Figures & data
Scheme 1. Reagents and conditions: (i) diethyl malonate, Piperidine, EtOH, 70–80 °C, 4–6 h, 82% (ii) NaOH, H2O, MeOH, rt., 2 h, 74% (iii) N-Boc piperazine, EDC.HCl, HOBt, DIPEA, DMF, rt, 8-12 h, 61% (iv) TFA, DCM, 0–5 °C to rt., 1 h, 69% (v) substituted sulphonyl chlorides, DIPEA, DCM, rt., 2–3 h, 75–81%. (vi) substituted phenylisothiocyanates, ACN, reflux, 2–3 h, 65–75%.
![Scheme 1. Reagents and conditions: (i) diethyl malonate, Piperidine, EtOH, 70–80 °C, 4–6 h, 82% (ii) NaOH, H2O, MeOH, rt., 2 h, 74% (iii) N-Boc piperazine, EDC.HCl, HOBt, DIPEA, DMF, rt, 8-12 h, 61% (iv) TFA, DCM, 0–5 °C to rt., 1 h, 69% (v) substituted sulphonyl chlorides, DIPEA, DCM, rt., 2–3 h, 75–81%. (vi) substituted phenylisothiocyanates, ACN, reflux, 2–3 h, 65–75%.](/cms/asset/e4058e16-e063-4253-8e09-f32410dce2a5/ienz_a_2185760_sch0001_b.jpg)
Scheme 2. Reagents and conditions: (i) diethyl malonate, piperidine, glacial acetic acid (Cat.), reflux, 80 °C, 4–6 h, 79% (ii) NaOH, H2O, MeOH, rt.,2 h, 70% (iii) substituted sulphonyl piperazines, EDC.HCl, HOBt, DIPEA, DMF, rt,8–12 h, 60–75% (iv) TFA, 90–100 °C 8 h, 88% Citation27.
![Scheme 2. Reagents and conditions: (i) diethyl malonate, piperidine, glacial acetic acid (Cat.), reflux, 80 °C, 4–6 h, 79% (ii) NaOH, H2O, MeOH, rt.,2 h, 70% (iii) substituted sulphonyl piperazines, EDC.HCl, HOBt, DIPEA, DMF, rt,8–12 h, 60–75% (iv) TFA, 90–100 °C 8 h, 88% Citation27.](/cms/asset/22800c82-0958-47c0-9528-a8bc3d8fc96a/ienz_a_2185760_sch0002_b.jpg)
Scheme 3. Reagents and conditions: (i) ethyl acetoacetate, piperidine, EtOH, rt, 4–6 h, 70% (ii) cat. AcOH, DMF, rt, 2–3 h, 70–73%.
![Scheme 3. Reagents and conditions: (i) ethyl acetoacetate, piperidine, EtOH, rt, 4–6 h, 70% (ii) cat. AcOH, DMF, rt, 2–3 h, 70–73%.](/cms/asset/1f6c537f-c52c-4d7b-90e0-d6e1d8fa7377/ienz_a_2185760_sch0003_b.jpg)
Table 1. Inhibition data for hCA isozymes I, II, IX and XII for synthesised compounds using AAZ as a standard CAI (Ki in µM).a,b
Figure 2. (A) Docking pose of compound 6c (green) (B) docking pose of compound 7c (grey) in the active site of hCA IX (PDB ID: 5DVX) Zn2+ is represented as grey sphere.
![Figure 2. (A) Docking pose of compound 6c (green) (B) docking pose of compound 7c (grey) in the active site of hCA IX (PDB ID: 5DVX) Zn2+ is represented as grey sphere.](/cms/asset/44058847-7618-4ac3-99c3-073ab0203b50/ienz_a_2185760_f0002_c.jpg)
Figure 3. Graph showing analysis of ligand RMSD for MD simulation time of 100 ns on hCA IX (PDB ID: 5DVX) (A) change in conformations of 6c. (B) change in conformations of 7c.
![Figure 3. Graph showing analysis of ligand RMSD for MD simulation time of 100 ns on hCA IX (PDB ID: 5DVX) (A) change in conformations of 6c. (B) change in conformations of 7c.](/cms/asset/b2550953-10d2-4fc8-9f45-4802609d3ccd/ienz_a_2185760_f0003_c.jpg)
Figure 4. (A) Docking pose of compound 6d (purple) (B) docking pose of compound 7b (teal) in the active site of hCA IX (PDB ID: 1JD0) Zn2+ is represented as grey sphere.
![Figure 4. (A) Docking pose of compound 6d (purple) (B) docking pose of compound 7b (teal) in the active site of hCA IX (PDB ID: 1JD0) Zn2+ is represented as grey sphere.](/cms/asset/2803dd62-4e43-4677-a063-605424a91079/ienz_a_2185760_f0004_c.jpg)
Figure 5. Graph showing analysis of ligand RMSD for MD simulation time of 100 ns on hCA XII (PDB ID: 1JD0) (A) change in conformations of 6d. (B) change in conformations of 7b.
![Figure 5. Graph showing analysis of ligand RMSD for MD simulation time of 100 ns on hCA XII (PDB ID: 1JD0) (A) change in conformations of 6d. (B) change in conformations of 7b.](/cms/asset/237b2168-f8c2-43ba-bb19-be500f9c4920/ienz_a_2185760_f0005_c.jpg)