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Synthesis and in vi...
Synthesis and in vitro biological evaluation of quinolinyl pyrimidines targeting type II NADH-dehydrogenase (NDH-2)
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- Lu, Lu, 1984- (author)
- Uppsala universitet,Strukturbiologi,Sherry Mowbray
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- Åkerbladh, Linda (author)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Ahmad, Shabbir (author)
- Uppsala universitet,Strukturbiologi
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- Konda, Vivek (author)
- Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling
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- Cao, Sha (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Vocat, Anthony (author)
- Global Health Institute, École Polytechnique Fédérale de Lausanne, EPFL SV / GHI / UPCOL, Station nº19, CH-1015 Lausanne, Switzerland
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- Maes, Louis (author)
- University of Antwerp, Laboratory of Microbiology, Parasitology and Hygiene(LMPH)Universiteitsplein 1, B-2610 Antwerp, Belgium
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- Cole, Stewart T. (author)
- Global Health Institute, École Polytechnique Fédérale de Lausanne, EPFL SV / GHI / UPCOL, Station nº19, CH-1015 Lausanne, Switzerland
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- Hughes, Diarmaid, 1956- (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Larhed, Mats (author)
- Uppsala universitet,Preparativ läkemedelskemi,Science for Life Laboratory, SciLifeLab
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- Brandt, Peter (author)
- Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling
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- Karlen, Anders (author)
- Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling
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- Mowbray, Sherry L, 1954- (author)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- 2022-02-21
- 2022
- English.
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In: ACS - Infectious Diseases. - : American Chemical Society (ACS). - 2373-8227. ; 8:3, s. 482-498
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Abstract
Subject headings
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- Type II NADH dehydrogenase (NDH-2) is an essential component of electron transfer in many microbial pathogens but has remained largely unexplored as a potential drug target. Previously, quinolinyl pyrimidines were shown to inhibit Mycobacterium tuberculosis NDH-2, as well as the growth of the bacteria [Shirude, P. S.; ACS Med. Chem. Lett. 2012, 3, 736−740]. Here, we synthesized a number of novel quinolinyl pyrimidines and investigated their properties. In terms of inhibition of the NDH-2 enzymes from M. tuberculosis and Mycobacterium smegmatis, the best compounds were of similar potency to previously reported inhibitors of the same class (half-maximal inhibitory concentration (IC50) values in the low-μM range). However, a number of the compounds had much better activity against Gram-negative pathogens, with minimum inhibitory concentrations (MICs) as low as 2 μg/mL. Multivariate analyses (partial least-squares (PLS) and principle component analysis (PCA)) showed that overall ligand charge was one of the most important factors in determining antibacterial activity, with patterns that varied depending on the particular bacterial species. In some cases (e.g., mycobacteria), there was a clear correlation between the IC50 values and the observed MICs, while in other instances, no such correlation was evident. When tested against a panel of protozoan parasites, the compounds failed to show activity that was not linked to cytotoxicity. Further, a strong correlation between hydrophobicity (estimated as clog P) and cytotoxicity was revealed; more hydrophobic analogues were more cytotoxic. By contrast, antibacterial MIC values and cytotoxicity were not well correlated, suggesting that the quinolinyl pyrimidines can be optimized further as antimicrobial agents.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Keyword
- antimicrobials
- NDH-2
- quinolinyl pyrimidines
- tuberculosis
- ESKAPE pathogens
- Biologi med inriktning mot strukturbiologi
- Biology with specialization in Structural Biology
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Lu, Lu, 1984-
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Åkerbladh, Linda
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Ahmad, Shabbir
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Konda, Vivek
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Cao, Sha
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Vocat, Anthony
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show more...
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Maes, Louis
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Cole, Stewart T.
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Hughes, Diarmaid ...
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Larhed, Mats
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Brandt, Peter
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Karlen, Anders
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Mowbray, Sherry ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Medical Biotechn ...
- Articles in the publication
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ACS - Infectious ...
- By the university
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Uppsala University