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Michael Adduct of Sulfonamide Chalcone Targets Folate Metabolism in Brugia Malayi Parasite

A series of Michael adducts of malononitrile and sulfonamide chalcones were synthesized, characterized, and evaluated for their antifilarial activity. Out of 14 compounds, N-(4-(4,4-dicyano-3-p-tolylbutanoyl)phenyl)benzenesulfonamide showed favorable drug-likeness properties with marked antifilarial...

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Autores principales: Bhoj, Priyanka S., Bahekar, Sandeep P., Chowdhary, Shambhavi, Togre, Namdev S., Amdare, Nitin P., Jena, Lingaraj, Goswami, Kalyan, Chandak, Hemant
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10045823/
https://www.ncbi.nlm.nih.gov/pubmed/36979702
http://dx.doi.org/10.3390/biomedicines11030723
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author Bhoj, Priyanka S.
Bahekar, Sandeep P.
Chowdhary, Shambhavi
Togre, Namdev S.
Amdare, Nitin P.
Jena, Lingaraj
Goswami, Kalyan
Chandak, Hemant
author_facet Bhoj, Priyanka S.
Bahekar, Sandeep P.
Chowdhary, Shambhavi
Togre, Namdev S.
Amdare, Nitin P.
Jena, Lingaraj
Goswami, Kalyan
Chandak, Hemant
author_sort Bhoj, Priyanka S.
collection PubMed
description A series of Michael adducts of malononitrile and sulfonamide chalcones were synthesized, characterized, and evaluated for their antifilarial activity. Out of 14 compounds, N-(4-(4,4-dicyano-3-p-tolylbutanoyl)phenyl)benzenesulfonamide showed favorable drug-likeness properties with marked antifilarial effects at micro-molar dosages. Apoptosis in Brugia malayi microfilariae was confirmed by EB/AO staining, MTT assay, and cytoplasmic cytochrome c ELISA. Since chalcone and folate synthesis pathways share the same substrate, we hypothesize a structural analogy-based inhibition of folate metabolism by this compound. Molecular docking against a pre-validated BmDHFR protein showed more favorable thermodynamic parameters than a positive control, epicatechin-3-gallate. The compound significantly suppressed the DHFR activity in a parasite extract in vitro. Our hypothesis is also supported by a significant reversal of DHFR inhibition by folate addition, which indicated a plausible mechanism of competitive inhibition. These results demonstrate that targeting filarial folate metabolism through DHFR with consequent apoptosis induction might be rewarding for therapeutic intervention. This study reveals a novel rationale of the structural analogy-based competitive inhibition of DHFR by Michael adducts of sulfonamide chalcones.
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spelling pubmed-100458232023-03-29 Michael Adduct of Sulfonamide Chalcone Targets Folate Metabolism in Brugia Malayi Parasite Bhoj, Priyanka S. Bahekar, Sandeep P. Chowdhary, Shambhavi Togre, Namdev S. Amdare, Nitin P. Jena, Lingaraj Goswami, Kalyan Chandak, Hemant Biomedicines Article A series of Michael adducts of malononitrile and sulfonamide chalcones were synthesized, characterized, and evaluated for their antifilarial activity. Out of 14 compounds, N-(4-(4,4-dicyano-3-p-tolylbutanoyl)phenyl)benzenesulfonamide showed favorable drug-likeness properties with marked antifilarial effects at micro-molar dosages. Apoptosis in Brugia malayi microfilariae was confirmed by EB/AO staining, MTT assay, and cytoplasmic cytochrome c ELISA. Since chalcone and folate synthesis pathways share the same substrate, we hypothesize a structural analogy-based inhibition of folate metabolism by this compound. Molecular docking against a pre-validated BmDHFR protein showed more favorable thermodynamic parameters than a positive control, epicatechin-3-gallate. The compound significantly suppressed the DHFR activity in a parasite extract in vitro. Our hypothesis is also supported by a significant reversal of DHFR inhibition by folate addition, which indicated a plausible mechanism of competitive inhibition. These results demonstrate that targeting filarial folate metabolism through DHFR with consequent apoptosis induction might be rewarding for therapeutic intervention. This study reveals a novel rationale of the structural analogy-based competitive inhibition of DHFR by Michael adducts of sulfonamide chalcones. MDPI 2023-02-27 /pmc/articles/PMC10045823/ /pubmed/36979702 http://dx.doi.org/10.3390/biomedicines11030723 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
Bhoj, Priyanka S.
Bahekar, Sandeep P.
Chowdhary, Shambhavi
Togre, Namdev S.
Amdare, Nitin P.
Jena, Lingaraj
Goswami, Kalyan
Chandak, Hemant
Michael Adduct of Sulfonamide Chalcone Targets Folate Metabolism in Brugia Malayi Parasite
title Michael Adduct of Sulfonamide Chalcone Targets Folate Metabolism in Brugia Malayi Parasite
title_full Michael Adduct of Sulfonamide Chalcone Targets Folate Metabolism in Brugia Malayi Parasite
title_fullStr Michael Adduct of Sulfonamide Chalcone Targets Folate Metabolism in Brugia Malayi Parasite
title_full_unstemmed Michael Adduct of Sulfonamide Chalcone Targets Folate Metabolism in Brugia Malayi Parasite
title_short Michael Adduct of Sulfonamide Chalcone Targets Folate Metabolism in Brugia Malayi Parasite
title_sort michael adduct of sulfonamide chalcone targets folate metabolism in brugia malayi parasite
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10045823/
https://www.ncbi.nlm.nih.gov/pubmed/36979702
http://dx.doi.org/10.3390/biomedicines11030723
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