HQSAR study of β-ketoacyl‐acyl carrier protein synthase III (FabH) inhibitors

Figures & data

Table I.  Diethyl sulfonamide and [3-phenoxybenzoylamino] benzoic acid derivatives as inhibitors of FabH.

	Structure
ID	R1	R2	R3	R4	PIC50
1	F	H		H	5.08
2*	Br	H		H	5.80
3	Ph	H		H	5.80
4*	Br	Me		H	3.80
5	OMe	H		H	4.94
6		H		H	5.66
7		H		H	5.21
8		H		H	5.68
9	H	H		H	5.57
10	F	H		H	5.42
11	Br	H		H	4.96
12		H		H	4.6
13		H		H	4.42
14		H		H	5.49
15		H		H	5.92
16		H		H	6.54
17		H		H	6.57
18		H		H	4.66
19		H		H	6.96
20		H		H	7.25
21	Br	H		OH	7.21

Table II.  Aromatic substitutions on the para position of [3-phenoxy-benzoylamino] benzoic acid derivatives as inhibitors of FabH.

		Structure
ID	R1	R2	PIC50
22	CF3	H	7.02
23	Me	H	6.80
24	CO2H	H	5.68
25	OH	H	6.39
26	OEt	H	6.66
27	SO2Me	H	7.55
28	OCF3	H	6.33
29*	iPr	H	6.10
30	3-Me–4-F	H	6.62
31	2,4-di-F	H	6.80
32	3,4-di-F	H	6.48
33	3-Me–4-Cl	H	6.60
34*	3-Cl–4-F	H	6.24
35	H	OH	8.40

Table III.  Ring A and C modified [3-Phenoxybenzoylamino] benzoic acid derivatives as inhibitors of FabH.

	Structure
ID	A	C	PIC50
36		Ph	5.00
37		Ph	4.37
38		Ph	5.22
39		Ph	6.39
40	Ph	4-Pyr	5.00
41	Ph	3-CO2H-Ph	5.43
42	Ph	4-CO2H-Ph	5.36
43	Ph	4-F-Ph	5.30

Table IV.  HQSAR analyses for various fragment distinctions using default fragment size (4–7); (LV_max=8).

Fragment distinction	q^2	SEcv	r^2	SEE	LV	Length
A/B	.678	.573	.920	.285	5	151
A/B/C	.621	.621	.932	.264	5	307
A/B/C/H	.493	.719	.793	.460	5	97
A/C/DA	.622	.611	.846	.390	4	71

Table V.  HQSAR analysis for the influence of various fragment sizes using the best fragment distinction (A/B).

Fragment size	q^2	SEcv	r^2	SEE	LV	Length
2–5	.674	.558	.932	.263	5	401
3–6	.677	.579	.915	.295	5	83
4–7	.679	.573	.938	.269	6	53
5–8	.588	.648	.916	.293	5	257
6–9	.621	.622	.922	.282	5	401
7–10	.645	.603	.923	.280	5	401

Table VI.  Experimental activities (_PIC₅₀) and predicted activities (PA) with residuals (Δ) by HQSAR.

		HQSAR
Compound	PIC50	PA	Δ
1	5.08	5.22	− 0.14
2*	5.80	5.61	0.19
3	5.80	5.85	− 0.05
4*	3.80	3.52	0.28
5	4.94	4.83	0.11
6	5.66	5.87	− 0.21
7	5.21	4.99	0.22
8	5.68	5.57	0.11
9	5.57	5.51	0.06
10	5.42	5.43	0.01
11*	4.96	5.16	− 0.20
12	4.60	4.47	0.13
13	4.42	4.32	0.10
14	5.49	5.86	− 0.37
15	5.92	5.94	− 0.02
16	6.54	6.23	0.31
17	6.57	6.85	− 0.28
18	4.66	4.68	− 0.02
19	6.96	6.33	0.63
20*	7.25	6.78	0.47
21	7.21	7.11	0.10
22	7.02	6.87	0.15
23	6.80	6.61	0.19
24	5.68	6.28	− 0.60
25	6.39	6.97	− 0.58
26	6.66	6.75	− 0.09
27	7.55	7.54	0.01
28	6.33	6.20	0.13
29*	6.10	6.93	− 0.83
30	6.62	6.63	− 0.01
31	6.80	6.87	− 0.07
32	6.48	6.60	− 0.12
33	6.60	6.74	− 0.14
34*	6.24	6.86	− 0.62
35	8.40	7.73	0.67
36	5.00	5.08	− 0.08
37	4.37	4.58	− .021
38	5.22	5.54	− 0.32
39	6.39	6.45	− 0.06
40	5.00	4.95	0.05
41	5.43	5.22	0.21
42	5.36	4.98	0.38
43	5.30	5.43	0.13

Figure 1 Correlation between the observed and the predicted activities (pIC₅₀).

Figure 2 Contribution map of compound 35 (see colour online).

Figure 3 Negative contribution of ring A ortho carbon of compound 12, 13 and 28 (see colour online).