Conformational analysis of the antiinflammatory fenamates: a molecular mechanics and semiempirical molecular orbital study

doi:10.1016/0166-1280(94)04003-B

Journal of Molecular Structure: THEOCHEM

Volume 335, Issues 1–3, 30 May 1995, Pages 215-227

https://doi.org/10.1016/0166-1280(94)04003-B Get rights and content

Abstract

The molecular structure and conformational properties of structurally related fenamates have been calculated by the molecular mechanics method and both AM1 and PM3 molecular orbital methods, and the results have been compared with crystal structure data. For the meclofenamic, mefenamic and flufenamic acids the two molecular orbital methods give values of the bridge torsion angles C2-C1-N1-C8 and C1-N1-C8-C9 in closest agreement with the crystal structure, and the molecular mechanics method yields values within about 20 ° of that found in the crystal structures. For niflumic acid the PM3 molecular orbital reproduced the X-ray crystallographic values. Meclofenamic acid is the only fenamate that adopts an almost perpendicular arrangement between the aromatic rings. This conformation causes difficulties for the conjugation of the amino group and the two aromatic rings simultaneously, localizing the HOMO in the phenyl ring bearing the carboxyl group and the nitrogen atom of the amino group. Global superimposition, based on the fitting of the common negative regions of the electrostatic potential, for all fenamates, yields good overlapping except an additional region of interaction around the bridging amino group and the second phenyl ring moiety for meclofenamic acid.

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However, this was challenged by X-ray data. [41,42]. However, the exact path way involved in the formation of these polymorphic forms is still a subject of intensive researches [43–47]. In our work, we show that the conformational features of MA in CO2 phase and in its polymorphic forms are interdependent.
In this paper we have studied the conformations of mefenamic acid molecules in its saturated solution in supercritical carbon dioxide being in contact with bottom phase containing different polymorphs of mefenamic acid under isochoric heating conditions in the temperature range of 80–220 °C. For this purpose, we used in situ IR and Raman spectroscopy as well as micro IR and micro Raman spectroscopy and quantum chemical calculations. We have found that there is a correlation between the polymorphic modifications of the crystalline form of mefenamic acid and its conformers in CO₂ fluid phase. The results of this work have shown that it is possible to monitor the polymorphic transformation of the crystalline phase of mefenamic acid by screening its molecular conformations in a fluid solution. This finding opens up the possibilities to manage the obtaining of certain polymorph of mefenamic acid with high purity degree from its fluid solution by means of variation of thermodynamic parameters of this solution.
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Mefenamic acid is classified as a NSAID due to its antiproliferative and antioxidant properties. These properties were found to be enhanced when coordinated with certain bivalent transition metals, and this enhancement makes the development of new drugs possible [4,5,12]. Antioxidant action is important for the restoration of homeostasis and for treating diseases originating from free radicals [3,13,14].
Lanthanide Mefenamate compounds were prepared in solid state. TG-DSC coupled to FTIR, elemental analysis, complexometry with EDTA, X-ray powder diffractometry, evaluation of scavenging free radical activity with DPPH (2,2-diphenyl-1-picryl-hydrazine), and a complete spectroscopic study in the ultraviolet, visible, near-, and middle-infrared regions were realized to obtain some physicochemical properties of the synthesized compounds. The thermal stability, minimum formula, thermal behavior and intermediate compounds were indicated by thermoanalytical results. Furthermore, vibrational spectroscopy data suggests that the complexes are binuclear and two modes of coordination are presented. The DR spectra could be reveal the presence of a large ligand-to-metal charge transfer band in the europium mefenamate. This compound also indicated the higher antioxidant activity with DPPH (77.03% at 200 μg L⁻¹).
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The crystal structure of fenamic acid-acridine complex is determined by X-ray diffraction. The strong OHN hydrogen bond linking the complex components and other interactions responsible for packing of the molecules into a crystal are investigated within the Quantum Theory of Atom in Molecule theory. The crystal structure is compared with the structure optimized at B3LYP/6-311++G** level and with the theoretical structures optimized under systematically changed pressure. Analysis of the lattice constants, hydrogen bond lengths, and angles of the inter- and intramolecular hydrogen bond under compression is performed. The structural transformation observed at 5 GPa is connected with a change in the intermolecular OHN hydrogen bond. The proton shifts to acceptor and a new interaction in the crystal appears.
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Mefenamic acid (2-[(2,3-dimethylphenyl)amino]benzoic acid) (H-Mef) is classified as a nonsteroidal anti-inflammatory drug (NSAID) which also displays antioxidant and antiproliferative activity in vitro against cells of three human cancer cell lines (human breast cancer cell line, bladder cancer cell line and non-small cell lung carcinoma) [4,11]. The therapeutic activity of NSAIDs is due to their ability to inhibit the biosynthesis of prostaglandins by competitive interaction with the cyclooxygenase-arachidonic acid complex in a reversible/irreversible manner (meclofenamic and indomethacin) or by radical quenching activity that interferes with the initiation of cyclooxygenase synthesis [4]. H-Mef has been found to exert neuroprotective effects and improve cognitive impairment in vitro and in vivo in Alzheimer’s disease models and also demonstrates neuroprotective activities against neurodegeneration [12].
Mefenamic acid (H-Mef) is a nonsteroidal anti-inflammatory drug (NSAID). Various adhesive dosage forms of NSAIDs have been developed, which include adhesive tablets, gels, ointments, patches and more recently, polymeric films. The objective of this study was the development of H-Mef adhesive films to be used as a drug-delivery system with different ratios of pectin and calcium chloride dihydrate by the casting technique. The materials were characterized by TG–DSC coupled FTIR, AFM (atomic force microscopy) and spectroscopic techniques. The results provided information about the dehydration, film roughness, surface morphology, thermal decomposition, as well as identification of gaseous products evolved during thermal decomposition. The characterizations indicated the A5 and A6 films functioned well, with 99% H-Mef released within 15 min at pH 5, suggesting these degradable films could be used as a topical delivery system.
Raman and IR spectroscopic studies of fenamates - Conformational differences in polymorphs of flufenamic acid, mefenamic acid and tolfenamic acid
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Inhibition of the COXs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs has been claimed to reduce the incidence of fatal thrombotic events, as well as the development of colon cancer [7] and Alzheimer’s disease [8]. Numerous individual analytical studies and quantitative methods have been documented, concerning various aspects of fenamates including important structural and physical properties [9–14]. Polymorphism is the ability of a compound, in the solid state, to exist in more than one crystalline form; such crystalline forms arise from a different arrangement of the molecules in a unit cell within a crystal lattice, and may involve conformational changes.
Solid-state Raman and IR spectra of two polymorphic forms of each of three fenamates (flufenamic acid, mefenamic acid and tolfenamic acid) display subtle but highly reproducible differences. Many of these spectral differences can be ascribed to different conformations of these molecules, involving two of four possible orientations of one substituted benzene ring with respect to the other. Interpretation of the vibrational spectra in terms of conformational differences has been facilitated by DFT calculations at the B3LYP/cc-pVDZ level for each conformer. The calculated spectra are compared with the experimental spectra in order to identify the conformers present in two polymorphic forms in each case, and detailed band assignments are obtained from the DFT calculations.
An experimental and theoretical vibrational spectroscopic study on niflumic acid, a non-steroidal anti-inflammatory drug
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The theoretically possible stable conformers of niflumic acid (NFA) molecule in electronic ground state were investigated by means of potential energy surface scan and thermochemistry calculations carried out at room temperature using DFT-B3LYP method and different Pople-style basis sets. The data obtained from these calculations confirmed that the two planar conformers in which the carboxyl and fluoromethyl functional groups are located either in “trans” or in “cis” position to each other are the most favorable ones in energy among all the stable conformers of the free molecule. This conclusion was also confirmed by the energy values obtained from the higher-accuracy thermochemistry calculations carried out using G3MP2B3 composite method. For both conformers and also for their most favorable dimer forms in energy, the equilibrium geometry, force field and vibrational spectral data were calculated first at B3LYP/6-31G(d) and then at B3LYP/6-311++G(d,p) levels of theory. On the basis of these theoretical data, the effects of the conformation and dimerization on the corresponding experimental data of NFA molecule were discussed in detail. The overestimations of the calculated harmonic wavenumbers were corrected by the aid of two different empirical scaling procedures referred to as “scaled quantum mechanical force field (SQM FF) methodology” and “dual scale factors”. In the light of the improved theoretical data obtained in these two approaches applied independently from each other, a successful assignment of the fundamental bands observed in the room-temperature IR and Raman spectra of the molecule was given.

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Conformational analysis of the antiinflammatory fenamates: a molecular mechanics and semiempirical molecular orbital study

Abstract

Pharmacol. Rev.

Comput. Aided Mol. Des.

Inhibitors and activators of prostaglandin biosynthesis

J. Biol. Chem.

Biochem. Pharmacol.

Acta Crystallogr.

Acta Crystallogr.

Acta Crystallogr.

Acta Crystallogr.

Cryst. Struct. Commun.

Cryst. Struct. Commun.

J. Am. Chem. Soc.

J. Comput. Chem.

J. Comput. Chem.