Search: WFRF:(Jones T Alwyn) >
Design, synthesis, ...
Design, synthesis, and in vitro biological evaluation of meta-sulfonamidobenzamide-based antibacterial LpxH inhibitors
-
- Benediktsdottir, Andrea (author)
- Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling
-
- Sooriyaarachchi, Sanjeewani (author)
- Uppsala universitet,Strukturbiologi
-
- Cao, Sha (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
-
show more...
-
- Ottosson, Nina E. (author)
- BKV, Linköping University; Science for Life Laboratory
-
- Lindström, Stefan (author)
- Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling
-
Lundgren, Bo (author)
-
Kloditz, Katharina (author)
-
- Lola, Daina (author)
- Latvian Institute of Organic Synthesis, Riga, Latvia
-
- Bobileva, Olga (author)
- Latvian Institute of Organic Synthesis, Riga, Latvia
-
- Loza, Einars (author)
- Latvian Institute of Organic Synthesis, Riga, Latvia
-
- Hughes, Diarmaid, 1956- (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
-
- Jones, T. Alwyn, 1947- (author)
- Uppsala universitet,Strukturbiologi
-
- Mowbray, Sherry L., 1954- (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Strukturbiologi
-
- Zamaratski, Edouard (author)
- Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling
-
- Sandström, Anja, 1973- (author)
- Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling
-
- Karlén, Anders (author)
- Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling
-
show less...
-
(creator_code:org_t)
- Elsevier, 2024
- 2024
- English.
-
In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 278
- Related links:
-
https://doi.org/10.1...
-
show more...
-
https://uu.diva-port... (primary) (Raw object)
-
https://urn.kb.se/re...
-
https://doi.org/10.1...
-
show less...
Abstract
Subject headings
Close
- New antibacterial compounds are urgently needed, especially for infections caused by the top-priority Gram-negative bacteria that are increasingly difficult to treat. Lipid A is a key component of the Gram-negative outer membrane and the LpxH enzyme plays an important role in its biosynthesis, making it a promising antibacterial target. Inspired by previously reported ortho-N-methyl-sulfonamidobenzamide-based LpxH inhibitors, novel benzamide substitutions were explored in this work to assess their in vitro activity. Our findings reveal that maintaining wild-type antibacterial activity necessitates removal of the N-methyl group when shifting the ortho-N-methyl-sulfonamide to the meta-position. This discovery led to the synthesis of meta-sulfonamidobenzamide analogs with potent antibacterial activity and enzyme inhibition. Moreover, we demonstrate that modifying the benzamide scaffold can alter blocking of the cardiac voltage-gated potassium ion channel hERG. Furthermore, two LpxH-bound X-ray structures show how the enzyme-ligand interactions of the meta-sulfonamidobenzamide analogs differ from those of the previously reported ortho analogs. Overall, our study has identified meta-sulfonamidobenzamide derivatives as promising LpxH inhibitors with the potential for optimization in future antibacterial hit-to-lead programs.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- LpxH inhibitors
- Lipopolysaccharide synthesis
- hERG ion channel affinity
- Antimicrobial drug discovery
- Gram-negative bacteria
- Meta-sulfonamidobenzamide
- N-demethylation
- Lipid A
- Medicinal Chemistry
- Läkemedelskemi
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
To the university's database
- By the author/editor
-
Benediktsdottir, ...
-
Sooriyaarachchi, ...
-
Cao, Sha
-
Ottosson, Nina E ...
-
Lindström, Stefa ...
-
Lundgren, Bo
-
show more...
-
Kloditz, Kathari ...
-
Lola, Daina
-
Bobileva, Olga
-
Loza, Einars
-
Hughes, Diarmaid ...
-
Jones, T. Alwyn, ...
-
Mowbray, Sherry ...
-
Zamaratski, Edou ...
-
Sandström, Anja, ...
-
Karlén, Anders
-
show less...
- About the subject
-
- MEDICAL AND HEALTH SCIENCES
-
MEDICAL AND HEAL ...
-
and Basic Medicine
-
and Medicinal Chemis ...
- Articles in the publication
-
European Journal ...
- By the university
-
Uppsala University