1.A straightforward microwave method for rapid synthesis of N-1, C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones.
Gising J1, Ortqvist P, Sandström A, Larhed M. Org Biomol Chem. 2009 Jul 7;7(13):2809-15. doi: 10.1039/b905501k. Epub 2009 May 27.
A rapid and versatile one-pot, 2 x 10 min microwave protocol for the preparation of N-1 and C-6 decorated 3,5-dichloro-2(1H)-pyrazinones was developed. Comparable reaction sequences using classical conditions require about 1-2 days of heating. The alpha-aminonitrile was first generated in a Strecker reaction and thereafter cyclized under microwave heating. The microwave approach developed offers the possibility of efficiently generating and utilizing functionalized 3-amino-5-chloro-2(1H)-pyrazinone-N-1-carboxylic acids as beta-strand inducing core structures in a medicinal chemistry context. To illustrate the usefulness of the method, the synthesis of two novel 2(1H)-pyrazinone-containing Hepatitis C virus NS3 protease inhibitors is reported.
2.Achiral pyrazinone-based inhibitors of the hepatitis C virus NS3 protease and drug-resistant variants with elongated substituents directed toward the S2 pocket.
Gising J1, Belfrage AK, Alogheli H, Ehrenberg A, Åkerblom E, Svensson R, Artursson P, Karlén A, Danielson UH, Larhed M, Sandström A. J Med Chem. 2014 Mar 13;57(5):1790-801. doi: 10.1021/jm301887f. Epub 2013 Apr 2.
Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1' position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R(6) substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors.
3.Paenibacillin A, a new 2(1H)-pyrazinone ring-containing natural product from the endophytic bacterium Paenibacillus sp. Xy-2.
Bian X1,2, Shao M1,2, Pan H3, Wang K1,2, Huang S1,2, Wu X4, Xue C1,2, Hua H1,2, Pei Y1,2, Bai J1,2. Nat Prod Res. 2016;30(2):125-30. doi: 10.1080/14786419.2015.1041941. Epub 2015 May 18.
A new 2(1H)-pyrazinone ring-containing natural product, paenibacillin A (1), together with five known diketopiperazine derivatives 2-6 and two known isoflavones 7-8, was isolated from the culture of an endophytic bacterium Paenibacillus sp. Xy-2. The structure of compound 1 was elucidated by extensive spectral methods, including UV, IR, HR-ESI-MS, 1D and 2D NMR and ECD experiments. Compound 1 exhibited moderate cytotoxicity against HL-60 cell line with IC50 value of 50.48 μM.
4.Lipid Peroxide-Mediated Oxidative Rearrangement of the Pyrazinone Carboxamide Core of Neutrophil Elastase Inhibitor AZD9819 in Blood Plasma Samples.
Gu C1, Lewis RJ2, Wells AS2, Svensson PH2, Hosagrahara VP2, Johnsson E2, Hallström G2. Drug Metab Dispos. 2015 Oct;43(10):1441-9. doi: 10.1124/dmd.115.065136. Epub 2015 Jul 22.
This study focused on the mechanistic interpretation of ex vivo oxidation of a candidate drug in blood plasma samples. An unexpected lipid peroxide-mediated epoxidation followed by a dramatic rearrangement led to production of a five-membered oxazole derivative from the original six-membered pyrazinone-carboxamide core of a human neutrophil elastase inhibitor, 6-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-N-ethyl-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxamide (AZD9819). The rearranged oxidation product 2-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-5-(N-ethylacetamido)-N-(3-(trifluoromethyl)phenyl)oxazole-4-carboxamide was characterized by accurate-mass tandem mass spectrometry fragmentations, by two-dimensional NMR and X-ray crystallography of an authentic standard, and by incorporation of an (18)O atom from molecular (18)O2 to the location predicted by our proposed mechanism. The lipid peroxide-mediated oxidation was demonstrated by using human low-density lipoprotein (LDL) in pH 7.