Table 6. Optimized 3-Aryl-4(1H)-quinolonesa.
Dihydroartemisinin (DHA), chloroquine (CQ), and atovaquone (ATO) are internal controls for each in vitro assay: DHA, 5.5 nM W2 and 5.9 nM TM90-C2B; CQ, 229 nM for TM90-C2B and 421 nM for W2; and ATO, 1.4 nM W2 and 18.4 μM TM90-C2B.
Standards for the solubility assay include carbamazepine and albendazole. Solubility for carbamazepine at pH 7.4, 4.0, and 2.0 is 95 μM, 100 μM, and 100 μM, respectively. Solubility for albendazole at pH 7.4, 4.0, and 2.0 is 6.1 μM, 12 μM, and 100 μM, respectively.
Standards for the permeability assay include verapamil HCl (Pe = 1405 × 10–6 cm/s at pH 7.4 and 39 × 10–6 cm/s at pH 4.0), carbamazepine (Pe = 112 ×10–6 cm/s at pH 7.4 and 108 × 10–6 cm/s at pH 4.0), and ranitidine HCl (Pe = 0.5 × 10–6 cm/s at pH 7.4 and 0 × 10–6 cm/s at pH 4.0).
Standards for the log D7.4 assay include cinnarizine (log D7.4 = 5.68), hydrocortisone-21-acetate (log D7.4 = 2.19), ketoconazole (log D7.4 = 3.83), metronidazole (log D7.4 = −0.02), nadolol (log D7.4 = 0.68), pyrene (log D7.4 = 4.88), theophyline (log D7.4 = −0.05), and tolnaftate (log D7.4 = 5.40).
C.N.C. = could not be calculated. These compounds displayed little to no observable degradation throughout the assay duration (typically 250 min). Analogue 1 was used as a control for comparing half-lives of 4(1H)-quinolones. Compound 1 possesses half-lives of 7.9 min in mouse microsomes and 10.2 min in human microsomes.