Screening of electrophilic compounds yields an aziridinyl peptide as new active-site directed SARS-CoV main protease inhibitor

Martina, Erika; Stiefl, Nikolaus; Degel, Björn; Schulz, F. A.; Breuning, Alexander; Schiller, Markus; Vičík, Radim; Baumann, Knut; Ziebuhr, John; Schirmeister, Tanja

doi:10.1016/j.bmcl.2005.09.012

Cited by 39 publications

(24 citation statements)

References 34 publications

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“…All amino acids used are l-configured. www.chemmedchem.org reomers (de = 0 %) as described earlier for compound 1 a, [15] namely by reaction of methyl-2-bromo acrylate with LeuOMe. …”

Section: Methodsmentioning

confidence: 99%

“…3) was synthesized as previously described, [15] namely by reaction of benzyl-2[(2-bromoacryloyl)amino]-3-phenylpropanoate with dibenzyl aspartate (AspA C H T U N G T R E N N U N G (OBn) 2 ). Yield: 11 % (mixture of diastereomers which were not separated, de = 0 %); IR: 128.43, 128.49, 128.62, 128.72, 129.27, 129.31 (CH, arom.…”

Section: Methodsmentioning

confidence: 99%

“…[15] The N-benzyl-3-methyl-or À3-phenyl aziridine-2-carboxylic acid derivatives 5-11 (Table 1) were synthesized by Cromwell synthesis starting from crotonic (compound 5) or cinnamic A broad protease-based and cell-based screening of protease inhibitors yielded the aziridine-2-carboxylic acid derivative 2 a and the N-acylated aziridine-2,3-dicarboxylic acid derivatives 32 a and 34 b as the most potent inhibitors of falcipain-2 and falcipain-3 (IC 50 falcipain-2: 0.079-5.4 mm, falcipain-3: 0.25-39.8 mm). As the compounds also display in vitro activity against the P. falciparum parasite in the submicromolar and low micromolar range, these compound classes are leads for new antiplasmodial falcipain inhibitors.…”

Section: Synthesesmentioning

confidence: 97%

“…[14] To identify new potential agents against P. falciparum we screened 88 compounds against falcipain-2, falcipain-3, and cultured P. falciparum. The scrutinized compound classes comprise electrophilic compounds, namely aziridine-2-carboxylic acid derivatives (35 compounds in total), [15] aziridine-2,3-dicarboxylic acid derivatives (42 compounds in total), [16][17][18] and corresponding epoxides (11 compounds in total), [19] all known to inhibit proteases by covalent reaction. In addition, one corresponding compound lacking the three-membered ring (TMR) was also tested.…”

Section: Introductionmentioning

confidence: 99%

“…not inhibit the enzymes. Furthermore, aziridine-2-carboxylic acid derivatives derived from less hydrophobic amino acid esters GlyOR, AlaOR, ValOR, MetOMe (Table S1: 14,15,16,17), and derivative 22 (Table S1) containing the space-filling trityl fragment attached to the aziridine nitrogen also do not inhibit falcipains. Within the N-benzylated aziridine series (Table 1) containing either a phenyl ring (6-11), a methyl group (5), or an ethyl ester group (12) at C3 of the TMR only one compound exhibits considerable inhibition of falcipain-2, namely inhibitor 8 (IC 50 = 14.6 mm) containing the tripeptide Phe-Ala-LeuOBn at C2.…”

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confidence: 95%

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Screening of Protease Inhibitors as Antiplasmodial Agents. Part I: Aziridines and Epoxides

et al. 2007

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A broad protease-based and cell-based screening of protease inhibitors yielded the aziridine-2-carboxylic acid derivative 2 a and the N-acylated aziridine-2,3-dicarboxylic acid derivatives 32 a and 34 b as the most potent inhibitors of falcipain-2 and falcipain-3 (IC(50) falcipain-2: 0.079-5.4 microM, falcipain-3: 0.25-39.8 microM). As the compounds also display in vitro activity against the P. falciparum parasite in the submicromolar and low micromolar range, these compound classes are leads for new antiplasmodial falcipain inhibitors.

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“…All amino acids used are l-configured. www.chemmedchem.org reomers (de = 0 %) as described earlier for compound 1 a, [15] namely by reaction of methyl-2-bromo acrylate with LeuOMe. …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Synthesesmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 95%

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Screening of Protease Inhibitors as Antiplasmodial Agents. Part I: Aziridines and Epoxides

et al. 2007

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Characterization and Inhibition of the Main Protease of Severe Acute Respiratory Syndrome Coronavirus

Kuo

Liang

2015

ChemBioEng Reviews

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The main protease of SARS-associated coronavirus (SARS-CoV), also called 3C-like protease (3CL pro ), is vital for the viral replication. It cleaves the replicase polyproteins at 11 sites and is a promising drug target. Several groups of inhibitors have been identified through high-throughput screening and rational drug design. In addition to the pharmaceuti-cal applications, a mutant 3CL pro (T25G) with an expanded S1 space has been demonstrated to tolerate larger residues at P1 , facilitating the cleavage behind the recognition sequence. This review summarizes current developments in anti-SARS agents targeting 3CL pro and the application of the mutant protease as a tag-cleavage endopeptidase.

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The Electron Localizability Indicator from X‐Ray Diffraction Data—A First Application to a Series of Epoxide Derivatives

Grabowsky

Jayatilaka

Mebs

et al. 2010

Chemistry A European J

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The description of electron pairs is at the heart of understanding the chemistry of a given compound because reorganization of electron pairs drives any chemical reaction. A widely used method to describe the electron distribution within a compound is the topological analysis of the electron density (ED).[1] The ED gives information on concentration and depletion of electrons, but not on the pairing of electrons. In contrast, the recently introduced electron localizability indicator (ELI [2] ) is a measure of electron pair localization. Up to now, a great advantage of the ED over the ELI was that only the ED could be derived from a crystallographic X-ray diffraction experiment. Herein, we describe how we made the ELI deducible from the experiment by using the X-ray constrained wavefunction (XCW) fitting procedure. [3] In this method, a wavefunction for an isolated molecule or one embedded in the crystal is constrained to reproduce the X-ray diffraction data while minimizing the electronic energy. We implemented the formula of the ELI (ELI-D(t), [4] ) into the program Tonto [5] and thus made it accessible to the experimentally derived wavefunction resulting from the XCW fitting procedure. [6] Epoxide derivatives serve as test cases for a first application of the new experimentally derived ELI. The high strain in the three-membered C-O-C ring causes broad synthetic [7] and pharmaceutical [8] applications of epoxides. Molecular orbital models describe the two main aspects of the ring strain: The Fçrster-Coulson-Moffitt model [9] shows that CÀ O and CÀC bonds are bent outwards, whereas the Walsh model [10] shows delocalization through the interior of the ring. Both imply that the epoxide ring is unsaturated and can interact with p systems. For cyclopropane, experimental ED studies confirm that bonds bend outwards; [11] but for epoxides, there are only few experimental ED studies with inconclusive results. [12] In this work, a series of epoxide derivatives is studied. From unsubstituted epoxide (1) to tetracyanoepoxide (4), the number and strength of electron-withdrawing substituents increase continuously. Compounds 3 and 4 serve as model compounds for pharmaceutically important protease inhibitors. [13] Single crystals were obtained and measured at low temperatures (25 and 100 K) and up to very high resolutions (d < 0.5 ) mainly using a synchrotron source.[14] The final geometries and the experimentally derived ED distributions were determined by multipole modeling.[15] Subsequent XCW fitting yielded experimentally derived wavefunctions (HF/cc-pVDZ), from which the ELI was calculated and topologically analyzed (model exp). For comparison, isolated-molecule calculations were performed at the experimental (model sp) and at the optimized (model opt) geometries at the same level of theory. For experimental and computational details, see the Supporting Information.The representations of the topology of the epoxide ring in Figure 1 are generally the same for all four compounds and for the three models, exp, sp, and opt, ...

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Screening of electrophilic compounds yields an aziridinyl peptide as new active-site directed SARS-CoV main protease inhibitor

Cited by 39 publications

References 34 publications

Screening of Protease Inhibitors as Antiplasmodial Agents. Part I: Aziridines and Epoxides

Screening of Protease Inhibitors as Antiplasmodial Agents. Part I: Aziridines and Epoxides

Characterization and Inhibition of the Main Protease of Severe Acute Respiratory Syndrome Coronavirus

The Electron Localizability Indicator from X‐Ray Diffraction Data—A First Application to a Series of Epoxide Derivatives

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