{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:29:06Z","timestamp":1772411346367,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T00:00:00Z","timestamp":1614643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A pharmacophore model for inhibitors of Escherichia coli\u2019s 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\u2013Miyaura 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.<\/jats:p>","DOI":"10.3390\/molecules26051326","type":"journal-article","created":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T10:36:37Z","timestamp":1614681397000},"page":"1326","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential E. coli DNA Gyrase B Inhibition"],"prefix":"10.3390","volume":"26","author":[{"given":"Rafael T.","family":"Aroso","sequence":"first","affiliation":[{"name":"Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5790-9181","authenticated-orcid":false,"given":"Rita C.","family":"Guedes","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4958-7677","authenticated-orcid":false,"given":"Mariette M.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10257","DOI":"10.1021\/jm501100b","article-title":"Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals","volume":"57","author":"Vitaku","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_2","first-page":"1","article-title":"Naturally occurring and synthetic imidazoles: Their chemistry and their biological activities","volume":"13","author":"Luca","year":"2006","journal-title":"Curr. Med. 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