- Synthesis and structure-activity relationship studies of 2,4-thiazolidinediones and analogous heterocycles as inhibitors of dihydrodipicolinate synthase
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Dihydrodipicolinate synthase (DHDPS), responsible for the first committed step of the diaminopimelate pathway for lysine biosynthesis, has become an attractive target for the development of new antibacterial and herbicidal agents. Herein, we report the di
- Christoff, Rebecca M.,Soares da Costa, Tatiana P.,Bayat, Saadi,Holien, Jessica K.,Perugini, Matthew A.,Abbott, Belinda M.
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supporting information
(2021/11/27)
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- Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-β-lactamases
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Metallo-β-lactamases (MBLs) enable bacterial resistance to almost all classes of β-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging ‘hydrolytic’ water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products.
- Zhang, Dong,Markoulides, Marios S.,Stepanovs, Dmitrijs,Rydzik, Anna M.,El-Hussein, Ahmed,Bon, Corentin,Kamps, Jos J.A.G.,Umland, Klaus-Daniel,Collins, Patrick M.,Cahill, Samuel T.,Wang, David Y.,von Delft, Frank,Brem, Jürgen,McDonough, Michael A.,Schofield, Christopher J.
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supporting information
p. 2928 - 2936
(2018/04/19)
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- Rhodanine as a Potent Scaffold for the Development of Broad-Spectrum Metallo-β-lactamase Inhibitors
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A series of rhodanines was constructed, their Z-configuration was confirmed by small molecule X-ray crystal structures, and their activity against metallo-β-lactamases (MβLs) was measured. The obtained 26 molecules and a thioenolate specifically inhibited the MβL L1 with an IC50 range of 0.02-1.7 μM, and compounds 2h-m exhibited broad-spectrum inhibition of the MβLs NDM-1, VIM-2, ImiS, and L1 with IC50 values 16 μM. All inhibitors increased the antimicrobial effect of cefazolin against E. coli cells expressing L1, resulting in a 2-8-fold reduction in MIC. Docking studies suggested that the nitro (NDM-1, CphA, and L1) or carboxyl group (VIM-2) of 2l coordinates one or two Zn(II) ions, while the N-phenyl group of the inhibitor enhances its hydrophobic interaction with MβLs. These studies demonstrate that the diaryl-substituted rhodanines are good scaffolds for the design of future broad-spectrum inhibitors of MβLs.
- Xiang, Yang,Chen, Cheng,Wang, Wen-Ming,Xu, Li-Wei,Yang, Ke-Wu,Oelschlaeger, Peter,He, Yuan
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supporting information
p. 359 - 364
(2018/04/19)
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- HETEROCYCLIC INHIBITORS OF LYSINE BIOSYNTHESIS VIA THE DIAMINOPIMELATE PATHWAY
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The present invention relates to certain heterocyclic compounds of formula (1) that have the ability to inhibit lysine biosynthesis via the diaminopimelate biosynthesis pathway in certain organisms. As a result of this activity these compounds can be used
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Paragraph 0197
(2018/11/10)
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- [Et3NH][HSO4] catalyzed efficient synthesis of 5-arylidene-rhodanine conjugates and their antitubercular activity
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Abstract: We have described a highly efficient, safer protocol for the synthesis of 5-arylidene-rhodanine conjugates catalyzed by Bronsted acidic ionic liquid [Et3NH][HSO4] in excellent yields. The protocol offers cost-effective, environmentally benign, solvent-free conditions and recycle–reuse of the catalyst. The synthesized 5-arylidene-rhodanine conjugates were characterized on the basis of 1H NMR, 13C NMR and HRMS spectral data. A series of 5-arylidene-rhodanine derivatives 3a–h, 4a–h were synthesized and evaluated for their in vitro antitubercular activity against dormant Mycobacterium tuberculosis H37Ra and M. bovis BCG strains. Moreover, compounds 3a, 3b, 3e, 3f, 3g, 3h and 4f exhibited good antitubercular activity and were also evaluated for anti-proliferative activity against MCF-7, A549 and HCT116 cell lines using modified MTT assay and found to be noncytotoxic. Compounds 3a–h and 4f were further screened for their antibacterial activity against four bacteria strains to assess their selectivity towards M. tuberculosis. Furthermore, in silico ADME prediction of all the tested compounds followed the criteria for orally active drug and, therefore, these compounds may have a good potential for eventual development as oral agents. Graphical Abstract: [Figure not available: see fulltext.]
- Subhedar, Dnyaneshwar D.,Shaikh, Mubarak H.,Nawale, Laxman,Yeware, Amar,Sarkar, Dhiman,Shingate, Bapurao B.
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p. 6607 - 6626
(2016/07/12)
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- Synthesis and biological evaluation of 5-benzylidenerhodanine-3-acetic acid derivatives as AChE and 15-LOX inhibitors
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A series of 5-benzylidenerhodanine-3-acetamides bearing morpholino-, 4-arylpiperazinyl-, or 4-benzylpiperidinyl- moieties were synthesized and their inhibitory activities against acetylcholinesterase (AChE) were evaluated. Alteration of amide part and substitution on the benzylidene moiety resulted in change of anti-AChE activity. The most active compound was the 1-benzylpiperidinyl derivative containing 4-(dimethylamino)benzylidene scaffold. Notably, the intermediate compounds, namely 5-arylidene-rhodanine-3-acetic acids (3), showed mild inhibitory activity against 15-lipoxygenase (15-LOX), while the final compound 4 showed no activity against 15-LOX.
- Shafii, Negah,Khoobi, Mehdi,Amini, Mohsen,Sakhteman, Amirhossein,Nadri, Hamid,Moradi, Alireza,Emami, Saeed,Saeedian Moghadam, Ebrahim,Foroumadi, Alireza,Shafiee, Abbas
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p. 389 - 395
(2015/07/27)
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- The synthesis of phenylalanine-derived C5-substituted rhodanines and their activity against selected methicillin-resistant Staphylococcus aureus (MRSA) strains
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A series of rhodanine compounds containing various substituents at the N3- and C5-positions were synthesized and their in vitro activity against a panel of clinically relevant MRSA strains was determined. The anti-MRSA activity of compounds 21 (MIC = 3.9
- Hardej, Diane,Ashby Jr., Charles R.,Khadtare, Nikhil S.,Kulkarni, Shridhar S.,Singh, Satyakam,Talele, Tanaji T.
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experimental part
p. 5827 - 5832
(2011/02/22)
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