Ureidobenzenesulfonamides as Selective Carbonic Anhydrase I, IX, and XII Inhibitors

Figures

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  Figure 1. Structure of SLC-0111 and of acetalzolamide (AAZ).

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  Scheme 1. Synthesis of compounds 1–15: (a) MeCN, 12 h, 23 °C: 1 naphthalen-1-yl, 2 4-benzylphenyl, 3 2-benzylphenyl, 4 4-methoxy-(1,1′-biphenyl)-3-yl, 5 4-methoxyphenyl, 6 3-methoxyphenyl, 7 3-fluorophenyl, 8 ethyl, 9 isopropyl, 10 butyl, 11 hexyl, 12 benzoyl, 13 ethyl-4-benzoate, 15 5-chloro-2-phenoxyphenyl; (b) KOH, MeOH, ∆, 4 h, 98%.

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  Figure 2. Depiction of Ki values for compounds 1–15 and AAZ.

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  Figure 3. (A): Comparison of Ki values for compounds 3 and 10 and standard acetazolamide (AAZ); (B): comparison of Ki values for compound 3 with respect to isoforms of hCA.

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  Figure 4. Comparison of selectivity index for compounds 1–15 with respect to the different isoforms.

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  Figure 5. Predicted ADME properties of clinically tested SLC-0111 (A) and compound 3 (B).

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  Figure 6. (A) Compound 8 inside the active site of hCA I. Hydrophobic (blue), hydrophilic (red), and π-stacking (green) interactions are labeled. (B) Electron density 2Fo-Fc map of 8 bound to zinc in hCA I active site; contoured at the 1.0 σ level.

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  Figure 7. (A) Compound 10 inside the active site of hCA I. Hydrophobic (blue), hydrophilic (red), and π-stacking (green) interactions are labeled. (B) Electron density 2Fo-Fc map of 10 bound to zinc in hCA I active site; contoured at the 1.0 σ level.