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Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies
Leishmaniasis is a neglected tropical disease, and there is an emerging need for the development of effective drugs to treat it. To identify novel compounds with antileishmanial properties, a novel series of functionalized spiro[indoline-3,2′-pyrrolidin]-2-one/spiro[indoline-3,3′-pyrrolizin]-2-one 2...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10302753/ https://www.ncbi.nlm.nih.gov/pubmed/37375374 http://dx.doi.org/10.3390/molecules28124817 |
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author | Sahu, Nawal Kishore Sharma, Ritu Suhas, Kshirsagar Prasad Joshi, Jyoti Prakash, Kunal Sharma, Richa Pratap, Ramendra Hu, Xiwen Kaur, Sukhbir Jain, Mukesh Coluccini, Carmine Coghi, Paolo Chaudhary, Sandeep |
author_facet | Sahu, Nawal Kishore Sharma, Ritu Suhas, Kshirsagar Prasad Joshi, Jyoti Prakash, Kunal Sharma, Richa Pratap, Ramendra Hu, Xiwen Kaur, Sukhbir Jain, Mukesh Coluccini, Carmine Coghi, Paolo Chaudhary, Sandeep |
author_sort | Sahu, Nawal Kishore |
collection | PubMed |
description | Leishmaniasis is a neglected tropical disease, and there is an emerging need for the development of effective drugs to treat it. To identify novel compounds with antileishmanial properties, a novel series of functionalized spiro[indoline-3,2′-pyrrolidin]-2-one/spiro[indoline-3,3′-pyrrolizin]-2-one 23a–f, 24a–f, and 25a–g were prepared from natural-product-inspired pharmaceutically privileged bioactive sub-structures, i.e., isatins 20a–h, various substituted chalcones 21a–f, and 22a–c amino acids, via 1,3-dipolar cycloaddition reactions in MeOH at 80 °C using a microwave-assisted approach. Compared to traditional methods, microwave-assisted synthesis produces higher yields and better quality, and it takes less time. We report here the in vitro antileishmanial activity against Leishmania donovani and SAR studies. The analogues 24a, 24e, 24f, and 25d were found to be the most active compounds of the series and showed IC(50) values of 2.43 µM, 0.96 µM, 1.62 µM, and 3.55 µM, respectively, compared to the standard reference drug Amphotericin B (IC(50) = 0.060 µM). All compounds were assessed for Leishmania DNA topoisomerase type IB inhibition activity using the standard drug Camptothecin, and 24a, 24e, 24f, and 25d showed potential results. In order to further validate the experimental results and gain a deeper understanding of the binding manner of such compounds, molecular docking studies were also performed. The stereochemistry of the novel functionalized spirooxindole derivatives was confirmed by single-crystal X-ray crystallography studies. |
format | Online Article Text |
id | pubmed-10302753 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-103027532023-06-29 Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies Sahu, Nawal Kishore Sharma, Ritu Suhas, Kshirsagar Prasad Joshi, Jyoti Prakash, Kunal Sharma, Richa Pratap, Ramendra Hu, Xiwen Kaur, Sukhbir Jain, Mukesh Coluccini, Carmine Coghi, Paolo Chaudhary, Sandeep Molecules Article Leishmaniasis is a neglected tropical disease, and there is an emerging need for the development of effective drugs to treat it. To identify novel compounds with antileishmanial properties, a novel series of functionalized spiro[indoline-3,2′-pyrrolidin]-2-one/spiro[indoline-3,3′-pyrrolizin]-2-one 23a–f, 24a–f, and 25a–g were prepared from natural-product-inspired pharmaceutically privileged bioactive sub-structures, i.e., isatins 20a–h, various substituted chalcones 21a–f, and 22a–c amino acids, via 1,3-dipolar cycloaddition reactions in MeOH at 80 °C using a microwave-assisted approach. Compared to traditional methods, microwave-assisted synthesis produces higher yields and better quality, and it takes less time. We report here the in vitro antileishmanial activity against Leishmania donovani and SAR studies. The analogues 24a, 24e, 24f, and 25d were found to be the most active compounds of the series and showed IC(50) values of 2.43 µM, 0.96 µM, 1.62 µM, and 3.55 µM, respectively, compared to the standard reference drug Amphotericin B (IC(50) = 0.060 µM). All compounds were assessed for Leishmania DNA topoisomerase type IB inhibition activity using the standard drug Camptothecin, and 24a, 24e, 24f, and 25d showed potential results. In order to further validate the experimental results and gain a deeper understanding of the binding manner of such compounds, molecular docking studies were also performed. The stereochemistry of the novel functionalized spirooxindole derivatives was confirmed by single-crystal X-ray crystallography studies. MDPI 2023-06-16 /pmc/articles/PMC10302753/ /pubmed/37375374 http://dx.doi.org/10.3390/molecules28124817 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Sahu, Nawal Kishore Sharma, Ritu Suhas, Kshirsagar Prasad Joshi, Jyoti Prakash, Kunal Sharma, Richa Pratap, Ramendra Hu, Xiwen Kaur, Sukhbir Jain, Mukesh Coluccini, Carmine Coghi, Paolo Chaudhary, Sandeep Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies |
title | Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies |
title_full | Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies |
title_fullStr | Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies |
title_full_unstemmed | Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies |
title_short | Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies |
title_sort | natural-product-inspired microwave-assisted synthesis of novel spirooxindoles as antileishmanial agents: synthesis, stereochemical assignment, bioevaluation, sar, and molecular docking studies |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10302753/ https://www.ncbi.nlm.nih.gov/pubmed/37375374 http://dx.doi.org/10.3390/molecules28124817 |
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