Constrained bithiazoles: small molecule correctors of defective ΔF508-CFTR protein trafficking.

Conformationally constrained bithiazoles were previously found to have improved efficacy over nonconstrained bithiazoles for correction of defective cellular processing of the ΔF508 mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. In this study, two sets of constrained bithiazoles were designed, synthesized, and tested in vitro using ΔF508-CFTR expressing epithelial cells. The SAR data demonstrated that modulating the constraining ring size between 7- versus 8-membered in these constrained bithiazole correctors did not significantly enhance their potency (IC50), but strongly affected maximum efficacy (Vmax), with constrained bithiazoles 9e and 10c increasing Vmax by 1.5-fold compared to benchmark bithiazole corr4a. The data suggest that the 7- and 8-membered constrained ring bithiazoles are similar in their ability to accommodate the requisite geometric constraints during protein binding.

3-(Arylthiomethyl)isoxazole-4,5-dicarboxamides: chemoselective nucleophilic chemistry and insecticidal activity.

A collection of 91 3-(arylthiomethyl)isoxazole-4,5-dicarboxamides was prepared starting from dimethyl 3-(chloromethyl)isoxazole-4,5-dicarboxylate. The thioether moieties in these compounds were subsequently oxidized to give the corresponding 3-(arylsulfonylmethyl)isoxazole-4,5-dicarboxamides. By carefully controlling stoichiometry and reaction conditions, the C4 and C5 carbomethoxy groups could be differentially derivatized to carboxamides. A total of 182 trisubstituted isoxazoles are reported and deposited in the National Institutes of Health Molecular Repository; an 80 compound subset was evaluated for insecticidal activity.