Quantitative structure-activity relationship study of benzylsulfanyl imidazoles as cytokine release inhibitors

Figures & data

Figure 1 Structures of 2,4,5-trisubstituted imidazole derivatives.

Figure 2 Plot of observed versus calculated –log IC₅₀(TNF-α) values.

Table I.  The cytokine release inhibitory activity of 2,4,5-trisubstituted imidazole derivatives (see Figure 1 for structure).

				− log IC50 (M)
				TNF-α				IL-Iβ
					Calcd				Calcd
S. No.	X	Y	R	Obsd^a	Eq(1)	F. B.	Prdctd	Obsd^a	Eq(2)	F. B.	Prdctd
1	F	SCH2	H	5.40	5.21	5.35	5.19	6.52	6.45	6.46	6.44
2	F	SCH2	4-SCH3	5.31	5.21	5.33	5.20	6.17	6.25	5.90	6.27
3	F	SCH2	4-SOCH3	5.82	5.64	5.81	5.61	6.60	6.94	6.79	7.00
4	F	SCH2	4-SO2CH3	5.60	5.64	5.64	5.65	6.64	6.96	6.72	7.02
5	F	SCH2	3-SCH3	5.12	5.31	5.12	5.34	6.26	6.24	6.38	6.24
6	F	SCH2	3-SOCH3	4.77	4.97	4.77	5.04	5.85	5.75	5.80	5.72
7	F	SCH2	2-SCH3	4.74^b	4.78	–	4.82	5.64^b	5.81	–	5.97
8	F	SCH2	2-SOCH3	4.82^b	4.78	–	4.74	6.00^b	5.81	–	5.64
9	Cl	SCH2	4-SCH3	4.85	4.80	4.88	4.79	5.59	5.52	5.62	5.50
10	Cl	SCH2	4-SOCH3	5.37	5.23	5.36	5.21	6.59	6.21	6.51	6.16
11	Cl	SCH2	4-SO2CH3	5.21	5.23	5.19	5.23	6.41	6.22	6.44	6.20
12	Br	SCH2	4-SCH3	4.89	4.80	4.78	4.78	5.52	5.59	5.39	5.61
13	Br	SCH2	4-SOCH3	5.11	5.23	5.26	5.25	6.15	6.28	6.28	6.30
14	Br	SCH2	4-SO2CH3	5.14	5.23	5.09	5.25	6.19	6.30	6.21	6.31
15	H	SCH2	4-SCH3	4.77	4.80	4.82	4.81	4.40	4.94	4.77	5.25
16	H	SCH2	4-SOCH3	5.37	5.23	5.29	5.21	5.89	5.63	5.65	5.54
17	H	SCH2	4-SO2CH3	5.10	5.23	5.12	5.25	5.72	5.64	5.59	5.62
18	F	SCH2	4-OH	5.17^c	–	–	–	6.43^c	–	6.49	–
19	F	SCH2	3-OH	5.27^b	5.11	–	5.09	6.51^b	6.28	–	6.27
20	F	SCH2	2-OH	4.61	4.73	4.61	4.79	6.36	6.36	6.36	6.36
21	F	SCH2	3-SCH3, 4-OH	5.85	5.73	5.75	5.70	6.55	6.46	6.41	6.45
22	F	SCH2	3-SOCH3, 4-OH	5.30	5.40	5.40	5.45	5.74	5.96	5.83	6.03
23	F	SCH2	3-SCH3, 6-OH	5.29	5.31	5.39	5.31	6.32	5.24	6.39	6.24
24	F	SCH2	3-SOCH3, 6-OH	5.14	4.97	5.04	4.92	5.89	5.75	5.81	5.71
25	F	SCH2	2-OH, 3-SCH3, 5-Cl	4.88	4.82	4.89	4.78	6.19	6.15	6.15	6.15
26	F	SCH2	2-OH, 3-SOCH3, 5-Cl	4.55	4.49	4.54	4.43	5.52	5.66	5.56	5.70
27	F	S(CH2)2	4-SOCH3	5.15	5.39	5.13	5.44	6.39	6.72	6.45	6.79
28	F	S(CH2)3	4-SOCH3	5.30	5.14	5.28	5.01	6.66	6.51	6.59	6.43
29	F	S(CH2)2	H	4.66	4.96	4.68	5.01	6.19	6.21	6.13	6.23
30	F	S(CH2)3	H	4.80	4.71	4.82	4.64	6.19	6.01	6.26	5.90
31	F	CH2CH2	H	5.27^b	5.25	–	5.25	6.82^b	6.73	–	6.70
32	F	CH = CH	H	5.24^b	5.32	–	5.34	6.89^b	6.76	–	6.71

^a Taken from Ref. 11

^b Compound ignored in Fujita-Ban (F.B.) study

^c ‘Outlier’ compound in present study.

Table II.  QSAR parameters of the substituents in various positions in 2,4,5- trisubstituted imidazoles.

Position	Substituent	Parameter
		RX	IX
X	H	0.00	0
	F	–0.34	1
	Cl	− 0.15	0
	Br	– 0.17	0
		VWY(10^− 2Å^3)	MWY
Y	SCH2	0.410	0.460
	S(CH2)2	0.564	0.600
	S(CH2)3	0.718	0.740
		MR(2)	HD(2)
2-R	H	0.103	0
	OH	0.285	1
		π(3)	σ (3)
3-R	H	0.00	0.00
	SCH3	0.61	0.15
	SOCH3	− 1.58	0.52
		π(4)	HA(4)
4-R	H	0.00	0
	OH	− 0.67	1
	SCH3	0.61	0
	SOCH3	− 1.58	1
	SO2CH3	− 1.63	1

Table III.  Fujita-Ban contributions of substituents and parent moiety to the cytokine inhibitory activities of the title compounds.

		Contribution to – log IC50 (M) for
Position	Substituent	TNF-α (n = 26)	IL-1β (n = 27)
Parent moiety	μ	5.352( ± 0.13)	6.462( ± 0.25)
X	H	− 0.517( ± 0.14)	− 1.137( ± 0.29)
	Br	− 0.549( ± 0.14)	− 0.515( ± 0.29)
	Cl	− 0.449( ± 0.14)	− 0.279( ± 0.29)
Y	S(CH2)2	− 0.673( ± 0.16)	− 0.335( ± 0.32)
	S(CH2)3	− 0.531( ± 0.16)	− 0.200( ± 0.32)
2-R	OH	− 0.746( ± 0.22)	− 0.105( ± 0.44)
3-R	SCH3	− 0.235( ± 0.19)	− 0.084( ± 0.32)
	SOCH3	− 0.580( ± 0.19)	− 0.666( ± 0.32)
4-R	OH	0.633( ± 0.17)	0.030( ± 0.29)
	SCH3	− 0.018( ± 0.16)	− 0.560( ± 0.32)
	SOCH3	0.455( ± 0.13)	0.328( ± 0.27)
	SO2CH3	0.290( ± 0.16)	0.261( ± 0.32)
5-R	Cl	0.516( ± 0.28)	− 0.126( ± 0.53)
6-R	OH	0.270( ± 0.17)	0.016( ± 0.35)

Table IV.  Intercorrelation matrix amongst independent variables of Equation(1).

	MR(2)	HD(2)	π(3)	HA(4)	IX	VWY
MR(2)	1.000	0.086	0.047	0.253	0.204	0.102
HD(2)		1.000	0.096	0.260	0.209	0.105
π(3)			1.000	0.087	0.156	0.078
HA(4)				1.000	0.367	0.109
IX					1.000	0.204
VWY						1.000

Table V.  Intercorrelation matrix amongst independent variables of Equation (2).

	RX	MR(2)	σ(3)	π(4)	MWY
RX	1.000	0.190	0.311	0.281	0.096
MR(2)		1.000	0.094	0.187	0.052
σ(3)			1.000	0.203	0.084
π(4)				1.000	0.190
MWY					1.000