- Identification of a New Zinc Binding Chemotype by Fragment Screening
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The discovery of a new zinc binding chemotype from screening a nonbiased fragment library is reported. Using the orthogonal fragment screening methods of native state mass spectrometry and surface plasmon resonance a 3-unsubstituted 2,4-oxazolidinedione fragment was found to have low micromolar binding affinity to the zinc metalloenzyme carbonic anhydrase II (CA II). This affinity approached that of fragment sized primary benzenesulfonamides, the classical zinc binding group found in most CA II inhibitors. Protein X-ray crystallography established that 3-unsubstituted 2,4-oxazolidinediones bound to CA II via an interaction of the acidic ring nitrogen with the CA II active site zinc, as well as two hydrogen bonds between the oxazolidinedione ring oxygen and the CA II protein backbone. Furthermore, 3-unsubstituted 2,4-oxazolidinediones appear to be a viable starting point for the development of an alternative class of CA inhibitor, wherein the medicinal chemistry pedigree of primary sulfonamides has dominated for several decades.
- Chrysanthopoulos, Panagiotis K.,Mujumdar, Prashant,Woods, Lucy A.,Dolezal, Olan,Ren, Bin,Peat, Thomas S.,Poulsen, Sally-Ann
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p. 7333 - 7349
(2017/09/22)
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- Design, synthesis, and anticonvulsant screening of some substituted piperazine and aniline derivatives of 5-phenyloxazolidin- 2,4-diones and 5,5-diphenylimidazolidin-2,4 diones
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Substituted piperazine and aniline derivatives of oxazolidin-2,4-diones and imidazolidin-2,4-diones were synthesized by N3 alkylation and screened for their anticonvulsant activity by the maximal electroshock (MES) test, and their neurotoxicity was evaluated by the rotarod test. Among all the synthesized derivatives, compounds 4b, 6c, 6d, 10b, 11a, 11b, and 11d were found to exhibit maximum seizure protection in MES test and were devoid of any neurotoxic effects. Furthermore, the functional activity of these compounds were evaluated in vivo for 5-HT1A receptor affinity by using rectal body temperature and lower lip retraction in rats, while head twitch response in mice was performed for the determination of probable affinity toward HT2A receptor. The results of these tests demonstrated that compounds 4b, 6c, 6d, 10b, 11a, 11b, and 11d exhibited 5-HT1A (pre- and postsynaptic) agonist/ antagonist features whereas compounds 11a and 11b exhibited antagonist action for HT2A receptor. From the in vivo studies it was observed that a majority of aniline derivatives (6c, 6d, 11a, 11b, 11d) were found to be more active as compared to their bulky piperazine congeners (4b, 10b). Thus, the overall reduction in the bulkiness of the derivatives without compromising the lipophilicity is well appreciated for providing insights into the structural requirements necessary for development of new effective molecules having anticonvulsant effect.
- Dhanawat, Meenakshi,Banerjee, Anupam G.,Shrivastava, S. K.
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p. 2807 - 2822,16
(2020/07/30)
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- N-Acyl and N-sulfonyloxazolidine-2,4-diones are pseudo-irreversible inhibitors of serine proteases
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The synthesis, inhibitory activity and mode of action of oxazolidine-2,4-diones against porcine pancreatic elastase, here used as a model for human neutrophil elastase, are reported. The nature of N-substitution at the oxazolidine-2,4-dione scaffold has large effect on the inhibitory potency against elastase. N-Acyl and N-sulfonyloxazolidine-2,4-diones emerged as potent pseudo-irreversible inhibitors, displaying high second-order rate constants for PPE inactivation. The title compounds were also shown to be potent inhibitors of human neutrophil elastase (HNE) and proteinase-3, and weak inhibitors of human cathepsin G. The results herein presented show that the oxazolidine-2,4-diones represent a new promising class of serine protease inhibitors.
- Santana, Ana Bela,Lucas, Susana D.,Goncalves, Lidia M.,Correia, Henrique F.,Cardote, Teresa A.F.,Guedes, Rita C.,Iley, Jim,Moreira, Rui
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supporting information; experimental part
p. 3993 - 3997
(2012/07/03)
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- A facile one-pot synthesis of 3-unsubstituted-2,4-oxazolidinediones via in situ generation of carbamates from α-hydroxyesters using trichloroacetyl isocyanate
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A convenient, high yield one-pot methodology for the synthesis of pharmaceutically interesting 3-unsubstituted-2,4-oxazolidinediones from α-hydroxyesters is described. A primary carbamate was generated in situ from the corresponding α-hydroxyester and tri
- Li, Yue H.,Zhang, Li,Tseng, Pei-San,Zhang, Yongliang,Jin, Yu,Shen, Jingkang,Jin, Jian
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body text
p. 790 - 792
(2009/05/07)
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- Structure elucidation of 2-amino-5-phenyl-2-oxazolin-4-one (pemoline) and X-ray structure of its hydrolysis product 5-phenyl-oxazolidine-2,4-dione
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In this study we compare spectroscopic properties of pemoline (2-amino-5-phenyl-2-oxazolin-4-one) and its acid hydrolysis product 5-phenyl-oxazolidine-2,4-dione. Crystallization of pemoline from aqueous acetic acid gave single crystals of compound 2, the structure of which was determined by X-ray studies. All four crystallographically independent molecules form dimers linked by N-H?O=C hydrogen bonds.
- Ku?, Piotr,Jones, Peter G.,Celiński, Rafa?
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p. 853 - 857
(2007/10/03)
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- Oxidative Hydroxylation of Heterocyclic β-Dicarbonyl Compounds
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3-Substituted 4-hydroxy-2-quinolones (1), 5-substituted barbituric acids (3) and 4-substituted pyrazolidine-2,4-diones were oxidized to yield the corresponding hydroxyderivatives 2,4 or 9, respectively. - Keywords: 5-Hydroxy-2,4,6-pyrimidine-triones; 4-Hy
- Stadlbauer, Wolfgang,Kappe, Thomas
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p. 1005 - 1016
(2007/10/02)
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- Hypoglycemic 5-substituted oxazolidine-2,4-diones
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Hypoglycemic 5-phenyl and 5-naphthyl oxazolidine-2,4-diones and the pharmaceutically-acceptable salts thereof; certain 3-acylated derivatives thereof; a method of treating hyperglycemic animals therewith; and intermediates useful in the preparation of said compounds.
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- ACYLATION OF 2-AMINO-5-PHENYL-4-OXAZOLINONE AND 2-AMINO-4-IMIDAZOLINONES
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The acylation of 2-amino-5-phenyl-4-oxazolinone and 2-amino-1-methyl-4-imidazolinone with acetyl chloride in benzene in the presence of triethylamine leads to the formation of 2-acetamido-5-phenyl-4-oxazolinone and 2-acetamido-1-methyl-4-imidazolinone.The acylation of 2-amino-4-imidazolinone under the indicated conditions, as well as acetic anhydride, gives 1-acetylimidazolidine-2,4-dione. 3-Acetyl-6-methyl-2H-pyran-2,4(3H)-dione (dehydroacetic acid) is formed as a side product in the acylation of 2-amino-4-azolinones with acetyl chloride in benzene in the presence of triethylamine.The IR and PMR spectra of the compounds obtained are presented.
- Ramsh, S. M.,Zheltonog, N. G.,Shamina, L. P.,Basova, Yu. G.,Ginak, A. I.
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p. 481 - 484
(2007/10/02)
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