Antiinflammatory and antioxidant evaluation of novel coumarin derivatives

Figures & data

Table I.  Lipophilicity values: Theoretically calculated C log P^a; Inhibition % of induced carrageenin rat paw edema CPE (%)^b; [14] In vitro Lipid Peroxidation (LP %); % scavenging activity on superoxide radicals (PMS%).

Compounds		C log P [28]	CPE (%)^b	LP (%)		PMS (%)
				0.1 mM	1 mM (IC50 LP mM)	0.1 mM	1 mM
1		1.13	55.1*	no	nt	no	50.1
2		1.13	29.3*	no	6.0	38.1	100
3		1.62	58.6**	no	5.0	55.9	100
4		1.51	31.1*	2.4		53.6	100
5		2.91	35.2*	9.8	no	82.1	97.2
6		0.39	54.0**^c	no	5.2	96.4	100
7		1.00	54.7*	12.2	60.9 (0.8)	80.9	100
8		2.12	42.5**	no	29.3	89.3	100
9		− 0.41	18.0*	14.6	51.1 (0.975)	80.1	91.8
Coumarin			30.2**	9.1	19.2	nt	88.9
Warfarin			41.0*	no	no	nt	25
7-hydroxy-coumarin				14.6	26.1	nt	80.6
Indomethacin			47.0**
Trolox				nt	20.3
Caffeic Acid				17.1	21.9	no	36.1
NDGA				no	26.1	89.3	100

no: no action shown under the experimental conditions; nt: not tested. ^aTheoretically calculated C log P values. ^bEach value represents the mean of two independent experiments with 5 animals in each group, statistical studies were done with student's T-test, *p < 0.01, **p < 0.05; The dose was 0.01 mmoles/kg body weight. ^c%CPE at 0.005 mmol/kg 55.1%; Percent inhibition is based on absorbance values of samples with the tested compounds: Standard deviation of absorbance values was less than ± 10%.

Table II.  In vitro inhibition of cyclooxygenase (COX%) and in vivo inhibition of yeast-induced paw edema (YPE %)^a.

Compounds	COX-1%	YPE%^a
	1 mM	1 mM
3	78.9	44.3**
Indomethacin	57.8	23.0*

^a Each value represents the mean of two independent experiments with 5 animals in each group, statistical studies were done with student's T-test, *p < 0.01, **p < 0.05; Percent inhibition is based on absorbance values of samples with the tested compounds: Standard deviation of absorbance values was less than ± 10%.

Table IIIa.  Effect of compounds 7-hydroxy-coumarin, 3, 5, 6 on the onset (day of appearance after Adjuvant's injection, FA) and severity of arthritis (arthritic scores) in Adjuvant Induced Disease (AID) rats.

Days after FA's injection	AID rats treated with 7-hydroxy-coumarin*	AID rats treated with compound 3*	AID rats treated with compound 5*	AID rats treated with compound 6*	AID rats controls *
0	0	0	0	0	0
2	0	0	0	0	0
4	0	0	0	0	0
6	0	0	0	0	0
8	0	0	0	0	0
10	0	0	0	0	0
12	0	0	0	0	0
14	0	0	0	0	6.6
16	1.2	0	1	1.25	8.1
18	1.8	0	1.25	1.75	11.8
20	2.6	0	2.25	3.25	14.0
22	5.2	0	3.5	4.5	10.8
24	4	0	3	2.5	8.8

*Number of arthritic scores (SD less than 10%); phenylbutazone 80 mg/kg p.o gave arthritic score of 0.3 on the 24^th day.

Table IIIb.  Assessment of the preventive action of 7-hydroxy-coumarin and of compounds 3, 5 and 6, on the Adjuvant Induced Disease (AID) manifestations (body weight change, inflammation-arthritic score, zoxazolamine paralysis).

Examined parameters (mean ± SD)	AID rats treated with 7-hydroxy-coumarin	AID rats treated with 3	AID rats treated with 5	AID rats treated with 6	AID rats-controls treated only with the liquid vehicle	Absolute-controls, normal animals, treated with the liquid vehicle only
Percent change of body weight (g ± SD)	18.6 ± 8.4^ns	8.6 ± 4.1**	11.9 ± 1.5***	9.6 ± 5.6*	− 14.8 ± 4.5**	18 ± 4.4
Inflammation-(arthritic scores)^#	4	0	3	2.5	8.80	no
Zoxazolamine paralysis (minutes ± SD)	232.5 ± 1.4***	176.6 ± 10.4**	132.5 ± 8.8**	233.3 ± 19**	347.0 ± 4.95**	218 ± 15.5

# Counted on the 24^th day after FA injection; statistical studies were done with student's T-test, comparison of the AID treated with the AID- rats controls and comparison of the AID-rats controls with the normal rats *p < 0.1, ***p < 0.01, **p < 0.05, ns non significant.

Table IVa.  Therapeutic effect of compound 3 on the onset (day of appearance after Adjuvant's injection, FA) and severity of arthritis (arthritic scores) in Adjuvant Induced Disease (AID) rats. Rats were treated with compound 3 after the appearance of arthritis.

Days after FA's injection	AID rats treated with compound 3*	AID rats controls *
14	0.6	6.6
16	2.8	8.1
18	2.4	11.8
20	3.4	14.0
22	3.4	10.8
24	3.4	8.8

*Number of arthritic scores (SD less than 10%); phenylbutazone 80 mg/kg p.o gave an arthritic score of 0.3 on the 24^th day.

Table IVb.  Assessment of the therapeutic action of compound 3 on the Adjuvant Induced Disease (AID) manifestations (body weight change, inflammation-arthritic score, zoxazolamine paralysis). Rats were treated with compound 3 after the 14^th day, when arthritis had appeared.

Examined parameters (mean ± SD)	AID rats treated with 3	AID rats-controls treated only with the liquid vehicle	Absolute-controls, normal animals, treated with the liquid vehicle only
Percent change of body weight (g ± SD)	− 0.94 ± 1.2	− 14.8 ± 4.5	18 ± 4.4
Inflammation-(arthritic scores)^#	3.4	8.80	no
Zoxazolamine paralysis (minutes ± SD)	233 ± 37	347.0 ± 4.95	311.5 ± 33.5

# Counted on the 24^th day after FA injection; Figs. in parentheses denote score for controls. no:no action under the experimental conditions.

Kontogiorgis CA, Hadjipavlou-Litina D. Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage. Bioorg Med Chem Lett 2004; 14: 611–614

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