QSAR study of substituted 2-pyridinyl guanidines as selective urokinase-type plasminogen activator (uPA) inhibitors

Figures & data

Table I.  Structure, biological activity and physicochemical descriptors of series 1 .

S. No	R	BA (μM)	− logBA	petitjeanSC	b_1rotR	KierFlex
1	H	29.5	4.5302	1	0.1667	1.4283
2	3-CH3	37.7	4.4237	1	0.1905	1.6467
3	4-CH3	83.8	4.0768	1	0.1905	1.6467
4	5-CH3	32.3	4.4908	0.75	0.1905	1.6467
5	6-CH3	173.0	3.7619	1	0.1905	1.6467
6	4-C6H5	7.10	5.1487	0.8	0.1379	2.0737
7	4-OCH3	53.3	4.2732	0.75	0.2273	2.1281
8	3-OH	147.0	3.8327	1	0.2105	1.6467
9	3-OCH3	62.0	4.2076	1	0.2273	2.1281
10	5-Cl	10.0	5.0000	0.75	0.1667	2.2402
11	5-Br	3.13	5.5044	0.75	0.1667	2.7614
12	3,5-diCl	5.47	5.2620	0.75	0.1667	3.2121
13	3-Br, 5-Cl	4.83	5.3160	0.75	0.1667	3.8483
14	3-Cl, 5-Br	2.90	5.5376	0.75	0.1667	3.8483
15	3-Cl, 5-CF3	40.7	4.3904	1	0.1905	2.9205
16	3,5-diCl-4-Me	8.70	5.0605	0.75	0.1905	3.4314

Table II.  Structure, biological activity and physicochemical descriptors of series 2 .

S.No	R	BA (μM)	− logBA	chi1v_C	b_double	E_sol	PMI − Z	logP (o/w)
1	(E)-CH = CHCO2H	1.5	5.8239	2.0267	3	− 15.3085	1328.947	1.04
2	(E)-CH = CHCONHMe	1.28	5.8928	2.0267	3	− 15.1895	1889.878	0.662
3	E)-CH = CHCO(1-morpholino)	2.1	5.6778	3.0267	3	− 15.4765	361.3822	0.425
4	(E)-CH = CHCONHCH2Ph	0.77	6.1135	4.2909	3	− 12.4917	1392.558	2.45
5	(E)-CH = CHCON(Me)CH2Ph	2	5.6990	4.2909	3	− 6.5011	2556.398	2.647
6	CH2CH2CO2H	9.31	5.0311	2.3231	2	− 14.8113	638.4941	0.572
7	OCH2CO2H	90.2	4.0448	1.4696	2	− 13.5755	609.7509	0.18
8	OCH2CONHCH2Ph	16.1	4.7932	3.7338	2	− 9.0434	353.2897	1.59
9	OCH2CH2OCH3	16.4	4.7852	1.6160	1	− 11.0577	1442.224	0.345
10	C6H5	166.3	3.7791	3.2767	1	− 9.12613	939.6092	2.679
11	OC6H5	2.13	5.6716	3.0267	1	− 12.9468	484.1166	2.329
12	OCH2C6H5	0.92	6.0362	3.3803	1	− 13.5082	2463.676	2.463
13	C = CC6H5	0.77	6.1135	3.7767	1	− 14.6776	1390.561	3.425
14	(E)-CH = CHC6H5	0.55	6.2596	3.9374	2	− 13.2539	1335.126	3.323
15	(E)-CH = CHC6H11	0.73	6.1367	4.8879	2	− 10.8807	118.8222	3.338
16	(E)-CH = CH(2-pyridinyl)	1.6	5.7959	3.3154	2	− 13.3939	1285.165	2.052
17	(E)-CH = CH(4-C6H4OMe)	0.69	6.1611	3.8481	2	− 12.8072	1330.748	3.279
18	E)-CH = CH[(3,4-OCH2O)C6H4]	0.49	6.3098	3.7647	2	− 14.2263	2392.332	3.028
19	(E)-CH = CH(3-C6H4CO2H)	0.17	6.7695	4.0981	3	− 14.1573	2820.975	3.037

Table III.  Correlation matrix for series 1.

	− log BA	petitjeanSC	b_1rotR	KierFlex
− log BA	1.00	− 0.77	− 0.70	0.75
PetitjeanSC	− 0.77	1.00	0.38	− 0.59
b_1rotR	− 0.70	0.38	1.00	− 0.30
KierFlex	0.75	− 0.59	− 0.30	1.00

Figure 1.  Experimental vs predicted activity of model 1.

Table IV.  Correlation matrix for series 2.

	− logBA	chi1v_C	B_double	E_sol	PMI − Z	logP(o/w)
− logBA	1.00	0.55	0.36	− 0.37	0.48	0.54
chi1v_C	0.55	1.00	0.10	0.37	0.17	0.86
b_double	0.36	0.10	1.00	− 0.15	0.20	− 0.19
E_sol	− 0.37	0.37	− 0.15	1.00	− 0.02	0.24
PMI − Z	0.48	0.17	0.20	− 0.02	1.00	0.31
logP(o/w)	0.54	0.86	− 0.19	0.24	0.31	1.00

Table V.  Variance inflation factor (VIF) value of descriptors in QSAR models.

Model No	Parameters	VIF
Model 1	PetitjeanSC	1.66
	b1rotR	1.17
	KierFlex	1.56
Model 2	chi1v_C	1.22
	E_sol	1.18
	PMI − Z	1.03
Model 3	b_double	1.03
	E_sol	1.04
	logP(o/w)	1.07

Table VI.  Predicted activity values of selected models.

	Series 1		Series 2
S. No	− logBA	Predicted activity of Model 1	− logBA	Predicted activity of Model 2	Predicted activity of Model 3
1	4.5302	4.2920	5.8239	5.3329	5.8936
2	4.4237	4.1166	5.8928	5.4878	5.6459
3	4.0767	4.1781	5.6778	5.6856	5.6233
4	4.4908	4.6426	6.1135	6.2420	6.1681
5	3.7619	4.2339	5.6989	5.5741	5.4028
6	5.1487	5.2213	5.0310	5.3285	5.4378
7	4.2733	4.3869	4.0448	4.8388	NA*
8	3.8327	3.9713	4.7932	5.1826	5.2746
9	4.2076	3.7601	4.7852	4.4258	4.3739
10	5.0000	5.0184	3.7791	NA*	NA*
11	5.5044	5.1105	5.6716	5.2796	5.6009
12	5.2620	5.2925	6.0362	6.2613	5.6597
13	5.3160	5.5237	6.1135	6.3142	6.3304
14	5.5376	5.4399	6.2596	6.1225	6.3503
15	4.3904	4.5799	6.1367	5.7474	6.0719
16	5.0605	5.1003	5.7959	5.8036	5.8212
17			6.1611	6.0032	6.2858
18			6.3098	6.5722	6.3229
19			6.7695	6.8517	6.5341

*Outlier compounds

Figure 2.  Experimental vs predicted activity of model 2.

Figure 3.  Experimental vs predicted activity of model 3.