Discovery of new 6-ureido/amidocoumarins as highly potent and selective inhibitors for the tumour-relevant carbonic anhydrases IX and XII

Figures & data

Figure 1. Chemical structure of SLC-0111, representative examples of reported coumarins as CAIs, and the designed compounds (5a–p and 7a–c).

Scheme 1. Reagents and reaction conditions: (i) Polyphosphoric acid, DMF, 145 °C, 6 h, 65%; (ii) SnCl₂·2H₂O, ethanol, reflux, 2 h, 71%; (iii) Fe powder, AcOH:EtOH:water (1:3:2 v/v), 40 °C, 1 h, 83%; (iv) Acetonitrile, rt, 2–18 h, DCM, rt, 18 h, 65–95%.

Scheme 2. Reagents and reaction conditions: (i) Benzoic acid derivative, DIPEA, HATU, DMF, rt, 18 h, 25–80%.

Table 1. CA inhibitory activity of compounds 5a–p, 7a–c against hCA isoforms I, II, IX, and XIII using AAZ as a standard CAI.

Compound No.	R	Ki (nM)^a,b
		hCA I	hCA II	hCA IX	hCA XII
5a	3-CF3	>100 μM	>100 μM	45.9	26.2
5b	4-CF3	>100 μM	>100 μM	71.4	38.5
5c	4-F	>100 μM	>100 μM	41.5	40.2
5d	4-Br	>100 μM	>100 μM	70.6	51.1
5e	4-n-Butyl	>100 μM	>100 μM	54.7	95.1
5f	4-Butoxy	>100 μM	>100 μM	32.5	81.8
5g	4-Cl-3-CF3	>100 μM	>100 μM	66.4	29.4
5h	3-Cl-4-F	>100 μM	>100 μM	24.1	10.3
5i	3,5-(CF3)2	>100 μM	>100 μM	14.7	5.9
5j	3,5-Di-Cl	>100 μM	>100 μM	19.9	23.4
5k	3,5-Di-CH3	>100 μM	>100 μM	42.9	27.4
5l	2,4-Di-Cl	>100 μM	>100 μM	50.6	56.7
5m	2,4-Di-F	>100 μM	>100 μM	25.6	7.2
5n	4-Cl-2-CH3	>100 μM	>100 μM	28.4	43.1
5o	2-Cl-6-CH3	>100 μM	>100 μM	19.2	13.8
5p	2,6-Di-Br-4-F	>100 μM	>100 μM	72.8	50.4
7a	4-Cl-3-CF3	>100 μM	>100 μM	82.4	42.8
7b	3,5-(CF3)2	>100 μM	>100 μM	55.6	37.5
7c	3,5-Di-F	>100 μM	>100 μM	61.0	40.5
SLC-0111		5080	960.0	45.0	4.5
AAZ	–	250	12.5	25.0	5.7

^aThe presented values are the mean of three different experiments, and the errors were in the range of ±5–10% of the reported values.

^bIncubation time of 6 h.

Table 2. In vitro antiproliferative activity of the target compounds against HCT116 and MCF7 human cancer cell lines and their CLogP values.

Compound No.	% Growth inhibition^a,b				CLogP value^c
	HCT116		MCF7
	100 µM	10 µM	100 µM	10 µM
5a	21.9 ± 4.6	8.0 ± 4.8	34.7 ± 4.4	3.7 ± 1.9	4.12
5b	77.0 ± 4.0	7.6 ± 2.8	77.8 ± 5.1	4.2 ± 1.4	4.12
5c	31.3 ± 4.6	10.9 ± 1.6	13.5 ± 4.3	9.5 ± 4.2	3.36
5d	31.7 ± 3.5	25.4 ± 2.7	18.5 ± 4.5	18.2 ± 3.2	4.08
5e	65.0 ± 6.0	20.1 ± 2.5	46.4 ± 4.9	38.2 ± 2.5	5.26
5f	67.7 ± 0.6	15.0 ± 5.2	46.9 ± 3.4	32.3 ± 2.6	4.70
5g	90.5 ± 1.4	15.2 ± 4.4	92.3 ± 0.6	10.0 ± 2.4	4.65
5h	92.3 ± 1.2	11.9 ± 1.5	91.2 ± 1.0	16.9 ± 5.3	4.08
5i	94.2 ± 1.1	70.4 ± 2.6	93.9 ± 0.4	51.5 ± 3.1	5.03
5j	91.9 ± 1.1	19.2 ± 3.8	91.1 ± 0.6	6.1 ± 2.0	4.65
5k	87.4 ± 1.8	14.5 ± 2.7	66.7 ± 5.0	33.2 ± 3.2	4.17
5l	6.7 ± 1.7	2.6 ± 1.8	6.6 ± 2.5	5.9 ± 2.7	4.09
5m	26.1 ± 4.0	25.7 ± 2.3	22.7 ± 3.3	15.2 ± 1.4	3.06
5n	20.5 ± 3.5	4.9 ± 2.5	19.9 ± 1.2	16.7 ± 4.9	3.86
5o	78.6 ± 3.7	9.7 ± 4.0	72.8 ± 5.5	30.3 ± 1.5	3.30
5p	75.2 ± 5.8	14.1 ± 3.0	79.5 ± 2.4	21.4 ± 3.0	3.98
7a	42.2 ± 2.5	14.0 ± 2.4	19.0 ± 2.1	9.9 ± 3.4	4.13
7b	76.0 ± 2.5	19.6 ± 2.4	62.9 ± 6.4	11.3 ± 4.0	4.51
7c	52.0 ± 5.1	21.8 ± 3.0	21.4 ± 4.7	21.1 ± 3.3	3.00

^aThe presented values are the mean of three different experiments with standard error of the mean (SEM).

^bBold figures refer to strong growth inhibition (GI > 65%).

^cCLogP values were calculated by ChemDraw Professional 15.0 software.