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Design, Synthesis and Comprehensive Investigations of Pyrrolo[3,4-d]pyridazinone-Based 1,3,4-Oxadiazole as New Class of Selective COX-2 Inhibitors

The long-term use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in treatment of different chronic inflammatory disorders is strongly restricted by their serious gastrointestinal adverse effects. Therefore, there is still an urgent need to search for new, safe, and efficient anti-inflammatory age...

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Autores principales: Szczukowski, Łukasz, Krzyżak, Edward, Zborowska, Adrianna, Zając, Patrycja, Potyrak, Katarzyna, Peregrym, Krzysztof, Wiatrak, Benita, Marciniak, Aleksandra, Świątek, Piotr
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766220/
https://www.ncbi.nlm.nih.gov/pubmed/33348757
http://dx.doi.org/10.3390/ijms21249623
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author Szczukowski, Łukasz
Krzyżak, Edward
Zborowska, Adrianna
Zając, Patrycja
Potyrak, Katarzyna
Peregrym, Krzysztof
Wiatrak, Benita
Marciniak, Aleksandra
Świątek, Piotr
author_facet Szczukowski, Łukasz
Krzyżak, Edward
Zborowska, Adrianna
Zając, Patrycja
Potyrak, Katarzyna
Peregrym, Krzysztof
Wiatrak, Benita
Marciniak, Aleksandra
Świątek, Piotr
author_sort Szczukowski, Łukasz
collection PubMed
description The long-term use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in treatment of different chronic inflammatory disorders is strongly restricted by their serious gastrointestinal adverse effects. Therefore, there is still an urgent need to search for new, safe, and efficient anti-inflammatory agents. Previously, we have reported the Mannich base-type derivatives of pyrrolo[3,4-d]pyridazinone which strongly inhibit cyclooxygenase, have better affinity to COX-2 isoenzyme and exert promising anti-oxidant activity. These findings encouraged us to perform further optimization of that structure. Herein, we present the design, synthesis, molecular docking, spectroscopic, and biological studies of novel pyrrolo[3,4-d]pyridazinone derivatives bearing 4-aryl-1-(1-oxoethyl)piperazine pharmacophore 5a,b–6a,b. The new compounds were obtained via convenient, efficient, one-pot synthesis. According to in vitro evaluations, novel molecules exert no cytotoxicity and act as selective COX-2 inhibitors. These findings stay in good correlation with molecular modeling results, which additionally showed that investigated compounds take a position in the active site of COX-2 very similar to Meloxicam. Moreover, all derivatives reduce the increased level of reactive oxygen and nitrogen species and prevent DNA strand breaks caused by oxidative stress. Finally, performed spectroscopic and molecular docking studies demonstrated that new compound interactions with bovine serum albumin (BSA) are moderate, formation of complexes is in one-to-one ratio, and binding site II (subdomain IIIA) is favorable.
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spelling pubmed-77662202020-12-28 Design, Synthesis and Comprehensive Investigations of Pyrrolo[3,4-d]pyridazinone-Based 1,3,4-Oxadiazole as New Class of Selective COX-2 Inhibitors Szczukowski, Łukasz Krzyżak, Edward Zborowska, Adrianna Zając, Patrycja Potyrak, Katarzyna Peregrym, Krzysztof Wiatrak, Benita Marciniak, Aleksandra Świątek, Piotr Int J Mol Sci Article The long-term use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in treatment of different chronic inflammatory disorders is strongly restricted by their serious gastrointestinal adverse effects. Therefore, there is still an urgent need to search for new, safe, and efficient anti-inflammatory agents. Previously, we have reported the Mannich base-type derivatives of pyrrolo[3,4-d]pyridazinone which strongly inhibit cyclooxygenase, have better affinity to COX-2 isoenzyme and exert promising anti-oxidant activity. These findings encouraged us to perform further optimization of that structure. Herein, we present the design, synthesis, molecular docking, spectroscopic, and biological studies of novel pyrrolo[3,4-d]pyridazinone derivatives bearing 4-aryl-1-(1-oxoethyl)piperazine pharmacophore 5a,b–6a,b. The new compounds were obtained via convenient, efficient, one-pot synthesis. According to in vitro evaluations, novel molecules exert no cytotoxicity and act as selective COX-2 inhibitors. These findings stay in good correlation with molecular modeling results, which additionally showed that investigated compounds take a position in the active site of COX-2 very similar to Meloxicam. Moreover, all derivatives reduce the increased level of reactive oxygen and nitrogen species and prevent DNA strand breaks caused by oxidative stress. Finally, performed spectroscopic and molecular docking studies demonstrated that new compound interactions with bovine serum albumin (BSA) are moderate, formation of complexes is in one-to-one ratio, and binding site II (subdomain IIIA) is favorable. MDPI 2020-12-17 /pmc/articles/PMC7766220/ /pubmed/33348757 http://dx.doi.org/10.3390/ijms21249623 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Szczukowski, Łukasz
Krzyżak, Edward
Zborowska, Adrianna
Zając, Patrycja
Potyrak, Katarzyna
Peregrym, Krzysztof
Wiatrak, Benita
Marciniak, Aleksandra
Świątek, Piotr
Design, Synthesis and Comprehensive Investigations of Pyrrolo[3,4-d]pyridazinone-Based 1,3,4-Oxadiazole as New Class of Selective COX-2 Inhibitors
title Design, Synthesis and Comprehensive Investigations of Pyrrolo[3,4-d]pyridazinone-Based 1,3,4-Oxadiazole as New Class of Selective COX-2 Inhibitors
title_full Design, Synthesis and Comprehensive Investigations of Pyrrolo[3,4-d]pyridazinone-Based 1,3,4-Oxadiazole as New Class of Selective COX-2 Inhibitors
title_fullStr Design, Synthesis and Comprehensive Investigations of Pyrrolo[3,4-d]pyridazinone-Based 1,3,4-Oxadiazole as New Class of Selective COX-2 Inhibitors
title_full_unstemmed Design, Synthesis and Comprehensive Investigations of Pyrrolo[3,4-d]pyridazinone-Based 1,3,4-Oxadiazole as New Class of Selective COX-2 Inhibitors
title_short Design, Synthesis and Comprehensive Investigations of Pyrrolo[3,4-d]pyridazinone-Based 1,3,4-Oxadiazole as New Class of Selective COX-2 Inhibitors
title_sort design, synthesis and comprehensive investigations of pyrrolo[3,4-d]pyridazinone-based 1,3,4-oxadiazole as new class of selective cox-2 inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766220/
https://www.ncbi.nlm.nih.gov/pubmed/33348757
http://dx.doi.org/10.3390/ijms21249623
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