Cesar Andres Flores Sandoval

Synthesis and theoretic calculations of benzoxazoles and docking studies of their interactions with triosephosphate isomerase

One-pot synthesis was carried out for Z or E stereoisomer derivates of 3-(benzoxazoyl)-2-propenoic acid following kinetic or thermodynamic control. All compounds were characterized by 1H and 13C NMR, and the single crystal X-ray structure of (2Z)-3-(6-methyl-1,3-benzoxazol-2-yl)prop-2-enoic acid (3) was obtained. Furthermore, a theoretic study was done for all the synthesized compounds at the B3LYP/6-31G(d,p) level. The target compounds were docked on triosephosphate isomerase and trypanocidal activity was explored for the 4 and 6 compounds. The Z isomers showed an intramolecular hydrogen bond O–H···N according to the X-ray structure of 3. The docking studies indicate that the test compounds insert themselves between the monomers of triosephosphate isomerase, reaching the known binding site located at interdimeric shapes of triosephosphate isomerase by means of π–π interactions and electrostatic interactions, and in this way interrupt interactions between these monomers. Thus, could explain the biologic effects of the E isomer on triosephosphate isomerase. Finally, compounds 4 and 6 showed trypanocidal activity, which could be mediated by triosephosphate isomerase inhibition.One-pot synthesis was carried out for Z or E stereoisomer derivates of 3-(benzoxazoyl)-2-propenoic acid following kinetic or thermodynamic control. All compounds were characterized by 1H and 13C NMR, and the single crystal X-ray structure of (2Z)-3-(6-methyl-1,3-benzoxazol-2-yl)prop-2-enoic acid (3) was obtained. Furthermore, a theoretic study was done for all the synthesized compounds at the B3LYP/6-31G(d,p) level. The target compounds were docked on triosephosphate isomerase and trypanocidal activity was explored for the 4 and 6 compounds. The Z isomers showed an intramolecular hydrogen bond O–H···N according to the X-ray structure of 3. The docking studies indicate that the test compounds insert themselves between the monomers of triosephosphate isomerase, reaching the known binding site located at interdimeric shapes of triosephosphate isomerase by means of π–π interactions and electrostatic interactions, and in this way interrupt interactions between these monomers. Thus, could explain the biologic effects of the E isomer on triosephosphate isomerase. Finally, compounds 4 and 6 showed trypanocidal activity, which could be mediated by triosephosphate isomerase inhibition.

Aromatic Regions Govern the Recognition of NADPH Oxidase Inhibitors as Diapocynin and its Analogues

Oxidative stress is related to the pathogenesis and progress of several human diseases. NADPH oxidase (NOX), and mainly the NOX2 isoform, produces superoxide anions (O2•−). To date, it is known that NOX2 can be inhibited by preventing the assembly of its subunits, p47phox and p22phox. In this work, we analyzed the binding to NOX2 of the apocynin dimer, diapocynin (C1), a known NOX2 inhibitor, and of 18 designed compounds (C2–C19) which have chemical relationships to C1, by in silico methods employing a p47phox structure from the Protein Data Bank (PDB code: 1WLP). C1 and six of the designed compounds were recognized in the region where p22phox binds to p47phox and makes π–π interactions principally with W193, W263, and Y279, which form an aromatic‐rich region. C8 was chosen as the best compound according to the in silico studies and was synthesized and evaluated in vitro. C8 was able to prevent the production of reactive oxygen species (ROS) similar to C1. In conclusion, targeting the aromatic region of p47phox through π‐interactions is important for inhibiting NOX activity.