Quantitative structure–activity relationship (QSAR) studies on a series of 1,3,4-thiadiazole-2-thione derivatives as tumor-associated carbonic anhydrase IX inhibitors

Figures & data

Figure 1.  The structures of 1,3,4-thiadiazole-2-thione derivatives (1a-r and 2a-c) under study.

Table I.  Calculated molecular descriptors used in this study.

Symbol	Description	Type	Server
Log P	Log of the octanol/water partition coefficient	Physicochemical	MOE [32]
W	Wiener index	Topological	Chem3D [33]
Wp	Wiener polarity number	Topological	MOE
	Fourth-order valence connectivity index	Topological	Manual [34]
Z	Zagreb index	Topological	MOE
PJ	Value of (diameter - radius)/diameter	Topological	MOE
Aw	Van der Waals surface area	Topological	MOE
Vw	Van der Waals volume	Topological	MOE
П	Mean polarizability	Electronic	MOPAC [35]
CAA	Connolly Accessible Area	Topological	Chem3D
μ	Magnitude of dipole moment	Electronic	MOPAC
IP	Ionization Potential	Electronic	MOPAC

Table II.  The inhibitory activity (log IC₅₀) and the structural descriptors of the selected compounds (1a-r and 2a-c).

No.	log IC50	Log P	W	Wp		Z	PJ	Aw	Vw	П	CAA	μ	IP	I
1a	1.362	4.73	745	19	0.738	86	0.50	275.17	238.13	177.15	484.17	19.66	9.21	1
1b	0.857	4.43	873	21	0.824	92	0.46	285.88	243.25	187.59	489.46	18.89	9.07	1
1c	1.380	4.69	1020	23	0.885	96	0.50	305.99	265.38	189.91	526.74	20.32	8.94	1
1d	1.415	4.42	1131	26	0.969	102	0.50	312.76	266.25	183.60	534.51	17.90	9.10	1
1e	1.462	5.33	849	22	1.000	92	0.50	291.58	251.25	174.86	483.15	25.46	6.89	1
1f	1.006	5.57	861	21	1.071	92	0.50	303.02	262.75	190.72	513.18	20.07	9.20	1
1g	1.342	5.54	873	21	1.115	92	0.46	303.27	264.13	184.46	513.99	18.78	9.20	1
1h	1.380	4.27	1097	26	0.959	102	0.50	298.04	254.13	187.12	516.41	22.04	9.25	1
1i	1.002	4.27	1169	25	0.927	102	0.50	299.06	256.50	189.84	522.14	16.49	9.25	1
1j	0.531	4.65	1169	25	1.231	102	0.50	329.65	284.63	217.69	561.79	20.10	9.02	1
1k	0.874	4.67	831	22	0.989	92	0.50	295.15	252.25	185.22	505.94	19.79	9.22	0
1l	0.934	5.26	965	24	1.205	98	0.46	311.56	267.00	192.65	528.08	19.21	9.20	0
1m	0.839	5.46	965	24	1.361	98	0.46	322.05	280.50	200.84	537.4	19.02	9.23	0
1n	0.880	4.20	1275	28	1.176	108	0.50	319.01	272.50	202.12	540.15	17.71	9.20	0
1o	0.928	6.33	1450	31	1.165	120	0.50	355.85	314.88	203.49	592.27	19.32	9.27	0
1p	0.707	3.43	745	22	0.726	92	0.50	289.92	248.13	197.65	473.04	17.45	9.16	0
1q	0.763	3.45	632	16	0.692	82	0.45	257.29	213.75	169.50	455.83	19.88	9.05	0
1r	0.948	4.28	627	17	0.958	78	0.45	293.39	246.00	165.49	499.38	21.54	9.12	0
2a	0.975	3.35	1025	28	1.139	110	0.50	294.51	256.63	206.35	503.31	20.17	8.94	0
2b	0.859	4.19	1157	30	1.486	116	0.50	319.46	283.38	217.97	534.89	20.14	8.98	0
2c	0.113	3.32	1467	34	1.316	126	0.46	317.05	273.38	253.03	539.98	21.94	9.01	0

Table III.  Intercorrelation matrix of the molecular descriptors.

	Log P	W	Wp		Z	PJ	Aw	Vw	П	CAA	μ	IP	I
Log P	1.00
W	0.07	1.00
Wp	0.07	0.94	1.00
	0.24	0.61	0.69	1.00
Z	− 0.06	0.94	0.99	0.68	1.00
PJ	0.06	0.29	0.31	− 0.04	0.27	1.00
Aw	0.47	0.79	0.73	0.74	0.72	0.22	1.00
Vw	0.5	0.78	0.74	0.75	0.74	0.26	0.99	1.00
П	− 0.22	0.75	0.83	0.68	0.85	0.07	0.59	0.6	1.00
CAA	0.44	0.84	0.73	0.7	0.72	0.22	0.96	0.95	0.57	1.00
μ	0.06	− 0.1	− 0.02	0.11	− 0.04	− 0.05	− 0.11	− 0.1	− 0.02	− 0.15	1.00
IP	− 0.1	0.13	0.07	0.02	0.09	− 0.14	0.16	0.13	0.15	0.26	− 0.72	1.00
I	0.27	− 0.07	− 0.25	− 0.33	− 0.26	0.29	− 0.16	− 0.14	− 0.3	− 0.08	0.09	− 0.21	1.00

Table IV.  Regression parameters for the bi-parametric models.

Descriptors	Se	R		F
П, Wp	0.2010	0.8154	0.6277	17.8609
П, Z	0.2098	0.7968	0.5943	15.6536
П, PJ	0.2102	0.7961	0.5931	15.5790
П, I	0.2106	0.7952	0.5914	15.4748
П, W	0.2192	0.7757	0.5574	13.5970
П, Vw	0.2289	0.7520	0.5172	11.7121
П, log P	0.2353	0.7355	0.4899	10.6055

Table V.  Regression parameters for the tri-parametric models.

Descriptors	Se	R		F
П, Wp, I	0.1527	0.9040	0.7850	25.3341
П, Z, I	0.1642	0.8882	0.7516	21.1671
П, Wp, PJ	0.1909	0.8453	0.6642	14.1857
П, PJ, I	0.1929	0.8417	0.6570	13.7708
П, Vw, I	0.1932	0.8412	0.6560	13.7108

Table VI.  Validation and cross-validation parameters for model (5).

		MLR validation			Cross validation (LOO)
No.	Obs. log IC50	Pred. log IC50	Residual	Z-score	Pred. log IC50	Residual	Z-score
1a	1.362	1.158	0.204	1.554	1.114	0.248	1.987
1b	0.857	1.043	− 0.185	1.411	1.077	− 0.219	1.732
1c	1.380	1.120	0.259	1.978	1.084	0.295	2.476
1d	1.415	1.435	− 0.020	0.153	1.441	− 0.026	0.197
1e	1.462	1.431	0.031	0.241	1.424	0.038	0.284
1f	1.006	1.042	− 0.036	0.273	1.051	− 0.044	0.329
1g	1.342	1.187	0.155	1.186	1.148	0.194	1.509
1h	1.380	1.366	0.014	0.109	1.362	0.018	0.134
1i	1.002	1.238	− 0.236	1.795	1.278	− 0.275	2.263
1j	0.531	0.720	− 0.189	1.436	0.827	− 0.295	2.383
1k	0.874	0.931	− 0.056	0.427	0.938	− 0.063	0.478
1l	0.934	0.917	0.017	0.135	0.914	0.0206	0.154
1m	0.839	0.781	0.058	0.442	0.759	0.079	0.595
1n	0.880	0.922	− 0.041	0.315	0.928	− 0.048	0.359
1o	0.928	1.034	− 0.105	0.800	1.082	− 0.154	1.171
1p	0.707	0.572	0.135	1.031	0.484	0.223	1.737
1q	0.763	0.866	− 0.103	0.782	0.924	− 0.160	1.221
1r	0.948	1.079	− 0.130	0.991	1.136	− 0.187	1.446
2a	0.975	0.823	0.152	1.160	0.801	0.174	1.344
2b	0.859	0.755	0.103	0.791	0.717	0.142	1.078
2c	0.113	0.146	− 0.032	0.245	0.191	− 0.077	0.577

Figure 2.  Correlation of observed and predicted log IC₅₀ using model 5 (R² = 0.8331, MLR method).

Table VII.  Some statistical parameters of the generated models.

Model No.	R		Q	PE
1	0.6931	0.4530	2.8459	0.0756
2	0.8154	0.6277	4.0567	0.0487
3	0.9040	0.7850	5.9201	0.0266
4	0.8882	0.7516	5.4080	0.0307
5	0.9120	0.7894	6.0304	0.0245

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Molecular Orbital Package (MOPAC) module (CS MOPAC 2000) of Chem. 3D Ultra version 8.0, Cambridge Software Corporation, USA.

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