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| | Eis inhibition assay |
| Description: | To investigate the potential of these compounds as Eis inhibitors for use in combination with KAN, their biochemical (IC50 values against purified Eis enzyme) and biological (effect on the MIC values of KAN in KAN-sensitive Mtb H37Rv and in Mtb K204, which is KAN-resistant due to Eis upregulation properties were evaluated in parallel studies (Table 2 and FIG. 1). The freshly synthesized compound 29 displayed robust inhibition of Eis in vitro (IC50=0.08±0.02 μM). When combined with KAN, sulfonamide 29, resulted in a four-fold reduced KAN MIC value (2.5 μg/mL) compared to KAN alone (10 μg/mL) for K204 Mtb. This was a reduction almost to the MIC level of KAN in the KAN-susceptible Mtb H37Rv (1.25 μg/mL) parent strain. To gain insight into the importance of the substitution pattern on the aniline portion of the sulfonamide scaffold, secondary (NHAr) and tertiary (N(Me)Ar) sulfonamides (29-47) were first generated. Eis inhibition assays with the synthesized sulfonamides were carried out in combination with KAN. The non-methylated counterpart of lead compound 29, compound 30, displayed lower Eis inhibitory activity (IC50=6.24±1.31 μM) and, contrary to 29, did not overcome KAN resistance in Mtb K204 (MICKAN=10 μg/mL). Two other non-methylated derivatives, 31 and 32, also resulted in lower Eis inhibitory activity (IC50>200 and 10.6±2.5 μM, respectively) and did not overcome KAN resistance in Mtb K204 (MICKAN=10 and 5 μg/mL, respectively). |
| Affinity data for this assay | |
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