. Singh, Neelu Latha, N. Singh, Brajendra K. Rawat, Manmeet Rathi, Brijesh Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation |
title | Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation |
title_full | Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation |
title_fullStr | Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation |
title_full_unstemmed | Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation |
title_short | Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation |
title_sort | hydroxyethylamine based phthalimides as new class of plasmepsin hits: design, synthesis and antimalarial evaluation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621027/ https://www.ncbi.nlm.nih.gov/pubmed/26502278 http://dx.doi.org/10.1371/journal.pone.0139347 |
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