Using the symmetrical, adiabatic, counterflow arrangement, the laminar flame speeds of methane + air and propane + air mixtures, with and without the addition of stoichiometrically small amounts of hydrogen, have been determined by first measuring the flame speeds with stretch and then linearly extrapolating these values to zero stretch. The results show that the flame speed is substantially increased with hydrogen addition, and that it can be linearly correlated with the flame speed without hydrogen addition and a single parameter indicating the extent of hydrogen addition.

N-(5-(2-(5-Chloro-2-methoxyphenylamino)thiazol-4-yl)-4-methylthiazol-2-yl)pivalamide 1 (compound 15Jf) was found previously to correct defective cellular processing of the cystic fibrosis protein ΔF508-CFTR. Eight C4′-C5 C,C-bond-controlling bithiazole analogs of 1 were designed, synthesized, and evaluated to establish that constraining rotation about the bithiazole-tethering has a significant effect on corrector activity. For example, constraining the C4′-C5 bithiazole tether in the s-cis conformation [N-(2-(5-chloro-2-methoxyphenyl-amino)-7,8-dihydro-6H-cyclohepta[1,2-d:3,4-d′]bithiazole-2′-yl)pivalamide; 29] results in improved corrector activity. Heteroatom placement in the bithaizole core is also critical as evidenced by the decisive loss of corrector activity with s-cis constrained N-(2-(5-chloro-2-methoxyphenylamino)-5,6-dihydro-4H-cyclohepta[1,2-d:3,4-d′]bithiazole-2′-yl)pivalamide 33. In addition, computational models were utilized to examine the conformational preferences for select model systems. Following our analysis, the “s-cis locked” cycloheptathiazolothiazole 29 was found to be the most potent bithiazole corrector, with an IC50 of ~450 nM.

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The synthesis and Delta F508-CFTR corrector activity of a 148-member methylbithiazole-based library are reported. Synthetic routes were devised and optimized to generate methylbithiazole analogs in four steps. Corrector potency and efficacy were assayed using epithelial cells expressing human Delta F508-CFTR. These structure-activity data establish that the bithiazole substructure plays a critical function; eight novel methylbithiazole correctors were identified with low micromolar potencies.