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Title: Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential E. coli DNA Gyrase B Inhibition
Authors: Aroso, Rafael T. 
Guedes, Rita C. 
Pereira, Mariette M. 
Keywords: computational chemistry; E. coli DNA Gyrase B; benzimidazole; cross-coupling; organic catalysis
Issue Date: 2-Mar-2021
Publisher: MDPI
Project: UIDB/ 00313/2020 
PhD grant PD/BD/143123/2019 
Serial title, monograph or event: Molecules
Volume: 26
Issue: 5
Abstract: A pharmacophore model for inhibitors of Escherichia coli'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)-1H-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 N-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-1H-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.
ISSN: 1420-3049
DOI: 10.3390/molecules26051326
Rights: openAccess
Appears in Collections:I&D CQC - Artigos em Revistas Internacionais

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