More effective dithiocarbamate derivatives inhibiting carbonic anhydrases, generated by QSAR and computational design

Figures & data

Table 1.  Chemical structures and experimental K_i and pK_i of dithiocarbamates inhibitors of carbonic anhydrases hCA I, hCA II, hCA IX and hCA XII R₁R₂N-CSSH.

Molecule	R1	R2	Ki (nM)				pKi
			hCA I	hCA II	hCA IX	hCA XII	hCA I	hCA II	hCA IX	hCA XII
1a	H	Ph	4.8	4.5	4.2	4.3	8.32	8.35	8.38	8.37
2a	H	O[(CH2CH2)]2N	4.8	3.6	29.1	9.2	8.32	8.44	7.54	8.04
3a	H	MeN[(CH2CH2)]2N	33.5	33.0	22.1	17.5	7.47	7.48	7.66	7.76
4a	H	2-butyl	21.1	29.4	4.6	31.7	7.68	7.53	8.34	7.50
5a	H	O[(CH2CH2)]2N(CH2)2	31.8	36.3	4.5	4.2	7.50	7.44	8.35	8.38
7a	H	PhCH2	4.1	0.70	19.2	11.5	8.39	9.15	7.72	7.94
8a	H	4-pyridylCH2	3.5	16.6	26	24.1	8.46	7.78	7.59	7.62
9a	H	[(CH2)5N]CH2CH2	4.5	20.3	3.6	20.5	8.35	7.69	8.44	7.69
10a	H	2-thiazolyl	3.9	4.6	12.6	22	8.41	8.34	7.90	7.66
11a	H	KOOCCH2	13.1	325	57.1	6.7	7.88	6.49	7.24	8.17
12a	H	imidazol-1-yl-(CH2)3	8.6	24.7	4.3	6.5	8.07	7.61	8.37	8.19
13a	Me	Me	699	6910	714	798	6.16	5.16	6.15	6.10
14a	Et	Et	790	3100	1413	1105	6.10	5.51	5.85	5.96
15a	(CH2)5	–	0.96	27.5	70.4	46.1	9.02	7.56	7.15	7.34
16a	iso-Bu	iso-Bu	0.97	0.95	4.5	0.99	9.01	9.02	8.35	9.00
17a	n-Pr	n-Pr	1838	55.5	53.8	7	5.74	7.26	7.27	8.15
18a	n-Bu	n-Bu	41.3	50.9	50.3	5.8	7.37	7.29	7.30	8.24
19a	n-Hex	n-Hex	48.0	51.3	27.4	16.1	7.32	7.29	7.56	7.79
20a	Et	n-Bu	157	27.8	25.9	7.5	6.80	7.56	7.59	8.12
21a	HOCH2CH2	HOCH2CH2	9.2	4.00	4.3	4.2	8.04	8.40	8.37	8.38
22a	Me	Ph	39.6	21.5	28.2	7.7	7.40	7.67	7.55	8.11
23a	Me	PhCH2	69.9	25.4	53	3	7.16	7.60	7.28	8.52
24a	O[(CH2CH2)]2	–	0.88	0.95	6.2	3.4	9.06	9.02	8.21	8.47
25a	NaS(S=C)N[(CH2CH2)]2	–	12.6	0.92	37.5	0.78	7.90	9.04	7.43	9.11
27a	(S)-[CH2CH2CH2CH(COONa)]	-	2.5	17.3	4.1	4	8.60	7.76	8.39	8.40

Table 2.  Short description of descriptors used to predict inhibitory activity of DTCs.

Descriptors	Description
Molecular polarizability	Electronic descriptor that calculates the sum of the atomic polarizabilities (including implicit hydrogens)
Logarithm of the octanol/water partition coefficient	The ratio between compound’s concentration in a given volume of n-octanol and concentration in a given volume of water after octanol and water reached equilibrium
Rotatable bonds	Single, non-ring bond between non-terminal, non-ring heavy atoms
Rigid bonds	A bond in a ring
Dipole moment	The product of magnitude of charge and distance of separation between charges
van der Waals surface areas of hydrophobic atoms	Approximation of the sum of van der Waals surface areas of hydrophobic atoms
van der Waals surface areas of polar atoms	Approximation of the sum of van der Waals surface areas of polar atoms
Globularity	Inverse condition number (smallest eigen value divided by the largest eigen value) of the covariance matrix of atomic coordinates. A value of 1 indicates a perfect sphere while a value of 0 indicates a two- or one-dimensional object.

Table 3.  Pearson correlation matrix of independent variables.

	vsa-hyd	glob	b-rigid	b-rot	apol	logP (o/w)	vsa-pol	a-hyd	dipole
vsa-hyd	1.00
Glob	0.233	1.00
b-rigid	−0.060	−0.108	1.00
b-rot	0.685	0.107	−0.480	1.00
Apol	0.078	−0.008	−0.024	0.447	1.00
logP(o/w)	0.714	0.190	−0.316	0.589	0.289	1.00
vsa-pol	−0.466	−0.232	0.264	−0.084	0.393	−0.502	1.00
a-hyd	0.905	0.134	0.225	0.561	0.165	0.655	−0.311	1.00
dipole	−0.226	−0.216	−0.343	0.226	0.717	0.122	0.381	−0.255	1.00

Table 4.  Summary of 2D-QSAR statistical parameters for QSAR models 1–4.

	Descriptors	q^2 cv	r^2 correlation	Standard prediction error	F test	QSAR coefficients
QSAR-1		0.66	0.80	0.43	13.918	constant = 6.732
	vsa-hyd					c1 = −0.017
	glob					c2 = +3.527
	brigid					c3 = +0.355
	brot					c4 = +0.376
QSAR-2		0.70	0.80	0.28	15.850	constant = 4.864
	vsa-pol					c5 = +0.074
	logP(o/w)					c6 = +0.411
	brigid					c7 = +0.139
	apol					c8 = −0.042
QSAR-3		0.55	0.75	0.44	10.821	constant = 5.754
	apol					c9 = +0.041
	brigid					c10 = +0.117
	brot					c11 = +0.260
	dipole					c12 = −0.181
QSAR-4		0.73	0.84	0.24	30.572	constant = 4.207
	a-hyd					c13 = +0.279
	vsa-pol					c14 = +0.042
	apol					c15 = +0.023

Table 5.  QSAR predicted pK_i of dithiocarbamates against human carbonic anhydrases and residual values for QSAR models 1-4.

Compounds	Model 1		Model 2		Model 3		Model 4
	Predicted pKi	Residual activity	Predicted pKi	Residual activity	Predicted pKi	Residual activity	Predicted pKi	Residual activity
1a	8.10	0.22	8.14	0.21	7.47	0.91	8.04	0.33
2a	8.48	−0.16	8.14	0.30	7.50	0.04	7.76	0.28
3a	8.02	−0.55	7.84	−0.36	7.59	0.07	8.03	−0.27
4a	7.03	0.65	7.58	−0.05	6.88	1.46	7.46	0.04
5a	8.48	−0.98	7.64	−0.20	8.37	−0.02	8.30	0.08
7a	8.44	−0.05	8.17	0.98	7.68	0.04	8.39	−0.45
8a	8.56	−0.10	8.04	−0.26	7.90	−0.31	8.33	−0.71
9a	8.70	−0.35	7.80	−0.11	8.10	0.34	8.53	−0.84
10a	8.24	0.17	8.48	−0.14	7.31	0.59	7.37	0.29
11a	7.96	−0.08	6.39	0.10	7.01	0.23	8.08	0.09
12a	9.23	−1.16	7.61	0.00	8.37	0.00	8.12	0.07
13a	6.23	−0.07	6.83	−1.67	6.01	0.14	6.51	−0.41
14a	6.46	−0.36	7.09	−1.58	6.72	−0.87	7.22	−1.26
15a	8.26	0.76	7.86	−0.30	6.99	0.16	7.54	−0.20
16a	6.84	2.17	7.28	1.74	7.80	0.55	8.63	0.37
17a	6.59	−0.85	7.21	0.05	7.48	−0.21	7.92	0.23
18a	7.22	0.15	7.28	0.01	8.29	−0.99	8.63	−0.39
19a	7.17	0.15	7.70	−0.41	9.29	−1.73	9.88	−2.09
20a	6.52	0.28	7.18	0.38	7.49	0.10	7.92	0.20
21a	7.41	0.63	8.40	0.00	7.06	1.31	8.42	−0.04
22a	7.55	−0.15	7.69	−0.02	7.42	0.13	8.15	−0.04
23a	8.04	−0.88	7.76	−0.16	7.82	−0.54	8.50	0.02
24a	8.30	0.76	7.73	1.29	7.14	1.07	7.31	1.16
25a	8.83	−0.93	8.59	0.45	7.68	−0.25	8.95	0.16
27a	9.21	−0.61	7.53	0.23	8.57	−0.18	8.39	0.01

Bold numbers correspond to molecules in testing set.

Figure 1.  Correlation between experimental and predicted pK_i of dithiocarbamates: (a) QSAR model 1 (q² = 0.66, r² = 0.80); (b) QSAR model 2 (q² = 0.70, r² = 0.80); (c) QSAR model 3 (q² = 0.55, r² = 0.75); (d) QSAR model 4 (q² = 0.73, r² = 0.84).

Table 6.  Predicted pK_i of 24a derivatives, indicating inhibition against hCA I (QSAR model 1), hCA II (QSAR model 2), hCA IX (QSAR model 3), hCA XII (QSAR model 4).

Derivative	R1	R2	R3	R4	pKi predicted by QSAR
					Model 1	Model 2	Model 3	Model 4
24a-1	H	CH3	CH	CH	8.15	7.75	7.17	7.67
24a-2	H	OH	CH	CH	8.74	8.65	7.20	7.63
24a-3	OH	OH	CH	CH	9.09	9.58	7.34	7.96
24a-4	COOH	OH	CH	CH	9.12	10.42	7.54	8.88
24a-5	COOCH3	OH	CH	CH	8.75	9.29	8.10	8.65
24a-6	COOH	COOH	CH	CH	11.11	11.26	8.22	9.80
24a-7	COOH	NH2	CH	CH	9.26	10.55	7.49	9.08
24a-8	COOH	HCO	CH	CH	9.46	10.11	8.07	9.20
24a-9	COOH	HCS	CH	CH	9.50	11.62	8.28	10.01
24a-10	–	HCS	C=O	CH	9.42	10.69	7.81	8.95
24a-11	–	HCS	C=O	CH	9.76	10.69	7.94	8.95
24a-12	–	O=C-SH	C=O	CH	9.72	9.33	7.81	8.21
24a-13	–	–	C=O	C=S	8.80	11.06	7.30	8.60
24a-14	HCO	–	CH	C=S	9.08	10.85	7.73	9.06
24a-15	CSSH	–	CH	CH2	9.31	9.99	7.78	8.84
24a-16	–	–	CO	CH2	8.79	9.16	7.08	7.79
24a-17	COOCH=CH2	COOH	CH	CH	9.77	10.25	8.82	9.89
24a-18	COOCCH	COOH	CH	CH	9.94	10.37	8.90	9.86
24a-19	COOCCH	COOCCH	CH	CH	10.28	9.49	9.72	9.92
24a-20	COOCH3	COOCH3	CH	CH	9.41	9.02	8.63	9.34
24a-21	COOCH=CH2	COOCH=CH2	CH	CH	10.12	9.24	9.63	9.99
24a-22	CONH2	CONH2	CH	CH	10.20	11.09	7.65	10.21

Bold letters correspond to compounds with higher inhibitory activity. Italic letters indicate compounds with higher activity simultaneously on hCA I, II, IX, XII.

Figure 2.  The predicted inhibitory residual activity of DTC 24a derivatives reflecting the antitumoral activity evaluated by QSAR models 1 and 2 (Figure 2a) and anti-glaucoma effect evaluated by QSAR models 3 and 4 (Figure 2b).

Figure 3.  The distribution of electrostatic (up) and hydrophobic (down) area of 24a-1(left), 24a (middle) and 24a-19 (right).