Proline-based hydroxamates targeting the zinc-dependent deacetylase LpxC: Synthesis, antibacterial properties, and docking studies. Issue 10 (15th May 2019)

• Record Type: Journal Article
• Authors: Kalinin, Dmitrii V.; Agoglitta, Oriana; Van de Vyver, Hélène; Melesina, Jelena; Wagner, Stefan; Riemann, Burkhard; Schäfers, Michael; Sippl, Wolfgang; Löffler, Bettina; Holl, Ralph
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 10(2019)
• Page Start: 1997
• Page End: 2018
• Publication Date: 2019-05-15
• Subjects: Proline derivatives -- Chiral pool synthesis -- Antibacterials -- LpxC inhibitors -- Structure-activity relationships -- Molecular docking studies -- MMP inhibitors; 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.2019.03.056
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The Zn 2+ -dependent deacetylase LpxC is an essential enzyme in Gram-negative bacteria, which has been validated as antibacterial drug target. Herein we report the chiral-pool synthesis of noveld - andl -proline-derived 3, 4-dihydroxypyrrolidine hydroxamates and compare their antibacterial and LpxC inhibitory activities with the ones of 4-monosubstituted and 3, 4-unsubstituted proline derivatives. With potent antibacterial activities against several Gram-negative pathogens, thel -proline-based tertiary amine41g (( S )- N -hydroxy-1-(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)pyrrolidine-2-carboxamide) was found to be the most active antibacterial compound within the investigated series, also showing some selectivity toward EcLpxC (Ki = 1.4 μM) over several human MMPs.