The antibiotic furagin and its derivatives are isoform-selective human carbonic anhydrase inhibitors

Figures & data

Figure 1. Structure of Furagin.

Scheme 1. Reagents and conditions: i. RCHO, EtOH, RT, 16 h

Table 1. Inhibition data of human CA isoforms CA I, II, IX, and XII with aminohydantoines (2–17, Furagin) using AAZ as a standard inhibitor.

Comp.	R	KI (nM)*
		CA I	CA II	CA IX	CA XII
2	C6H5	39 600	900	3500	5600
3	4-OCH3-C6H4	57 600	6400	1200	4700
4	4-NO2-C6H4	>100 000	11 100	7400	2800
5	4-(CO2CH3)-C6H4	>100 000	8300	4900	930
6	-	19 100	4000	1100	160
7	3-furanyl	16 800	710	850	1700
8	4-(OCH2C6H5)-C6H4	>100 000	540	350	910
9	CHCH(CO2C2H5)	45 900	23 600	810	440
10	CHC(CH3)2	28 800	16 500	2900	880
11	CHCH(4-OCH3-C6H4)	>100 000	3100	400	360
12	2,4-(OH)2-C6H3	>100 000	59 900	5800	150
13	4-(B(OH)2)-C6H4	90 700	14 200	7300	230
14	2-pyridyl	51 800	4200	4500	1300
15	3-pyridyl	45 600	620	2300	3200
16	4-pyridyl	26 600	3300	1600	810
17	5-imidazolyl	9600	12 400	560	350
Furagin	-	>100 000	9600	260	57
AAZ	-	250	12	25	6

*Mean from 3 different assays, by a stopped flow technique (errors were in the range of ± 5–10% of the reported values).

Figure 2. Predicted docking orientations of 7 (green) and Furagin (pink) to (A) CA II, (B) CA IX and (C) CA XII.

Figure 3. RMSD analysis of Furagin heavy atoms and (A) CA II, (B) CAIX and (C) CA XII backbone over the 100 ns MD simulation. The ligand colour darkens over the dynamic simulation.

Figure 4. Dynamics evolution of the binding mode of Furagin to (A) CA II, (B) CA IX and (C) CA XII over the course of 100 ns. Water molecules are represented as red spheres. The ligand colour darkens over the dynamic simulation.

Figure 5. RMSD analysis of 12 heavy atoms and (A) CA II, (B) CAIX and (C) CA XII backbone over the 100 ns MD simulation. The ligand colour darkens over the dynamic simulation.

Figure 6. Dynamics evolution of the binding mode of 12 to (A) CA II, (B) CA IX and (C) CA XII over the course of 100 ns. Water molecules are represented as red spheres. The ligand colour darkens over the dynamic simulation.