Computational investigation of the radical-mediated mechanism of formation of difluoro methyl oxindoles: Elucidation of the reaction selectivity and yields.

Oxindoles are an important class of heterocyclic alkaloids with demonstrated pharmacological activity at multiple biological targets. Preparation of new analogs through novel synthetic routes is therefore highly attractive. In this work, we report a computational study to investigate the synthesis of ethoxycarbonyldifluoromethylated oxindoles from N-arylmethacrylamides. The reaction tolerates a diverse range of acrylamides, shows yields ranging from approximately 38%-96%. We have applied density functional theory (DFT) to explore the reaction mechanism, kinetics and thermodynamics to gain further understanding. We demonstrate that a radical-based ring closure reaction is energetically more favorable than a heterolytic process, that the rate-determining step is the formation of the arylmethacrylamide radical, and that the product yields and selectivities are consistent with experiment. The results demonstrate that theoretical methods can prove useful to understand how such reaction and could be potentially employed to rapidly explore the reaction scope further.

Computational design, synthesis and biological evaluation of PDE5 inhibitors based on N2,N4-diaminoquinazoline and N2,N6-diaminopurine scaffolds.

We report the synthesis, and characterization of twenty-nine new inhibitors of PDE5. Structure-based design was employed to modify to our previously reported 2,4-diaminoquinazoline series. Modification include scaffold hopping to 2,6-diaminopurine core as well as incorporation of ionizable groups to improve both activity and solubility. The prospective binding mode of the compounds was determined using 3D ligand-based similarity methods to inhibitors of known binding mode, combined with a PDE5 docking and molecular dynamics based-protocol, each of which pointed to the same binding mode. Chemical modifications were then designed to both increase potency and solubility as well as validate the binding mode prediction. Compounds containing a quinazoline core displayed IC50s ranging from 0.10 to 9.39 µM while those consisting of a purine scaffold ranging from 0.29 to 43.16 µM. We identified 25 with a PDE5 IC50 of 0.15 µM, and much improved solubility (1.77 mg/mL) over the starting lead. Furthermore, it was found that the predicted binding mode was consistent with the observed SAR validating our computationally driven approach.