Nickel(II)-meclofenamate complexes: Structure, in vitro and in silico DNA- and albumin-binding studies, antioxidant and anticholinergic activity.

Five novel nickel(II) complexes with the non-steroidal anti-inflammatory drug sodium meclofenamate (Na-mclf) have been synthesized and characterized in the absence or co-existence of the nitrogen-donors imidazole (Himi), 2,2'-bipyridylamine (bipyam), 2,2'-bipyridylketoxime (Hpko) and 2,9-dimethyl-1,10-phenanthroline (neoc); namely [Ni(mclf-O)2(Himi)2(MeOH)2], [Ni(mclf-O)2(MeOH)4], [Ni(mclf-O)(mclf-O,O')(bipyam)(MeOH)]·0.25MeOH, [Ni(mclf-O,O')2(neoc)] and [Ni(mclf-O)2(Hpko-N,N')2]·MeOH·0.5H2O. The affinity of the complexes for calf-thymus (CT) DNA was investigated by various techniques and intercalation is suggested as the most possible interaction mode. The interaction of the complexes for bovine and human serum albumins was also investigated in order to determine the binding constants, concluding that the complexes bind reversibly to albumins for the transportation towards their target cells or tissues and their release upon arrival at biotargets. The antioxidant activity of the compounds was evaluated via their ability to scavenge 1,1-diphenyl-picrylhydrazyl and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) free radicals and to reduce H2O2. For the determination of the anticholinergic ability of the complexes the in vitro inhibitory activity against the enzymes acetylcholinesterase and butyrylcholinesterase was evaluated and presented promising results. The in silico molecular modeling calculations employed provide useful insights for the understanding of the mechanism of action of the studied complexes at a molecular level. This applies on both the impairment of DNA by its binding with the studied complexes and transportation through serum albumins, as well as the ability of these compounds to act as anticholinergic agents.

Copper(II) complexes with meclofenamate ligands: Structure, interaction with DNA and albumins, antioxidant and anticholinergic activity.

The interaction of copper(II) with the non-steroidal anti-inflammatory drug sodium meclofenamate (Na-mclf) in the presence or absence of the nitrogen-donor co-ligands pyridine (py) or 2,2'-bipyridylamine (bipyam), yielded the novel Cu(II) complexes [Cu2(mclf-O,O')4(MeOH)2]·2MeOH (1·2MeOH), [Cu(mclf-O)2(py)3]·H2O·0.5MeOH (2·H2O·0.5MeOH) and [Cu(mclf-O,O')2(bipyam)] (3). The characterization of the complexes was achieved by various techniques, including single-crystal X-ray crystallography. In order to study the binding mode and strength of the complexes to calf-thymus (CT) DNA, various techniques were employed which suggested intercalation between the DNA-bases as the most possible interaction mode. Competitive studies with ethidium bromide (EB) revealed the ability of the complexes to displace the EB from the EB-DNA adduct, verifying the intercalative binding mode. The affinity of the complexes to bovine and human serum albumin proteins (SAs) was investigated by fluorescence emission spectroscopy and the corresponding binding constants bear relatively high values, showing that the complexes bind tightly and possibly reversibly to SAs. The antioxidant activity of the complexes against 1,1-diphenyl-picrylhydrazyl (DPPH), 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals and the ability to reduce H2O2 proved to be of significant magnitude. The in vitro inhibitory activity against the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was evaluated, in order to assess the anticholinergic ability of the complexes, which appeared promising.

In vitro antibacterial activity of meclofenamate metal complexes with Cd(II), Pb(II), Co(II), and Cu(II). Crystal structures of [Cd(C14H10NO2Cl2)2∙(CH3OH)]n and [Cu(C14H10NO2Cl2)2(C5H5N)2].

The synthesis and characterization of five metal complexes derived from sodium meclofenamate (1) are reported: [Cd(C14H10NO2Cl2)2∙(CH3OH)]n∙nCH3OH (6), [Pb(C14H10NO2Cl2)2]n (7), [Co(C14H10NO2Cl2)]n (8), [Cu(C14H10NO2Cl2)]n (9), and [Cu(C14H10NO2Cl2)2(C5H5N)2] (10) (C14H10NO2Cl2=meclofenamate; C5H5N=pyridine). The characterization of the compounds was based on FTIR and UV-visible spectroscopy, mass spectrometry and, in the case of complexes 6 and 10, single crystal X-ray diffraction analysis. For compound 6, the structural analysis revealed a 1-D polymeric chain structure, in which pentagonal planar [Cd(RCOO)2(CH3OH)] units were linked through bridging carboxylate functions of the meclofenamate ligands. The overall coordination environment of the Cd(II) ions was seven-coordinate, since each carboxylate group exhibited a µ3-bridging coordination mode. On the other hand, for complex 10 a discrete mononuclear structure was observed, in which the six-coordinate copper(II) metal atoms were coordinated by two pyridine molecules and the carboxylate functions of two meclofenamate entities, in an anisobidentate coordination mode. The antibacterial activity of compounds 6-9 against four strains of Gram positive (Staphylococcus aureus and Bacillus subtilis) and Gram negative (Escherichia coli and Pseudomonas aeruginosa) bacteria was examined, finding that only complex 6 was active. Additionally, it was found that the Co(II) and Cu(II) complexes 8 and 9 showed peroxidase activity.

Synthesis, crystal structures and spectroscopy of meclofenamic acid and its metal complexes with manganese(II), copper(II), zinc(II) and cadmium(II). Antiproliferative and superoxide dismutase activity.

Some new complexes of meclofenamic acid (N-(2,6-dichloro-m-tolyl)anthranilic acid), Hmeclo (1), with potentially interesting biological activities are described. Complexes [Mn(meclo)(2)] (2), [Cu(meclo)(2)(H(2)O)(2)] (3), [Zn(meclo)(2)(H(2)O)(2)] (4) and [Cd(meclo)(2)(H(2)O)(2)] (5) were prepared and structurally characterized by means of vibrational, electronic and (1)H and (13)C NMR spectroscopies. The crystal structure of complexes [Cu(4)(meclo)(6)(OH)(2)(DMSO)(2)]2DMSO (3a) and [Cd(meclo)(2)(DMSO)(3)] (5a) have been determined by X-ray crystallography. Complex (3a) is a centrosymmetric tetramer built up around the planar cyclic Cu(2)(OH)(2) unit. Complex 5a is mononuclear seven-coordinated complex with the meclofenamato ligand behaving as a bidentate deprotonated chelating ligand. Intra and intermolecular hydrogen bonds stabilize these two structures, while the crystal packing is determined by π-π and C-H--π interactions. Meclofenamic acid and its metal complexes have been evaluated for antiproliferative activity in vitro against the cells of three human cancer cell lines, MCF-7 (breast cancer cell line), T24 (bladder cancer cell line), and A-549 (non-small cell lung carcinoma), and a mouse fibroblast L-929 cell line. Complex 5 exhibits the highest selectivity against MCF-7 and 4 shows the highest selectivity against T-24. Complexes 2-5 were found to be more potent cytotoxic agents against T-24 and complex 5 against MCF-7 cancer cell lines than the prevalent benchmark metallodrug, cis-platin. The superoxide dismutase activity was measured by the Fridovich test which showed that complex [Cu(meclo)(2)(H(2)O)(2)] is a good superoxide scavenger.

QSAR analysis of meclofenamic acid analogues as selective COX-2 inhibitors.

The use of quantitative structure-activity relationships, since its advent, has become increasingly helpful in understanding many aspects of biochemical interactions in drug research. This approach was utilized to explain the relationship of structure with biological activity of selective COX-2 inhibitors. The enormity of the COX-2 discovery is reflected in the unprecedented speed at which research laboratories have sought to validate its clinical implications. Presented herein is a series of 21 derivatives of meclofenamic acid with selective COX-2 inhibitory activity. Several statistically significant regression expressions were obtained for both COX-1 and COX-2 inhibition using sequential multiple linear regression analysis method. Two of these models were selected and validated further, which revealed the importance of Kier molecular flexibility index for COX-2 inhibitory activity and the number of hydrogen bond donor atoms for COX-1 inhibitory activity. Additionally, linear correlation of molecular flexibility with COX-1 and COX-2 inhibitory activities revealed that flexibility of molecules at COX-2 active site can improve the selectivity of COX-2 inhibitors.

Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors.

This paper describes SAR studies involved in the transformation of the NSAID meclofenamic acid into potent and selective cyclooxygenase-2 (COX-2) inhibitors via neutralization of the carboxylate moiety in this nonselective COX inhibitor.

Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors.

All nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) isozymes to different extents, which accounts for their anti-inflammatory and analgesic activities and their gastrointestinal side effects. We have exploited biochemical differences between the two COX enzymes to identify a strategy for converting carboxylate-containing NSAIDs into selective COX-2 inhibitors. Derivatization of the carboxylate moiety in moderately selective COX-1 inhibitors, such as 5,8,11,14-eicosatetraynoic acid (ETYA) and arylacetic and fenamic acid NSAIDs, exemplified by indomethacin and meclofenamic acid, respectively, generated potent and selective COX-2 inhibitors. In the indomethacin series, esters and primary and secondary amides are superior to tertiary amides as selective inhibitors. Only the amide derivatives of ETYA and meclofenamic acid inhibit COX-2; the esters are either inactive or nonselective. Inhibition kinetics reveal that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Site-directed mutagenesis of murine COX-2 indicates that the molecular basis for selectivity differs from the parent NSAIDs and from diarylheterocycles. Selectivity arises from novel interactions at the opening and at the apex of the substrate-binding site. Lead compounds in the present study are potent inhibitors of COX-2 activity in cultured inflammatory cells. Furthermore, indomethacin amides are orally active, nonulcerogenic, anti-inflammatory agents in an in vivo model of acute inflammation. Expansion of this approach can be envisioned for the modification of all carboxylic acid-containing NSAIDs into selective COX-2 inhibitors.