Anti-oxidant, in vitro, in vivo anti-inflammatory activity and antiproliferative activity of mefenamic acid and its metal complexes with manganese(II), cobalt(II), nickel(II), copper(II) and zinc(II)

Figures & data

Figure 1.  The structure of Hmef^10a.

Figure 2.  The structure of [Cu(mef)₂(DMSO)]₂^10b.

Table I.  Spectral data (UV-vis) and μ_eff values for the prepared complexes and the parent drug.

		Solution (CHCl3)			Solution (DMF)
Compound	μeff	λ(nm)	v(cm^− 1)	log ε	λ(nm)	v(cm^− 1)	log ε	Assignments
Mefenamic acid		356	28,090	3,72	351	28,490	3,77	n → π*
		282	35,461	3,76	284	35,211	3,92	π → π*
[Mn(mef)2(H2O)2]	5.39	503sh	19,881	2,11	500sh	20,000	1,70	^6A1g → ^4T1g (G)
		430	23,255	2.45	370	27,027	3.34	^6A1g → ^4T2g (G)
		354	28,249	4,04	339	29,500	3,98	^6A1g → ^4T2g (D)
		283	35,336	4,13	292	34,246	4,27	π → π*
[Co(mef)2(H2O)2]	4.53	574	17,422	1,65	568	17,606	1,83	^4T1g → ^4A2g
		536	18,657	1,5	536	18,657	1,80	^4T1g → ^4T1g (P)
		355	28,169	3,97	340	29,412	4,00	n → π*
		283	35,336	4,03	291	34,364	4,28	π → π*
[Ni(mef)2(H2O)2]	3.88	749sh	13,550	0,77	742sh	13,369	0,81	^3A2g → ^3T1g
		680	14,706	0,88	680	14,706	0,85	^3A2g → ^1Eg
		378	26,455	2,36	400sh	25,000	2,99	^3A2g → ^3T1g (P)
		351	28,490	4,44	342	29,240	4,17	n → π*
		289	34,602	4,51	290	34,483	4,43	π → π*
[Cu(mef)2(H2O)]2	2.02	672	14.880	2.24	715	13,986	2,34	d-d
		445	22.470	2.56	400	25,000	2,88	d-d
		355	28,169	3,93	334	29,940	3,98	n → π*
		282	35,461	4,03	291	34,364	4,03	π → π*

Table II.  Interaction % with DPPH- Reducing ability (RA %).

Compounds	RA % 0.1 mM		RA % 0.5 mM
	20 min	60 min	20 min	60 min
Mefenamic	2.1	2.6	7.5	8.3
[Mn(mef)2(H2O)2]	44.0	69.9	59.7	69.9
[Co(mef)2(H2O)2]	8.0	10.2	9.1	10.1
[Ni(mef)2(H2O)2]	6.2	8.1	13.0	13.1
[Cu(mef)2(H2O)]2	18.4	25.8	40.1	52.7
[Zn(mef)2]	3.8	8.5	5.2	18.8
MnCl2	4.2	4.1	3.2	3.5
CoCl2	3.1	2.7	2.7	2.9
NiCl2·6H2O	3.1	6.1	5.1	4.9
CuCl2	4.6	5.6	4.9	5.8
ZnCl2	3.5	5.2	3.8	5.3
Ascorbic acid	99.5	99.9	94.5	93.9

Table III.  Competition % with DMSO (0.1 mM) for hydroxyl radical HO^·, inhibition of LOX and antiproteolytic activity of mefenamic acid and its metal complexes.

Compounds	Competition % with DMSO (0.1 mM)	Inhibition of LOX at 5 min (0.033 mM)	% Inhibition of Glucuronidase (0.1 mM)	% Inhibition of trypsin (0.3 mM)
Mefenamic acid	99.7	No	91.8	NA
[Mn(mef)2(H2O)2]	NA	94.7	NA	47.8
[Co(mef)2(H2O)2]	61	12.5	94.3	58.2
[Ni(mef)2(H2O)2]	67.7	39.4	78.3	34.4
[Cu(mef)2(H2O)]2	51.3	No	NA	31
[Zn(mef)2]	60.2	26.5	NA	23
MnCl2	NA	–	–	26
CoCl2	NA	–	–	27
NiCl2·6H2O	NA	–	–	75
CuCl2	NA	–	–	24
ZnCl2	NA	–	–	–
Salicylic acid			56.4	IC50 0.1 mM
trolox	88.2

NA, no activity.

Table IV.  The antiproliferative activity in vitro of mefenamic acid its metal complexes (expressed as IC₅₀ (M) against MCF-7, T-24, A-549 and L-929 cancer cell lines.

Compounds	MCF-7 IC50 (M) ± SD	T-24 IC50 (M) ± SD	A-549 IC50 (M) ± SD	L-929 IC50 (M) ± SD
Mefenamic acid	14.92* ± 3.1	8.12* ± 4.5	16.83* ± 2.3	17.82* ± 2.8
[Mn(mef)2(H2O)2]	7.26* ± 3.5	3.51* ± 1.0	< 17.56*	< 17.56*
[Co(mef)2(H2O)2]	9.36* ± 3.0	2.70* ± 1.7	11.59* ± 2.5	< 17.44*
[Ni(mef)2(H2O)2]	5.93* ± 2.3	2.40* ± 1.9	8.66* ± 3.5	6.34* ± 2.2
[Cu(mef)2(H2O)]2	2.51* ± 3.3	7.77** ± 2.2	< 10.03*	1.95* ± 3.0
[Zn(mef)2]	4.07* ± 5.0	3.77* ± 2.0	11.12* ± 3.0	7.44* ± 1.0
Cis Pt	8.00**	41.7**	1.53**	0.70**

* × 10^{− 5}; ** × 10^{− 6}. Each value represents the mean obtained from 3 measurements ( ± SD).

Table V.  Inhibition % of induced carrageenin rat paw edema (CPE %) at 0.1 mmol/kg.

Compounds	% CPE ± SD
Mefenamic acid	61.5** ± 2.3
[Co(mef)2(H2O)2]	71** ± 1.1
[Ni(mef)2(H2O)2]^a	17.5* ± 0.4
[Zn(mef)2]	81.5* ± 1.3

The effect on edema is expressed as percent of weight increase of hind paw (and as percent of inhibition of edema) in comparison to controls. Each value represents the mean obtained from 6 to 8 animals in two independent experiments ( ± SD). In all cases, significant difference from control: *p < 0.1 **p < 0.01 (Student's T test)

^a This compound has been tested at 0.01 mmol/kg.