Manganese-mefenamic acid complexes exhibit high lipoxygenase inhibitory activity

Abstract

The coordination of non-steroidal anti-inflammatory drugs (NSAIDs) to metal ions could improve the pharmaceutical efficacy of NSAIDs due to the unique characteristics of metal complexes. However, the structures of many metal-NSAID complexes are not well characterized; the functional mechanism and pharmaceutical effect of these complexes thus are not fully understood. In this work, three manganese-mefenamic acid (Mn-mef) complexes were synthesized and structurally characterized, and their pharmaceutical effect was investigated. We found that the three Mn-mef complexes exhibit higher lipoxygenase (LOX-1) inhibitory activity (IC50 values are 16.79, 38.63 and 28.06 μM, respectively) than the parent ligand mefenamic acid (78.67 μM). More importantly, the high inhibitory activity of the Mn-mef complexes is closely related to their spatial arrangements, which determine their interaction with LOX-1. Computer docking of the Mn-mef complexes with the LOX-1 confirms the experimental results: smaller Mn-mef complexes tend to bind competitively to LOX-1 at the substrate binding site, which is also analogous to the binding of the ligand mefenamic acid, while the bulky metal complexes inhibit the enzyme activity un-competitively. In addition, the Mn-mef complexes exhibit higher anti-oxidant activity than the ligand mefenamic acid. The higher anti-oxidant activity of the Mn-mef complexes apparently originated from the manganese centre of the complexes. We thus conclude that Mn-mef complexes enhance the anti-inflammatory activity of mefenamic acid by increasing their activity via changing their interaction mode with the enzymes, and/or by improving their anti-oxidant ability using metal ions. This work provides experimental evidence that with the unique spatial arrangements, metal-NSAID complexes could interact with the target enzymes more specifically and efficiently, which is superior to their parent NSAID ligand.

Synthesis, Spectroscopic, and Thermal Investigations of Metal Complexes with Mefenamic Acid

“…In particular, divalent metal complexes with several NSAID are better anti-inflammatory candidates then NSAIDs, because they have unique structures that could interact with the target enzymes more specifically. In addition, metal ions introduce extra antioxidant activity [13] and antiproliferative activity against cancer [14][15][16]. Furthermore gastrointestinal toxicities associated with the administration of complexes are much lower than those of the parent drug and improved safety of these drugs [17].…”

Non‐Steroidal Anti‐Inflammatory Drugs (NSAIDs) in Metal Complexes and Their Effect at the Cellular Level

“…[11,15] The complex of fenoprofen (fen) of formula [Cu 2 (fen) 4 (DMF) 2 ] (10, Scheme 12) was tested in vivo for anti-inflammatory properties in comparison with fenoprofen. [18] Compounds with ketoprofen of the general formula [M(ket) 3 ] {M = Gd (15), Tb (16), Dy (17), Ho (18), Er (19), Tm (20), Yb (21), Lu (22), Y (23), Scheme 13} were evaluated for their antiinflammatory activities. Oral administration of the compound inhibited the development of carrageenaninduced edema in mice.…”

“…A kinetic study of the catecholase mimetic activity was carried out spectrophotometrically, showing that the complex presents catechol oxidase mimetic activity. [22] Rare-earth complexes of naproxen (nap) with formula M(nap) 3 , where M = Ce (38), Dy (39), Er (40), Eu (41), Ho (42), La (43), Nd (44), Pr (45), Sm (46), Tb (47), Yb (48), and Y (49), were prepared. The stability of the complexes in solution was confirmed by UV/Vis spectroscopy.…”

Novel mefenamic acid PVC membrane sensor based on a new Cd Schiff's base complex containing a phenanthroline unit

“…Recently, structures of various metales mefenamato complexes have been reported. [67][68][69] As shown clearly in Fig. 2, demonstrates the suggested the coordination scheme of mefenamat with centre in Cd-Schiff base ionophore (Scheme 3).…”