Cleaning the Cellular Factory-Deletion of McrA in NSAR1 and the Generation of a Novel Kojic Acid Deficient Strain for Cleaner Heterologous Production of Secondary Metabolites.

The use of filamentous fungi as cellular factories, where natural product pathways can be refactored and expressed in a host strain, continues to aid the field of natural product discovery. Much work has been done to develop host strains which are genetically tractable, and for which there are multiple selectable markers and controllable expression systems. To fully exploit these strains, it is beneficial to understand their natural metabolic capabilities, as such knowledge can rule out host metabolites from analysis of transgenic lines and highlight any potential interplay between endogenous and exogenous pathways.

Structure-Based Design, Synthesis and Biological Evaluation of Bis-Tetrahydropyran Furan Acetogenin Mimics Targeting the Trypanosomatid F1 Component of ATP Synthase.

The protozoan parasites and . are responsible for the severely debilitating neglected Tropical diseases of African sleeping sickness, Chagas disease and leishmaniasis, respectively. As part of our ongoing programme exploring the potential of simplified analogues of the acetogenin chamuvarinin we identified the FoF1-ATP synthase as a target of our earlier triazole analogue series.

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Aim: to assess the prevalence of bendopnea and association of this symptom with clinical, laboratory and echocardiographic features, clinical outcomes during 2 years of follow-up in ambulatory elderly patients with chronic heart failure (CHF).

Materials And Methods: We conducted an open, prospective, non-randomized study of 80 ambulatory patients aged ≥60 years admitted with heart failure II-IV NYHA class CHF. Baseline survey included physical examination, estimation of Charlson comorbidity index, echocardiography and laboratory tests.

Design and Synthesis of Broad Spectrum Trypanosomatid Selective Inhibitors.

Neglected tropical diseases caused by parasitic infections are an ongoing and increasing concern that have a devastating effect on the developing world due to their burden on human and animal health. In this work, we detail the preparation of a focused library of substituted-tetrahydropyran derivatives and their evaluation as selective chemical tools for trypanosomatid inhibition and the follow-on development of photoaffinity probes capable of labeling target protein(s) in vitro. Several of these functionalized compounds maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, and Leishmania donovani.

Photo-affinity labelling and biochemical analyses identify the target of trypanocidal simplified natural product analogues.

Current drugs to treat African sleeping sickness are inadequate and new therapies are urgently required. As part of a medicinal chemistry programme based upon the simplification of acetogenin-type ether scaffolds, we previously reported the promising trypanocidal activity of compound 1, a bis-tetrahydropyran 1,4-triazole (B-THP-T) inhibitor. This study aims to identify the protein target(s) of this class of compound in Trypanosoma brucei to understand its mode of action and aid further structural optimisation.