Discovery and Optimization of a Compound Series Active against , the Causative Agent of Chagas Disease.

Chagas disease is caused by the protozoan parasite . It is endemic in South and Central America and recently has been found in other parts of the world, due to migration of chronically infected patients. The current treatment for Chagas disease is not satisfactory, and there is a need for new treatments.

Antibacterial Isoquinoline Alkaloids from the Fungus Em19.

In the search for new microbial antibacterial secondary metabolites, two new compounds ( and ) were isolated from culture broths of Em19. Structure determination by nuclear magnetic resonance and mass spectrometry identified the compounds as 6,7-dihydroxy-5,10-dihydropyrrolo[1,2-]isoquinoline-3-carboxylic acid (, spathullin A) and 5,10-dihydropyrrolo[1,2-]isoquinoline-6,7-diol (, spathullin B). The two compounds displayed activity against both Gram-negative and -positive bacteria, including , , , , , and .

Antibacterial 3,6-Disubstituted 4-Hydroxy-5,6-dihydro-2H-pyran-2-ones from Serratia plymuthica MF371-2.

Bioassay-guided fractionation of culture extracts of Serratia plymuthica strain MF371-2 resulted in the isolation of two new antibacterial compounds with potent activity against Gram-positive bacteria, including Staphylococcus aureus LMG 15975 (MRSA). A spectroscopic investigation, in combination with synthesis, enabled the characterization of the compounds as 3-butyryl-4-hydroxy-6-heptyl-5,6-dihydro-2H-pyran-2-one (plymuthipyranone A, 1) and 3-butyryl-4-hydroxy-6-nonyl-5,6-dihydro-2H-pyran-2-one (plymuthipyranone B, 2). The MIC values for 1 and 2 against S.

Labradorins with Antibacterial Activity Produced by Pseudomonas sp.

The urgent need for new antibacterial drugs has led to renewed interest in microorganisms, which historically have been the main source of previously discovered antibiotics. The present study describes the discovery of two new antibacterial oxazolylindole type alkaloids, labradorins 5 () and 6 (), which were isolated and characterized from two isolates of sp., along with four previously known tryptophane derived alkaloids.

Backbone nuclear magnetic resonance assignment of human deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase).

Nuclear-associated deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) is an enzyme that hydrolyses deoxyuridine 5'-triphosphate (dUTP) to the monophosphate, thereby controlling the dUTP levels of the organism, which is essential for survival. Further, dUTPase is up-regulated in many cancers. Thus, dUTPase is a highly interesting potential drug target.

Aliskiren displays long-lasting interactions with human renin.

Aliskiren is a selective renin inhibitor recently approved for use in hypertension. Efficacy duration appears longer than what would be expected based on its circulating half-life. The aim was therefore to characterize the kinetics of the interaction between aliskiren and renin.

Design and synthesis of potent macrocyclic renin inhibitors.

Two types of P1-P3-linked macrocyclic renin inhibitors containing the hydroxyethylene isostere (HE) scaffold just outside the macrocyclic ring have been synthesized. An aromatic or aliphatic substituent (P3sp) was introduced in the macrocyclic ring aiming at the S3 subpocket (S3sp) in order to optimize the potency. A 5-6-fold improvement in both the K(i) and the human plasma renin activity (HPRA)IC(50) was observed when moving from the starting linear peptidomimetic compound 1 to the most potent macrocycle 42 (K(i) = 3.

Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant.

The K103N substitution is a frequently observed HIV-1 RT mutation in patients who do not respond to combination-therapy. The drugs Efavirenz, MSC194 and PNU142721 belong to the recent generation of NNRTIs characterized by an improved resistance profile to the most common single point mutations within HIV-1 RT, including the K103N mutation. In the present study we present structural observations from Efavirenz in complex with wild-type protein and the K103N mutant and PNU142721 and MSC194 in complex with the K103N mutant.