Structure-guided design and development of novel benzimidazole class of compounds targeting DNA gyraseB enzyme of Staphylococcus aureus

Renuka, Janupally; Jeankumar, Variam Ullas; Bobesh, Karyakulam Andrews; Soni, Vijay; Devi, Parthiban Brindha; Pulla, Venkat Koushik; Suryadevara, Priyanka; Chennubhotla, Keerthana Sharma; Kulkarni, Pushkar; Yogeeswari, Perumal; Sriram, Dharmarajan

doi:10.1016/j.bmc.2014.09.008

Cited by 18 publications

(14 citation statements)

References 42 publications

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“…As reported in our earlier publication , 12 compounds were procured from Asinex database through e‐pharmacophore‐based screening approach using PDB Id: (3TTZ). Among the promising in silico results of the 12 virtual screening hits obtained, compound 5 (considered as lead in this series) was one among them with S. aureus DNA gyraseB activity of 12.88 ± 1.39 μ m and an MIC of 79.03 μ m .…”

Section: Biological Activities Of Furan/pyrrole/thiophene‐2‐carboxamimentioning

confidence: 99%

“…The DNA gyraseB assay was performed as per the protocol . Absence of highly active DNA gyraseB ATPase activity of the purified S. aureus gyraseB in vitro such as other bacteria made us to use the E. coli DNA gyraseA for enhancing the activity of S. aureus gyraseB . Subsequently, E. coli DNA gyraseA in combination with S. aureus DNA gyraseB was used to do the ATPase activity.…”

Section: Biological Activities Of Furan/pyrrole/thiophene‐2‐carboxamimentioning

confidence: 99%

“…The concentration of the drugs used was in a range of 256-0.75 lg/mL. While almost all the compounds showed an MIC less than 100 lM, in MTCC 3160 strain, they showed two-to threefold higher MIC values in MRSA 96 strain elucidating the drugs efficiency to inhibit the multiresistant strain as well (1). As per the table, compounds 22 and 17 showed better MIC values at 18.92 and 16.56 lM almost one-fourth less concentration when compared to the lead 5.…”

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confidence: 99%

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Design and Biological Evaluation of Furan/Pyrrole/Thiophene‐2‐carboxamide Derivatives as EfficientDNAGyraseB Inhibitors ofStaphylococcus aureus

et al. 2015

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DNA topoisomerases are well-validated targets in micro-organisms. DNA gyraseB is one of the most important enzymes among them as per their clinical importance. In earlier study, a novel lead 4-((4-(furan-2-carboxamido)phenyl)amino)-4-oxobutanoic acid was identified as inhibitor against DNA gyraseB with an IC50 of 12.88 ± 1.39 μm. Subsequently, analogues of this lead were developed and evaluated through in vitro assays and in vivo studies. Among the 24 analogues, compound 22 was found to be the top hit with an improved DNA gyraseB activity of 5.35 ± 0.61 μm, and the binding affinity of this compound was further ascertained biophysically through differential scanning fluorimetry. The most potent ligand did not show any signs of cardiotoxicity in zebra fish ether-ago-go-related gene, ascertaining the safety profile of this series a breakthrough among the previously reported cardiotoxic gyraseB inhibitors.

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Section: Biological Activities Of Furan/pyrrole/thiophene‐2‐carboxamimentioning

confidence: 99%

Section: Biological Activities Of Furan/pyrrole/thiophene‐2‐carboxamimentioning

confidence: 99%

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confidence: 99%

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Design and Biological Evaluation of Furan/Pyrrole/Thiophene‐2‐carboxamide Derivatives as EfficientDNAGyraseB Inhibitors ofStaphylococcus aureus

et al. 2015

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“…Benzimidazoles are abundant in a broad number of pharmaceutical compounds, and are widely applied as bactericides (1), anticarcinogens (2), and peptic ulcer agents (3) owing to their promising bioactivities (4)(5)(6)(7)(8). Therefore, tremendous efforts have been devoted to develop a methodology to construct benzimidazoles during the past decades.…”

Section: Introductionmentioning

confidence: 99%

α-Chymotrypsin-catalyzed synthesis of 2-substituted benzimidazole through retro-Claisen reaction

Liu

Xie

Zhang

et al. 2018

Green Chemistry Letters and Reviews

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Benzimidazoles are important components of pharmaceutical compounds owing to their promising bioactivities. The green, safe, and efficient synthesis of benzimidazoles has always been one of the hot topics for chemical workers. α-Chymotrypsin-catalyzed synthesis of benzimidazoles was developed by a reaction between β-keotester and o-phenylenediamine via retro-Claisen reaction. In this eco-friendly medium, a variety of benzimidazole derivatives were obtained in good to excellent yields, with just 10 mg/mL α-Chymotrypsin as catalyst. α-Chymotrypsin catalyzed synthesis of 2-substituted benzimidazole.

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“…[3] Bacterial DNA gyrase Bi savalidated drug target involved in bacterial DNA synthesis. [4][5][6][7][8][9] Ta rgeting this enzymeb yu sing fragment-based screening has been reported. [10][11][12][13][14][15] Most of the early fragment screens were focusedo nu sing nuclear magnetic resonance (NMR) spectroscopy techniques to identify fragments.…”

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confidence: 99%

Application of Fragment‐Based Drug Discovery against DNA Gyrase B

Chen

Tan

et al. 2015

ChemPlusChem

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Bacterial resistance to antibiotics remains a serious threat to global health. The gyrase B enzyme is a well‐validated target for developing antibacterial drugs. Despite being an attractive target for antibiotic development, there are currently no gyrase B inhibitory drugs on the market. A fragment screen using 1,800 compounds identified 14 fragments that bind to Escherichia coli (E. coli) gyrase B. The detailed characterization of binding is described for all 14 fragments. With the aid of X‐ray crystallography, modifications on a low‐affinity fragment (KD=253 μM, IC50=634 μM) has led to the development of a new class of potent phenyl aminopyrazole inhibitors against E. coli gyrase B (IC50=160 nM). The study presented here combines the use of a set of biophysical techniques including differential scanning fluorimetry, nuclear magnetic resonance, isothermal titration calorimetry, and X‐ray crystallography to methodically identify, quantify, and optimize fragments into new chemical leads.

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Structure-guided design and development of novel benzimidazole class of compounds targeting DNA gyraseB enzyme of Staphylococcus aureus

Cited by 18 publications

References 42 publications

Design and Biological Evaluation of Furan/Pyrrole/Thiophene‐2‐carboxamide Derivatives as EfficientDNAGyraseB Inhibitors ofStaphylococcus aureus

Design and Biological Evaluation of Furan/Pyrrole/Thiophene‐2‐carboxamide Derivatives as EfficientDNAGyraseB Inhibitors ofStaphylococcus aureus

α-Chymotrypsin-catalyzed synthesis of 2-substituted benzimidazole through retro-Claisen reaction

Application of Fragment‐Based Drug Discovery against DNA Gyrase B

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