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https://hdl.handle.net/10316/105270
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: | PTDC/QUI-OUT/27996/2017 UIDB/00313/2020 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. | URI: | https://hdl.handle.net/10316/105270 | ISSN: | 1420-3049 | DOI: | 10.3390/molecules26051326 | Rights: | openAccess |
Appears in Collections: | I&D CQC - Artigos em Revistas Internacionais |
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molecules-26-01326-v2.pdf | 2.44 MB | Adobe PDF | View/Open |
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