Pair wise binding affinity: 3D QSAR studies on a set of triazolo [1, 5-a] quinoxalines as antagonists of AMPA and KA receptors

Figures & data

Table 1.  Actual and predicted values of triazolo [1,5-a] quinoxaline derivatives.

Comp. No.	R	R8	R7	Actual values pIC50 (μM)			CoMFA Predicted values pIC50 (μM)			CoMSIA-ALL Predicted values pIC50 (μM)			Ref.
				AMPA	KA	Pair wise*	AMPA	KA	Pair wise	AMPA	KA	Pair wise
1	H	NO2	Cl	−0.18	−2.09	−2.27	−0.34	2.05	−2.39	−0.56	1.96	−2.24	15
2	Et	1H-imidazol-1-yl	Cl	−0.47	−2.32	−2.79	−0.42	2.22	−2.72	−0.31	−2.07	−2.51	15
3	H	1H-imidazol-1-yl	Cl	−0.10	−1.23	−1.33	0.36	1.33	−1.21	−0.01	−1.20	−1.28	15
4	Et	4H-1,2,4-triazol-4-yl	Cl	0.04	−2.08	−2.03	0.26	2.04	−2.09	0.04	2.11	−1.97	15
5	H	4H-1,2,4-triazol-4-yl	Cl	0.74	−1.06	−0.32	0.58	1.14	−0.36	0.58	−1.01	−0.66	15
6	Et	4H-1,2,4-triazol-4-yl	CF3	0.58	−1.96	−1.37	0.56	1.88	−1.32	0.62	−1.96	−1.20	16
7	H	4H-1,2,4-triazol-4-yl	CF3	0.91	−0.98	−0.07	0.93	0.95	−0.06	1.08	1.23	0.06	16
8	Et	3-formyl-1H- pyrrol-1-yl	CF3	0.32	−1.49	−1.17	−0.07	1.65	−1.31	0.01	−1.60	−1.59	16
9	H	3-formyl-1H- pyrrol-1-yl	CF3	0.81	−0.75	0.06	0.61	0.79	0.27	0.63	0.85	0.01	16
10	Et	1H-pyrrol-1-yl	CF3	−0.45	−3.00	−3.45	−0.20	2.52	−2.82	−0.33	−1.90	−2.35	16
11	H	1H-pyrrol-1-yl	CF3	0.44	−1.26	−0.81	0.38	1.64	−1.17	0.34	−1.16	−0.67	16
12	Et	3-carboxy-1H-pyrrol-1-yl	CF3	0.34	−1.11	−0.76	0.46	1.33	−0.65	0.55	−1.79	−1.10	16
13	H	3-carboxy-1H-pyrrol-1-yl	CF3	1.32	−0.73	0.59	1.26	0.49	0.73	1.24	−0.96	0.48	16
14	Et	3-formyl-2,5- dioxo-2,5-dihydro-1H-pyrrol-1-yl	CF3	−1.21	−1.62	−2.84	−1.41	1.56	−2.90	−1.12	−1.76	−2.90	16
15	Et	1H-imidazol-1-yl	CF3	0.34	−1.85	−1.50	0.09	1.94	−1.79	0.02	−1.95	−2.02	16
16	H	1H-imidazol-1-yl	CF3	0.81	−1.11	−0.30	0.71	1.05	−0.43	0.77	1.11	−0.30	16
17	Et	3-formyl-1H-pyrrol-1-yl	NO2	0.07	−1.65	−1.57	0.13	1.53	−1.54	0.08	−1.63	−1.18	16
18	H	3-formyl-1H- pyrrol-1-yl	NO2	0.63	−0.91	−0.28	0.68	0.92	−0.06	0.88	0.79	0.05	16
19	Et	1H-pyrrol-1-yl	NO2	−0.25	−1.61	−1.87	−0.33	1.81	−1.78	0.06	−1.94	−1.51	16
20	H	1H-pyrrol-1-yl	NO2	0.94	−0.71	0.24	0.77	0.72	−0.03	0.53	1.09	−0.29	16
21	Et	3-carboxy-1H-pyrrol-1-yl	NO2	1.05	−2.12	−1.06	1.09	2.16	−1.15	0.88	1.72	−0.82	16
22	H	3-carboxy-1H-pyrrol-1-yl	NO2	1.61	−1.23	0.38	1.31	0.71	0.81	1.64	−0.67	0.50	16
23	Et	NO2	CF3	−1.06	−2.32	−3.38	−0.83	2.35	−3.55	−1.16	2.61	−3.34	16
24	H	NO2	CF3	−0.48	−1.63	−2.11	−0.47	1.71	−2.25	−0.70	−1.39	−1.97	16
25	Et	NH2	CF3	−0.84	−2.05	−2.90	−0.68	2.13	−2.82	−0.75	−2.14	−2.72	16
26	H	NH2	CF3	−0.18	−1.38	−1.57	−0.24	1.40	−1.43	−0.12	1.40	−1.48	16
27	Et	NHCOCH3	NO2	−0.92	−1.61	−2.53	−0.97	1.69	−2.61	−0.88	−1.98	−2.54	16
28	H	NHCOCH3	NO2	−0.25	−1.35	−1.60	−0.16	1.24	−1.18	−0.42	−1.24	−1.61	16
29	Et	NH2	NO2	−0.18	−1.84	−2.03	−0.21	1.99	−2.21	−0.32	−2.02	−2.20	16
30	H	NH2	NO2	0.04	−1.30	−1.26	0.25	1.19	−0.85	0.15	−1.30	−0.99	16

*pIC₅₀ AMPA + pIC₅₀ KA

Figure 1.  Alignment of triazolo [1,5-a] quinoxaline derivatives.

Table 3.  Prediction of test series by CoMFA and CoMSIA methods.

Comp. No.	R	R8	R7	Actual values pIC50 (μM)			CoMFA Predicted values pIC50 (μM)			CoMSIA Predicted values pIC50 (μM)			Ref.
				AMPA	KA	Pair wise*	AMPA	KA	Pair wise	AMPA	KA	Pair wise
1	H	H	4H-1,2,4-triazol-4-yl	−0.74	−2.05	−2.79	−0.71	−1.53	−2.02	−0.46	−1.12	−1.73	17
2	Et	H	4H-1,2,4-triazol-4-yl	−1.11	−2.15	−3.26	−0.41	−1.82	−2.91	−0.11	−1.80	−3.94	17
3	H	3-formyl-1H-pyrrol-1-yl	Cl	0.16	−0.94	−0.78	0.62	−1.89	−1.01	0.16	−1.76	−0.84	17
4	Et	3-formyl-1H-pyrrol-1-yl	Cl	−0.38	−1.94	−2.33	−0.79	−1.63	−2.21	−0.33	−1.16	−1.78	17
5	H	H	H	−	−2.65	−2.65	−0.04	−2.24	−2.97	−0.19	−1.96	−2.35	18

*pIC₅₀ AMPA + pIC₅₀ KA

Table 2.  The PLS statistics results of CoMFA and CoMSIA 3D QSAR models.

Parameter	CoMFA Analysis			CoMSIA Analysis
	AMPA	KA	Pair wise	AMPA				KA				Pair wise
				S,E	S,E,H	S,E,D,A	ALL	S,E	S,E,H	S,E,D,A	ALL	S,E	S,E,H	S,E,D,A	ALL
r^2CV	0.766	0.509	0.806	0.712	0.617	0.760	0.758	0.516	0.561	0.486	0.504	0.773	0.751	0.786	0.780
N	5	6	6	6	5	5	5	2	3	1	2	6	5	5	5
SEP	0.355	0.520	0.305	0.387	0.401	0.359	0.361	0.511	0.501	0.599	0.523	0.321	0.340	0.311	0.315
r^2 boot strap	0.953	0.944	0.964	0.954	0.920	0.965	0.937	0.743	0.803	0.666	0.732	0.959	0.921	0.958	0.982
r^2	0.944	0.875	0.946	0.920	0.855	0.920	0.919	0.674	0.713	0.634	0.684	0.916	0.881	0.908	0.908
SEE	0.187	0.216	0.292	0.227	0.299	0.222	0.223	0.320	0.308	0.335	0.317	0.364	0.424	0.372	0.373
F-value	68.23	28.89	67.25	44.01	28.24	55.40	54.75	27.93	21.50	48.54	29.24	41.83	35.58	47.61	47.46
Prob. of r^2 = 0	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00	0.00
Press	0.48	0. 51	0.39	0.62	0.53	0.59	0.67	0. 56	0.61	0.57	0.54	0.52	0.58	0.57	0.41
Contribution (%)
Steric	0.545	0.477	0.524	0.311	0.200	0.096	0.066	0.427	0.278	0.164	0.128	0.283	0.210	0.112	0.079
Electrostatic	0.455	0.522	0.476	0.689	0.510	0.337	0.250	0.573	0.391	0.200	0.159	0.717	0.486	0.318	0.252
Hydrophobic					0.290		0.228		0.331		0.249		0.304		0.240
Donor						0.263	0.189			0.266	0.174			0.308	0.187
Acceptor						0.304	0.267			0.370	0.289			0.262	0.242

r²_CV = cross-validated coefficient of determination; N= No. of component; SEP= standard error of prediction; r² boot strap = coefficient of determination to boot strap run; r² = conventional coefficient of determination; SEE = standard error of estimate; Press = Predicted residual sum of square; S= Steric field; E: Electrostatic field; H= hydrophobic field; D= hydrogen bond donor field; A= hydrogen bond acceptor field; ALL= S, E, D, A, H.

Figure 2.  Graph between predicted and actual activity for pair wise models of CoMFA and CoMSIA.

Figure 3.  CoMFA STDEV*COEFF contour maps for steric and electrostatic fields of a) AMPA, b) KA, c) Pair wise Model. The most active molecule 22 is displayed in the background.

Figure 4.  CoMSIA STDEV*COEFF contour maps for steric and electrostatic fields of a) AMPA, c) KA, e) Pair wise model. Hydrophobic, donor and acceptor field of b) AMPA, d) KA, f) Pair wise model. The most active molecule 22 is displayed in the background.