CoMFA and CoMSIA 3D-QSAR analysis on hydroxamic acid derivatives as urease inhibitors

Figures & data

Table I.  Structure of the compounds 1–35 used for 3D-QSAR analyses.

R-CONHOH
Compound	R	pIC50
1	CH3–	6.22
2	C2H5–	6.25
3	C5H11–	6.34
4	C6H13–	6.51
5	C7H15–	6.51
6	C8H17–	6.40
7	C9H19–	6.26
8	C10H21–	6.08
9	C11H23–	5.77
10	C13H27–	5.04
11*	C15H31–	4.68
12	m-Cl-Ph–	6.37
13	m-NO2–Ph–	6.43
14*	m-CH3–Ph–	6.20
15	m-CH3O–Ph–	6.27
16*	m-C4H9O–Ph–	6.44
17	m-C6H13O–Ph–	6.15
18*	m-C8H17O–Ph–	6.44
19	Ph–	6.43
20	p-Cl–Ph–	6.52
21	p-NO2–Ph–	6.43
22	p-CH3–Ph–	5.96
23	p-OH–Ph–	6.37
24*	p-CH3O–Ph–	6.64
25	p-C4H9O–Ph–	5.74
26	p-C6H13O–Ph–	5.64
27	p-C8H17O–Ph–	5.68
28	Ph–CH2–	5.92
29	Ph–CH2–CH2–	6.70
30		4.96
31*		6.34
32		6.00
33		5.05
34*		5.92
35		5.07

* Test set compounds, pIC50 = − log IC₅₀.

Figure 1.  Structure of compound 29 used as a template on which all the compounds were superimposed using the atom-fit method; asterisks indicate the atoms selected for the fitting centers.

Figure 2.  Alignment of compounds used to create the 3D-QSAR models.

Table II.  summary Of Comfa And Comsia Results.

PLS statistics	CoMFA	CoMSIA
q^2	0.532	0.665
r^2	0.969	0.976
Standard Error of Estimate	0.117	0.103
F	103.996	135.69
Optimal component	06	06
Outlier	01	01
Field distribution (%)
Steric	70.0%	43.0%
Electrostatic	30.0%	26.4%
Hydrophobic	–	20.3%
Hydrogen donor	–	6.2%
Hydrogen acceptor	–	4.2%

Table III.  Actual and predicted inhibitory activities by CoMFA and CoMSIA analyses.

Compound	pIC50 activity	CoMFA prediction	CoMFA residual	CoMSIA prediction	CoMSIA residual
1	6.22	6.26	− 0.04	6.23	− 0.01
2	6.25	6.17	0.08	6.20	0.05
3	6.34	6.31	0.04	6.29	0.05
4	6.51	6.58	− 0.07	6.59	− 0.08
5	6.51	6.52	− 0.01	6.54	− 0.03
6	6.40	6.40	0.00	6.38	0.02
7	6.26	6.11	0.15	6.23	0.03
8	6.08	6.08	0.00	6.17	− 0.09
9	5.77	5.65	0.09	5.69	0.08
10	5.04	5.02	0.02	5.05	− 0.01
11*	4.68	5.04	− 0.36	5.04	− 0.36
12	6.37	6.43	− 0.06	6.38	− 0.01
13	6.43	6.33	0.10	6.41	0.02
14*	6.20	6.52	− 0.32	6.50	− 0.30
15	6.27	6.38	− 0.11	6.38	− 0.11
16*	6.44	6.41	0.03	6.35	0.09
17	6.15	6.11	0.04	6.12	0.03
18*	5.44	5.77	− 0.33	5.89	− 0.45
19	6.43	6.42	0.01	6.41	0.02
20	6.52	6.51	0.01	6.54	− 0.02
21	6.43	6.45	− 0.02	6.43	0.00
22	5.96	6.54	0.06	6.52	0.08
23	6.37	6.37	0.01	6.38	− 0.01
24*	6.64	6.34	0.30	6.42	0.22
25	5.74	5.71	0.03	5.81	− 0.07
26	5.64	5.38	0.26	5.34	0.30
27	4.68	4.94	− 0.26	4.92	− 0.23
28 outlier	5.92	5.51	0.41	4.90	1.02
29	6.70	6.82	− 0.11	6.75	− 0.04
30	4.96	5.12	− 0.16	4.93	0.03
31*	6.34	6.37	− 0.03	6.44	− 0.10
32	6.00	6.13	− 0.12	5.93	0.07
33	5.04	4.97	0.08	5.07	− 0.01
34*	5.92	6.13	− 0.21	6.14	− 0.22
35	5.07	5.09	− 0.02	5.12	− 0.05

Figure 3.  CoMFA contour plots for steric and electrostatic fields with compound 29 as a reference compound. Sterically favored areas are shown in green while the yellow isopleths depict sterically disfavored areas. Blue isopleths depict areas where positively charged groups increase activity and red areas indicate increase in the activity with negatively charged groups.

Figure 4.  CoMSIA contour plots for steric and electrostatic fields with compound 29 as a reference compound. Sterically favored areas are shown in green while the yellow isopleths depict sterically disfavored areas. Blue isopleths depict areas where positively charged groups increase activity and red areas indicate increase in the activity with negatively charged groups.

Figure 5.  CoMSIA contour plots for hydrophobic interaction with compound 29 as a reference compound. Yellow regions indicate area where hydrophobic groups increase activity, and white regions indicate area where hydrophobic groups decrease activity.

Figure 6.  The predicted activities versus experimental activities (pIC₅₀) derived from the CoMFA model of the training set.

Figure 7.  The predicted activities versus experimental activities (pIC₅₀) derived from the CoMSIA model of the training set.