Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential <i>E. coli</i> DNA Gyrase B Inhibition
A pharmacophore model for inhibitors of <i>Escherichia coli</i>’s DNA Gyrase B was developed, using computer-aided drug design. Subsequently, docking studies showed that 2,5(6)-substituted benzimidazole derivatives are promising molecules, as they possess key hydrogen bond donor/acceptor...
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MDPI AG
2021-03-01
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author | Rafael T. Aroso Rita C. Guedes Mariette M. Pereira |
author_facet | Rafael T. Aroso Rita C. Guedes Mariette M. Pereira |
author_sort | Rafael T. Aroso |
collection | DOAJ |
description | A pharmacophore model for inhibitors of <i>Escherichia coli</i>’s DNA Gyrase B was developed, using computer-aided drug design. Subsequently, docking studies showed that 2,5(6)-substituted benzimidazole derivatives are promising molecules, as they possess key hydrogen bond donor/acceptor groups for an efficient interaction with this bacterial target. Furthermore, 5(6)-bromo-2-(2-nitrophenyl)-1<i>H</i>-benzimidazole, selected as a core molecule, was prepared on a multi-gram scale through condensation of 4-bromo-1,2-diaminobenzene with 2-nitrobenzaldehyde using a sustainable approach. The challenging functionalization of the 5(6)-position was carried out via palladium-catalyzed Suzuki–Miyaura and Buchwald-Hartwig amination cross-coupling reactions between <i>N</i>-protected-5-bromo-2-nitrophenyl-benzimidazole and aryl boronic acids or sulfonylanilines, with yields up to 81%. The final designed molecules (2-(aminophen-2-yl)-5(6)-substituted-1<i>H</i>-benzimidazoles), which encompass the appropriate functional groups in the 5(6)-position according to the pharmacophore model, were obtained in yields up to 91% after acid-mediated N-boc deprotection followed by Pd-catalyzed hydrogenation. These groups are predicted to favor interactions with DNA gyrase B residues Asn46, Asp73, and Asp173, aiming to promote an inhibitory effect. |
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spelling | doaj.art-afb21e5e16e24137af1053ab1477df232023-12-03T12:10:45ZengMDPI AGMolecules1420-30492021-03-01265132610.3390/molecules26051326Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential <i>E. coli</i> DNA Gyrase B InhibitionRafael T. Aroso0Rita C. Guedes1Mariette M. Pereira2Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra, PortugalFaculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, PortugalCoimbra Chemistry Centre, Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra, PortugalA pharmacophore model for inhibitors of <i>Escherichia coli</i>’s DNA Gyrase B was developed, using computer-aided drug design. Subsequently, docking studies showed that 2,5(6)-substituted benzimidazole derivatives are promising molecules, as they possess key hydrogen bond donor/acceptor groups for an efficient interaction with this bacterial target. Furthermore, 5(6)-bromo-2-(2-nitrophenyl)-1<i>H</i>-benzimidazole, selected as a core molecule, was prepared on a multi-gram scale through condensation of 4-bromo-1,2-diaminobenzene with 2-nitrobenzaldehyde using a sustainable approach. The challenging functionalization of the 5(6)-position was carried out via palladium-catalyzed Suzuki–Miyaura and Buchwald-Hartwig amination cross-coupling reactions between <i>N</i>-protected-5-bromo-2-nitrophenyl-benzimidazole and aryl boronic acids or sulfonylanilines, with yields up to 81%. The final designed molecules (2-(aminophen-2-yl)-5(6)-substituted-1<i>H</i>-benzimidazoles), which encompass the appropriate functional groups in the 5(6)-position according to the pharmacophore model, were obtained in yields up to 91% after acid-mediated N-boc deprotection followed by Pd-catalyzed hydrogenation. These groups are predicted to favor interactions with DNA gyrase B residues Asn46, Asp73, and Asp173, aiming to promote an inhibitory effect.https://www.mdpi.com/1420-3049/26/5/1326computational chemistry<i>E. coli</i> DNA Gyrase Bbenzimidazolecross-couplingorganic catalysis |
spellingShingle | Rafael T. Aroso Rita C. Guedes Mariette M. Pereira Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential <i>E. coli</i> DNA Gyrase B Inhibition Molecules computational chemistry <i>E. coli</i> DNA Gyrase B benzimidazole cross-coupling organic catalysis |
title | Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential <i>E. coli</i> DNA Gyrase B Inhibition |
title_full | Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential <i>E. coli</i> DNA Gyrase B Inhibition |
title_fullStr | Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential <i>E. coli</i> DNA Gyrase B Inhibition |
title_full_unstemmed | Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential <i>E. coli</i> DNA Gyrase B Inhibition |
title_short | Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential <i>E. coli</i> DNA Gyrase B Inhibition |
title_sort | synthesis of computationally designed 2 5 6 benzimidazole derivatives via pd catalyzed reactions for potential i e coli i dna gyrase b inhibition |
topic | computational chemistry <i>E. coli</i> DNA Gyrase B benzimidazole cross-coupling organic catalysis |
url | https://www.mdpi.com/1420-3049/26/5/1326 |
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