Synthesis and biological evaluation of triazolyl-substituted benzyloxyacetohydroxamic acids as LpxC inhibitors. Issue 13 (1st July 2020)

• Record Type: Journal Article
• Authors: Hoff, Katharina; Mielniczuk, Sebastian; Agoglitta, Oriana; Iorio, Maria Teresa; Caldara, Manlio; Bülbül, Emre F.; Melesina, Jelena; Sippl, Wolfgang; Holl, Ralph
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 13(2020)
• Publication Date: 2020-07-01
• Subjects: LpxC inhibitors -- Structure-activity relationships -- Azide-alkyne cycloadditions -- Triazole derivatives -- Hydroxamic acids -- Enantioselective synthesis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115529
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The bacterial deacetylase LpxC is a promising target for the development of antibiotics selectively combating Gram-negative bacteria. To improve the biological activity of the reported benzyloxyacetohydroxamic acid 9 (( S )- N -hydroxy-2-{2-hydroxy-1-[4-(phenylethynyl)phenyl]ethoxy}acetamide), its hydroxy group was replaced by a triazole ring. Therefore, in divergent syntheses, triazole derivatives exhibiting rigid and flexible lipophilic side chains, different configurations at their stereocenter, and various substitution patterns at the triazole ring were synthesized, tested for antibacterial and LpxC inhibitory activity, and structure-activity relationships were deduced based on docking and binding energy calculations.