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Keywords = diaminopimelate desuccinylase

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16 pages, 5796 KiB  
Article
Synthesis of Pyrazole-Based Inhibitors of the Bacterial Enzyme N-Succinyl-l,l-2,6-Diaminopimelic Acid Desuccinylase (DapE) as Potential Antibiotics
by Thomas DiPuma, Emma H. Kelley, Teerana Thabthimthong, Alayna Bland, Katherine Konczak, Katherine J. Torma, Thahani S. Habeeb Mohammad, Kenneth W. Olsen and Daniel P. Becker
Int. J. Mol. Sci. 2025, 26(1), 22; https://doi.org/10.3390/ijms26010022 - 24 Dec 2024
Viewed by 1233
Abstract
Based on the inhibitory potencies from earlier reported tetrazole thioether analogs, we now describe the synthesis and inhibition of pyrazole-based inhibitors of N-succinyl-l,l-2,6-diaminopimelic acid desuccinylase (DapE) from Haemophilus influenzae (HiDapE). The most potent pyrazole analog 7d [...] Read more.
Based on the inhibitory potencies from earlier reported tetrazole thioether analogs, we now describe the synthesis and inhibition of pyrazole-based inhibitors of N-succinyl-l,l-2,6-diaminopimelic acid desuccinylase (DapE) from Haemophilus influenzae (HiDapE). The most potent pyrazole analog 7d bears an aminopyridine amide with an IC50 of 17.9 ± 8.0 μM, and the single enantiomer of ɑ-methyl analog 7q has an IC50 of 18.8 µM, with potency residing in the (R)-enantiomer. Thermal shift revealed strong stabilization upon binding inhibitor (R)-7q with Tm = 50.2 °C and a Ki of 17.3 ± 2.8 μM. Enzyme kinetic experiments confirm competitive inhibition, and docking reveals key active site interactions. Full article
(This article belongs to the Special Issue Advances in Enzyme Inhibitors: Mechanisms, Applications, and Future Perspectives)
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22 pages, 2834 KiB  
Article
Cyclobutanone Inhibitors of Diaminopimelate Desuccinylase (DapE) as Potential New Antibiotics
by Thahani S. Habeeb Mohammad, Emma H. Kelley, Cory T. Reidl, Katherine Konczak, Megan Beulke, Janielle Javier, Kenneth W. Olsen and Daniel P. Becker
Int. J. Mol. Sci. 2024, 25(2), 1339; https://doi.org/10.3390/ijms25021339 - 22 Jan 2024
Cited by 3 | Viewed by 2107
Abstract
Based on our previous success in using cyclobutanone derivatives as enzyme inhibitors, we have designed and prepared a 37-member library of α-aminocyclobutanone amides and sulfonamides, screened for inhibition of the bacterial enzyme diaminopimelate desuccinylase (DapE), which is a promising antibiotic target, and identified [...] Read more.
Based on our previous success in using cyclobutanone derivatives as enzyme inhibitors, we have designed and prepared a 37-member library of α-aminocyclobutanone amides and sulfonamides, screened for inhibition of the bacterial enzyme diaminopimelate desuccinylase (DapE), which is a promising antibiotic target, and identified several inhibitors with micromolar inhibitory potency. Molecular docking suggests binding of the deprotonated hydrate of the strained cyclobutanone, and thermal shift analysis with the most potent inhibitor (3y, IC50 = 23.1 µM) enabled determination of a Ki value of 10.2 +/− 0.26 µM and observed two separate Tm values for H. influenzae DapE (HiDapE). Full article
(This article belongs to the Special Issue Rational Design and Synthesis of Bioactive Molecules)
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15 pages, 5979 KiB  
Article
Indoline-6-Sulfonamide Inhibitors of the Bacterial Enzyme DapE
by Cory T. Reidl, Tahirah K. Heath, Iman Darwish, Rachel M. Torrez, Maxwell Moore, Elliot Gild, Boguslaw P. Nocek, Anna Starus, Richard C. Holz and Daniel P. Becker
Antibiotics 2020, 9(9), 595; https://doi.org/10.3390/antibiotics9090595 - 11 Sep 2020
Cited by 12 | Viewed by 4753
Abstract
Inhibitors of the bacterial enzyme dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE; EC 3.5.1.18) hold promise as antibiotics with a new mechanism of action. Herein we describe the discovery of a new series of indoline sulfonamide DapE inhibitors from a high-throughput screen [...] Read more.
Inhibitors of the bacterial enzyme dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE; EC 3.5.1.18) hold promise as antibiotics with a new mechanism of action. Herein we describe the discovery of a new series of indoline sulfonamide DapE inhibitors from a high-throughput screen and the synthesis of a series of analogs. Inhibitory potency was measured by a ninhydrin-based DapE assay recently developed by our group. Molecular docking experiments suggest active site binding with the sulfonamide acting as a zinc-binding group (ZBG). Full article
(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)
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