Synthesis and Characterization of 3s,5s,7s-Adamantan-1-Amine Complexes with Metals of Biological Interest

3s,5s,7s-adamantan-1-amine, tricyclo[3.3.1.13,7]decan-1-amine, 1-adamantanamine, 1-aminoadamantane, 1-aminotricyclo[3.3.1.13,7]decane, 1-adamantylamine or amantadine with a tricyclic amine with cage like structure is an antiviral and antiparkinsonian compound. It also is used to prevent and treat respiratory infections caused by influenza A virus. Eleven metal complexes of amantadine with metals of biological interest as MgII, CaII, CrII, MnII, FeII, FeIII, CoII, NiII, CuII, ZnII and CdII have been synthesized and characterized by spectroscopic techniques IR, 1H NMR, elemental analysis and atomic absorption spectroscopy. Prior to synthesis condutometric titrations were carried out to determine the mole ratios of drug metal interactions. In all complexes, amantadine acted as a monodentate ligand, two molecules of which are bound to the metal through the amino nitrogen showing a square planar geometry. *Corresponding author: Saeed Arayne M, Department of Chemistry, University of Karachi, Karachi-75270, Pakistan, Tel: +92-213-466-4402-03; E-mail: msarayne@gmail.com Received November 22, 2013; Accepted February 26, 2014; Published March 03, 2014 Citation: Sultana N, Arayne MS, Haider A, Shahnaz H (2014) Synthesis and Characterization of 3s,5s,7s-Adamantan-1-Amine Complexes with Metals of Biological Interest. Mod Chem appl 2: 120. doi:10.4172/2329-6798.1000120 Copyright: © 2014 Sultana N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Introduction
Tricyclic amines have a great potential in the treatment and prevention of influenza A of which the most significant is amantadine, a synthetic alicyclic antiviral agent with an unusual cage like structure ( Figure 1) [1]. Amantadine is an orally active antiparkinsonian and antiviral agent [2,3] discovered by workers at DuPont via an empiric screening program [1].
Amantadine hydrochloride possesses a unique, rigid, relatively unstrained ring system that is composed of three fused cyclohexane rings in the chair conformation [4]. Amantadine is considered to be the smallest repeating unit of the diamond lattice [5]. The symmetrical cage structure causes the infrared, nuclear magnetic resonance and mass spectra to be comparatively simple, as will be illustrated later.
Several metal complexes of amantadine are reported with iron [6], platinum [7], while other polyoxometalates containing Ce, W, Pr, Ni, V and Mn were reported by Liu and others [8]. Compounds of molybdenum and amantadine with the formulae, (C 10 H 18 N) 5 [10] and trans-(AdNH) 2 Mo(OSiMe 3 ) 4 [11] have also been reported. At physiological pH amatadine forms complex with sodium molybdate, as the amino group of the drug is free for its function as antiviral, this study suggests that the co-administration of amantadine with molybdenum supplements should be avoided [8].
Physical properties as solubility in water, size and ionic nature which in turn are dependent on the pH of the medium [12][13][14] effect the absorption of a drug through gastrointestinal tract. As only the free and unchanged drug can function at the active site in the body, if molybdate reacts with amantadine or when the two are administered together, the solubility and absorption can be affected. Owing to the fact that molybdnium is neither present in the body nor is administered as drug. Alternatively, essential and trace elements can be studied for complexation with amantadine, as being the metals of biological interest. In this paper we report synthesis and characterization of eleven metal complexes of amantadine with Mg II , Ca II , Cr II , Mn II , Fe II , Fe III , Co II , Ni II , Cu II , Zn II and Cd II , which were characterized by FT-IR, 1 H NMR, atomic absorption spectroscopy and elemental analysis.

Chemicals
Amantadine was purchased from Sigma-Aldrich USA. The essential and trace elements used were in the form of their hydrated chloride salts of magnesium, calcium, chromium, manganese, ferric, cobalt, nickel, copper, zinc and cadmium, all of analytical grade. Methanol (TEDIA ® , USA), hydrochloric acid, sodium hydroxide from Merck, Darmstadt, Germany. Deionized water was freshly prepared in the laboratory and all glasswares were washed with chromic acid and then thoroughly rinsed with deionized water.

Conductometric titration of amantadine metal complexes
Prior to synthesis conductometric titrations were performed to study the stoichiometric ratio of amantadine metal interactions in aqueous medium using conductivity/TDS meter. In individual experiments metal solutions of 1 mM were prepared and titrated with 1 mM ligand solution at 25°C. Conductivity of reacting mixtures were recorded after each addition of metal solution aliquots.

Synthesis of amantadine metal complexes
Amantadine (2 mM) was dissolved in 0.1 N HCl and 1 mM of each of these element salts were individually dissolved in 10 mL of methanol. Both of these solutions were mixed together and refluxed for three hours; the solution was concentrated and filtered while hot and then kept undisturbed for crystal growth at room temperature. The growth of crystals had a different time of crystallization. Crystals of magnesium, calcium, and chromium and manganese complexes with amantadine appeared in 15 days while the iron complex took one month for crystallization. On the other hand, cobalt, nickel, copper, zinc and cadmium complexes took 25~30 days for their growth. These metal complexes were recrystallized in absolute methanol, filtered, dried and physical characteristics were recorded.

Synthesis of complexes
A venture has been made to synthesize metal complexes of amantadine with various essential and trace elements in equimolar ratio in a mixture of hydrochloric acid and methanol. These complexes were than studied for their physicochemical parameters and characterized using techniques as IR, NMR and elemental analysis. Metals in all amantadine complexes were determined by using Pye-Unicam atomic absorption spectrometer (Table 1). Melting points were recorded on Gallenkamp melting point apparatus, while solubilities of all the complexes were checked and are present in Table 2.

IR Studies
All the synthesized complexes were studied spectroscopically in the IR region 4000 to 400 wavenumbers (cm -1 ). The infrared spectrum of amantadine and their metal complexes were recorded as a potassium bromide disc method on a Nicolet Avatar 330 IR spectrophotometer. The main peak assignments are given in Table 3.

N-H stretch
The N-H stretching band of the amino group expected for amantadine is in the region 2961-3087 [15,16] was observed for pure amantadine at 3038 cm -1 which shifts to 2900-3600 cm -1 .
For magnesium complex, N-H stretch band appeared at 3400 cm -1 as small band where as for calcium complex, a broad band was observed in the range of 3600-3100 cm -1 due to N-H stretching. In chromium and cadmium complexes, N-H stretch showed a short band at 3400 cm -1 , similarly in case of manganese, ferric chloride, cobalt, nickel, copper, zinc complexes a medium band was observed in the range of 3600-3100 cm -1 due to N-H stretching. While in ferrous ammonium citrate complex, N-H stretching showed a weak band in the region of 3400-3100 cm -1 .
The second incredibly significant peaks were asymmetric and symmetric stretching and their scissoring wagging and rocking which is the evidence of the attachment of metal with nitrogen of amine group. The CH 2 symmetric stretching was recorded at 2860 cm -1 , scissoring at 1449 cm -1 , rocking at 1263 cm -1 and wagging was at 1143 cm -1 . The comparison of the IR spectra of amantadine with metal complexes divulged that in case of all complexes the N-H stretching peak was shifted to 2914-3395 cm -1 in doublet and triplet weak bands.

CH 2 stretching (antisymmetric and symmetric)
Amantadine showed a very sharp band at 2900 cm -1 due to CH 2 antisymmetric and 2850 cm -1 due to CH 2 symmetric stretching whereas the reported peaks for antisymmetric is 2923 cm -1 and symmetric stretching at 2900 cm -1 [5]. For magnesium and calcium complex antisymmetric peaks appeared at 2900 cm -1 , 2950 cm -1 and symmetric very short band and sharp bands were observed at 2850 cm -1 for magnesium and calcium complexes. This band disappeared in chromium complex, whereas manganese, ferric chloride and ferric ammonium citrate nickel complexes showed suppressed bands of CH 2 stretching (antisymmetric and symmetric) at 2900 cm -1 . In cobalt complex very sharp symmetric band of CH 2 stretching was observed at 2850 cm -1. and in zinc and cadmium complexes very sharp asymmetric bands were observed at 2900 cm -1 and incredibly very short symmetric bands appeared between 2850-2860 cm -1 .
Due to the coordination of the metal ion with amantadine the N-H, C-N bands shifted to higher frequencies and overlapped [15]. It may be inferred that metal ions were strongly coordinated with amantadine through direct association with primary amine group [16,17].
In case of all complexes the shifting of protons was observed at C2, C3 and C10 (Table 4). All the complexes showed resonance of methylene protons and other spectroscopic studies also account that there is an attachment of metal with the nitrogen of amine in amantadine molecule.

Structure of amantadine metal complexes
On the basis of above studies the amantadine nitrogen binds with metals and their proposed structures are shown as Figure 2. From the results obtained, it is proposed that amantadine forms complexes in the ratio of 2: 1 (drug: metal) [18]. The crystals of the complexes were very thin and we did not cope to obtain their X-ray crystallographs. The proposed formulae is established on the basis of spectroscopic and elemental analysis (Table 5) [6].

Conclusion
Complexes of metals of biological interest were synthesized with amantadine. The results from the elemental analysis, conductometric titration, AA spectroscopy, proton nuclear magnetic resonance and infrared studies reveals that in all complexes, amantadine acted as a monodentate ligand, two molecules of which were bound to the metal through the amino nitrogen showing a square planar geometry.   Table 5: CHN microanalysis of amantadine and its metal complexes.