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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Main Authors: Rafael T. Aroso, Rita C. Guedes, Mariette M. Pereira
Format: Article
Language:English
Published: MDPI AG 2021-03-01
Series:Molecules
Subjects:
Online Access:https://www.mdpi.com/1420-3049/26/5/1326
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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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AT mariettempereira synthesisofcomputationallydesigned256benzimidazolederivativesviapdcatalyzedreactionsforpotentialiecoliidnagyrasebinhibition