Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-β-Lactamase Inhibitors

Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-β-Lactamase Inhibitors

Metallo-β-lactamases (MβLs) are the target enzymes of β-lactam antibiotic resistance, and there are no effective inhibitors against MβLs available for clinic so far. In this study, thirteen halogen-substituted triazolethioacetamides were designed and synthesized a...

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Main Authors: Yilin Zhang, Yong Yan, Lufan Liang, Jie Feng, Xuejun Wang, Li Li, Kewu Yang
Format: Article
Language:English
Published: MDPI AG 2019-03-01
Series:Molecules
Subjects:
halogen-substitutedtriazolethioacetamides
MβLs
inhibitor
Online Access:https://www.mdpi.com/1420-3049/24/6/1174
id doaj-2ccf77b901fd4957b23404430430d39c
record_format Article
spelling doaj-2ccf77b901fd4957b23404430430d39c2020-11-25T00:30:55ZengMDPI AGMolecules1420-30492019-03-01246117410.3390/molecules24061174molecules24061174Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-β-Lactamase InhibitorsYilin Zhang0Yong Yan1Lufan Liang2Jie Feng3Xuejun Wang4Li Li5Kewu Yang6College of Biology Pharmacy and Food Engineering, Shangluo University, Shangluo 726000, ChinaCollege of Biology Pharmacy and Food Engineering, Shangluo University, Shangluo 726000, ChinaCollege of Biology Pharmacy and Food Engineering, Shangluo University, Shangluo 726000, ChinaCollege of Biology Pharmacy and Food Engineering, Shangluo University, Shangluo 726000, ChinaCollege of Biology Pharmacy and Food Engineering, Shangluo University, Shangluo 726000, ChinaCollege of Biology Pharmacy and Food Engineering, Shangluo University, Shangluo 726000, ChinaKey Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi’an 710127, ChinaMetallo-&#946;-lactamases (M&#946;Ls) are the target enzymes of &#946;-lactam antibiotic resistance, and there are no effective inhibitors against M&#946;Ls available for clinic so far. In this study, thirteen halogen-substituted triazolethioacetamides were designed and synthesized as a potent skeleton of M&#946;Ls inhibitors. All the compounds displayed inhibitory activity against ImiS with an IC<sub>50</sub> value range of 0.032&#8211;15.64 &#956;M except <b>7</b>. The chlorine substituted compounds (<b>1</b>, <b>2</b> and <b>3</b>) inhibited NDM-1 with an IC<sub>50</sub> value of less than 0.96 &#956;M, and the fluorine substituted <b>12</b> and <b>13</b> inhibited VIM-2 with IC<sub>50</sub> values of 38.9 and 2.8 &#956;M, respectively. However, none of the triazolethioacetamides exhibited activity against L1 at inhibitor concentrations of up to 1 mM. Enzyme inhibition kinetics revealed that <b>9</b> and <b>13</b> are mixed inhibitors for ImiS with <i>K</i><sub>i</sub> values of 0.074 and 0.27&#956;M using imipenem as the substrate. Docking studies showed that <b>1</b> and <b>9</b>, which have the highest inhibitory activity against ImiS, fit the binding site of CphA as a replacement of ImiS via stable interactions between the triazole group bridging ASP120 and hydroxyl group bridging ASN233.https://www.mdpi.com/1420-3049/24/6/1174halogen-substitutedtriazolethioacetamidesMβLsinhibitor
collection DOAJ
language English
format Article
sources DOAJ
author Yilin Zhang
Yong Yan
Lufan Liang
Jie Feng
Xuejun Wang
Li Li
Kewu Yang
spellingShingle Yilin Zhang
Yong Yan
Lufan Liang
Jie Feng
Xuejun Wang
Li Li
Kewu Yang
Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-β-Lactamase Inhibitors
Molecules
halogen-substitutedtriazolethioacetamides
MβLs
inhibitor
author_facet Yilin Zhang
Yong Yan
Lufan Liang
Jie Feng
Xuejun Wang
Li Li
Kewu Yang
author_sort Yilin Zhang
title Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-β-Lactamase Inhibitors
title_short Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-β-Lactamase Inhibitors
title_full Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-β-Lactamase Inhibitors
title_fullStr Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-β-Lactamase Inhibitors
title_full_unstemmed Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-β-Lactamase Inhibitors
title_sort halogen-substituted triazolethioacetamides as a potent skeleton for the development of metallo-β-lactamase inhibitors
publisher MDPI AG
series Molecules
issn 1420-3049
publishDate 2019-03-01
description Metallo-&#946;-lactamases (M&#946;Ls) are the target enzymes of &#946;-lactam antibiotic resistance, and there are no effective inhibitors against M&#946;Ls available for clinic so far. In this study, thirteen halogen-substituted triazolethioacetamides were designed and synthesized as a potent skeleton of M&#946;Ls inhibitors. All the compounds displayed inhibitory activity against ImiS with an IC<sub>50</sub> value range of 0.032&#8211;15.64 &#956;M except <b>7</b>. The chlorine substituted compounds (<b>1</b>, <b>2</b> and <b>3</b>) inhibited NDM-1 with an IC<sub>50</sub> value of less than 0.96 &#956;M, and the fluorine substituted <b>12</b> and <b>13</b> inhibited VIM-2 with IC<sub>50</sub> values of 38.9 and 2.8 &#956;M, respectively. However, none of the triazolethioacetamides exhibited activity against L1 at inhibitor concentrations of up to 1 mM. Enzyme inhibition kinetics revealed that <b>9</b> and <b>13</b> are mixed inhibitors for ImiS with <i>K</i><sub>i</sub> values of 0.074 and 0.27&#956;M using imipenem as the substrate. Docking studies showed that <b>1</b> and <b>9</b>, which have the highest inhibitory activity against ImiS, fit the binding site of CphA as a replacement of ImiS via stable interactions between the triazole group bridging ASP120 and hydroxyl group bridging ASN233.
topic halogen-substitutedtriazolethioacetamides
MβLs
inhibitor
url https://www.mdpi.com/1420-3049/24/6/1174
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AT yongyan halogensubstitutedtriazolethioacetamidesasapotentskeletonforthedevelopmentofmetalloblactamaseinhibitors
AT lufanliang halogensubstitutedtriazolethioacetamidesasapotentskeletonforthedevelopmentofmetalloblactamaseinhibitors
AT jiefeng halogensubstitutedtriazolethioacetamidesasapotentskeletonforthedevelopmentofmetalloblactamaseinhibitors
AT xuejunwang halogensubstitutedtriazolethioacetamidesasapotentskeletonforthedevelopmentofmetalloblactamaseinhibitors
AT lili halogensubstitutedtriazolethioacetamidesasapotentskeletonforthedevelopmentofmetalloblactamaseinhibitors
AT kewuyang halogensubstitutedtriazolethioacetamidesasapotentskeletonforthedevelopmentofmetalloblactamaseinhibitors
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