Iron(III) Complexes with Non-Steroidal Anti-Inflammatory Drugs: Structure, Antioxidant and Anticholinergic Activity, and Interaction with Biomolecules

Abstract

One the main research goals of bioinorganic chemists is the synthesis of novel coordination compounds possessing biological potency. Within this context, three novel iron(III) complexes with the non-steroidal anti-inflammatory drugs diflunisal and diclofenac in the presence or absence of the nitrogen donors 1,10-phenanthroline or pyridine were isolated and characterized by diverse techniques. The complexes were evaluated for their ability to scavenge in vitro free radicals such as hydroxyl, 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals, revealing their selective potency towards hydroxyl radicals. The in vitro inhibitory activity of the complexes towards the enzymes acetylcholinesterase and butyrylcholinesterase was evaluated, and their potential to achieve neuroprotection appeared promising. The interaction of the complexes with calf-thymus DNA was examined in vitro, revealing their ability to intercalate in-between DNA nucleobases. The affinity of the complexes for serum albumins was evaluated in vitro and revealed their tight and reversible binding.

Keywords: anticholinergic activity; antioxidant activity; interaction with DNA; interaction with albumins; iron(III) complexes; non-steroidal anti-inflammatory drugs.

Figure 1

Syntax formula of (A) sodium diclofenac (Nadicl), (B) diflunisal (H₂difl), (C) 1,10-phenanthroline (phen), and (D) pyridine (py).

Figure 2

Molecular structure of complex 1. Aromatic and methyl hydrogen atoms and water solvate molecules are omitted for clarity. Symmetry: (′) −x + 1, −y + 1, −z + 1. (Atom color code: C in grey; O in red; N in blue; Fe in orange; F in light blue-green).

Figure 3

(A) Molecular structure of the cationic complex [Fe₃O(μ₂-dicl-O,O′)₆(py)₃]⁺. Aromatic hydrogen atoms, counter anions, and solvate molecules are omitted for clarity. (B) The core structure of complex [Fe₃O(μ₂-dicl-O,O′)₆(py)₃]⁺. (Atom color code: C in grey; H in white; O in red’ N in blue; Fe in orange; Cl in light green).

Figure 4

(A) The molecular structure of complex [Fe₃O(μ₂-dicl-O,O′)₆(ΜeOH)₃][FeCl₄]. Aromatic and methyl hydrogen atoms as well as diclofenac acid and methanol and water solvate molecules are omitted for clarity. (B) The core structure of the cationic complex [Fe₃O(μ₂-dicl-O,O′)₆(MeOH)₃]⁺. (Atom color code: C in grey; H in white; O in red; N in blue; Fe in orange; Cl in light green).

Figure 5

Mössbauer spectra from powder samples of 1 and 2 at 80 K. The black solid lines are theoretical simulations obtained with the parameters listed in Table 4.

Figure 6

X-band EPR spectrum from a powder sample of 2 at 4.2 K. EPR conditions: modulation amplitude, 10 G_pp, microwave power, 2 mW; microwave frequency, 9.42 GHz.

Figure 7

(A) Plot of % relative BSA fluorescence emission intensity (I/Io, %) at λ_em,max = 343 nm versus r (= [complex]/[BSA]) for complexes 1–3 (up to 24.4% of the initial BSA fluorescence for 1, 7.5% for 2, and 2.4% for 3). (B) Plot of % relative HSA fluorescence emission intensity (I/Io %) at λ_em,max = 351 nm versus r (=[complex]/[HSA]) for complexes 1–3 (up to 18.3% of the initial HSA fluorescence for 1, 0.6% for 2, and 3.5% for 3).

Figure 8

Relative viscosity of CT DNA (η/η_ο)^1/3 in buffer solution (150-mM NaCl and 15-mM trisodium citrate at pH 7.0) in the presence of complexes 1–3 at increasing amounts (r = [complex]/[DNA]).

Figure 9

(A) Fluorescence emission spectra (λ_ex = 540 nm) of EB–DNA ([EB] = 20 μM, [DNA] = 26 μM) in buffer solution (150-mM NaCl and 15-mM trisodium citrate at pH7.0) in the absence and presence of increasing amounts of complex 3 (different colors). The arrow shows the changes in intensity upon increasing amounts of 3. (B) Plot of relative EB–DNA fluorescence intensity (I/Io, %) at λ_em = 592 nm versus r (r = [complex]/[DNA]) in the presence of complexes 1–3 (up to 33.2% of the initial EB–DNA fluorescence for 1, 41.8% for 2, and 25.7% for 3).