Antimalarial hit 1SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.

Cyclopeptides containing the complete bradykinin sequence have been synthesized using the pentafluorophenyl esters procedure. Cyclization was performed either by directly connecting the terminal amino acids or via one or two ω‐aminododecanoic acid residues. Preparative liquid chromatography with an axial adsorbent compression system was employed for purification of intermediates. Cyclo‐bradykinin and cyclo‐(ω‐aminododecanoyl‐bradykinin) exhibit prolonged hypotensive activity, whereas cyclo‐(ω‐aminododecanoyl‐ω‐aminododecanoyl‐bradykinin) appeared inactive in our experiments.

The hydrogenation of ethyl 4- R-2,4-dioxobutyrates (R = phenyl, 2-furyl) at 5% Pt/Al 2 O 3 catalyst, modified with cinchonidine, and at palladium black was investigated. The former had low activity under the conditions we tested. The main products during the hydrogenation of these compounds at palladium black are ethyl 4-R-2-hydroxy-4-oxobutyrates. The yield of the phenyl derivative amounts to 68.5%, while the yield of the corresponding 2-furyl derivative amounts to 97%. In the last case ethyl 2-hydroxy-4-oxo-4-(2-tetrahydrofuryl)butyrate was detected as impurity. The optimum conditions for the formation of ethyl 2-hydroxy-4-phenylbutyrate (yield 88.2%) were determined.Keywords: ethyl 4-substituted 2,4-dioxobutyrates, platinum and palladium catalysts, hydrogenation.The derivatives of 4-substituted 2-hydroxybutyric acids are valuable synthons for the production of antihypertensive substances, homoamino acids, hydroxamic acids, and other compounds [1,2].We studied the hydrogenation of sodium 2-oxo-4-phenyl-, 4-(2-furyl)-2-oxo-, 2-oxo-4-(2-thienyl)-, and 2-oxo-4-(3-pyridyl)butenoates at nickel and palladium catalysts.During the hydrogenation of sodium 2-oxo-4-phenylbutenoate at nickel catalysts the corresponding salt of 2-hydroxy-4-phenylbutyric acid is formed [3].The use of palladium black and 10% Pd/C catalyst leads to the formation of sodium 2-oxo-4phenylbutyrate. During the hydrogenation of sodium 4-(2-furyl)-2-oxobutenoate at Raney nickel catalyst the corresponding 4-(2-furyl)-2-oxobutyrates and 4-(2-furyl)-2-hydroxybutyrates and aliphatic compounds from hydrogenolysis of the molecule of the original compound are formed [4].During the hydrogenation of sodium and ethyl 2-oxo-4-(2-thienyl)butenoates at Raney nickel the corresponding derivatives of 2-oxo-4-(2-thienyl)butyric acid and 2-hydroxy-4-(2-thienyl)butyric acid are formed [5]. Palladium catalysts secure the more selective formation of the corresponding oxo compound than Raney nickel. The formation of ethyl 2-oxo-4-(2-tetrahydrothienyl)butyrate in addition to the above-mentioned compounds was also observed during the hydrogenation of ethyl 2-oxo-4-(2-thienyl)butenoate at palladium black.During the hydrogenation of sodium 2-oxo-4-(3-pyridyl)butenoate at palladium black the reaction products were sodium 2-oxo-4-(3-pyridyl)butyrate and 2-hydroxy-4-(3-pyridyl)butyrate and hydrogenolysis products. The reaction takes place by a parallel-consecutive mechanism [6].During the hydrogenation of derivatives of 4-substituted 2-oxobutenoic acids the double bond is saturated, and the carbonyl group is partly hydrogenated. The latter depends on the composition of the catalyst and on the structure of the initial compound. __________________________________________________________________________________________

Hydrogenation O 0220 Hydrogenation of Ethyl Esters of 4-Phenyl-and (2-Furyl)-Substituted 2,4-Dioxobutyric Acids at PalladiumBlack. -The optimization of the hydrogenation conditions is reported. -(SLAVINSKA, V.; SILE*, D.; ROZENTHAL, G.; MAUROPS, G.; POPELIS, J.; KATKEVICH, M.; STONKUS, V.; LUKEVICS, E.; Chem. Heterocycl.