Synthesis and biological evaluation of 4,7,9-trisubstituted benzoxazepines as antileishmanial agents.

Herein we report a series of antileishmanial analogues derived from 4-[(3,5-dimethyl-4-isoxazolyl)acetyl]-9-[(1-methyl-3-piperidinyl)methoxy]-7-(5-methyl-2-thienyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (1), which was identified through a previously reported high-throughput phenotypic screen. The analogue series was designed, synthesized, and evaluated for antileishmanial activity to establish pharmacophore elements and preliminary structure-activity relationships as key steps in validating the series for further optimization. This study led to identification of the early lead compound 46, which exhibited sub-micromolar proliferation inhibitory activity against intra-macrophage L.

Hydroxysteroid 17-β dehydrogenase 14 (HSD17B14) is an L-fucose dehydrogenase, the initial enzyme of the L-fucose degradation pathway.

L-Fucose (6-deoxy-L-galactose), a monosaccharide abundant in glycolipids and glycoproteins produced by mammalian cells, has been extensively studied for its role in intracellular biosynthesis and recycling of GDP-L-fucose for fucosylation. However, in certain mammalian species, L-fucose is efficiently broken down to pyruvate and lactate in a poorly understood metabolic pathway. In the 1970s, L-fucose dehydrogenase, an enzyme responsible for the initial step of this pathway, was partially purified from pig and rabbit livers and characterized biochemically.

Crystal structure of L-2-keto-3-deoxyfuconate 4-dehydrogenase reveals a unique binding mode as a α-furanosyl hemiketal of substrates.

L-2-Keto-3-deoxyfuconate 4-dehydrogenase (L-KDFDH) catalyzes the NAD-dependent oxidization of L-2-keto-3-deoxyfuconate (L-KDF) to L-2,4-diketo-3-deoxyfuconate (L-2,4-DKDF) in the non-phosphorylating L-fucose pathway from bacteria, and its substrate was previously considered to be the acyclic α-keto form of L-KDF. On the other hand, BDH2, a mammalian homolog with L-KDFDH, functions as a dehydrogenase for cis-4-hydroxy-L-proline (C4LHyp) with the cyclic structure. We found that L-KDFDH and BDH2 utilize C4LHyp and L-KDF, respectively.

The Iron Metabolism with a Specific Focus on the Functioning of the Nervous System.

Iron is the micronutrient with the best-studied biological functions. It is widely distributed in nature, and its involvement in the main metabolic pathways determines the great importance of this metal for all organisms. Iron is required for cellular respiration and various biochemical processes that ensure the proper functioning of cells and organs in the human body, including the brain.