Novel silver ( I ) compounds with 1-adamantanamine

In this work, three novel silver(I) complexes with an almost completely rigid and bulky monodentate ligand, 1-adamantanamine, were synthesized. The aliphatic amine, 1-adamantanamine, is the sole electron donor ligand in these complexes. In addition to spectroscopic characterization, the basic biological activities of the new compounds were investigated and their minimum inhibitory concentrations were determined. The antifungal and antibacterial activities indicate that these compounds could potentially be applied as new therapeutics.


INTRODUCTION
Adamantane is a hydrocarbon that consists of three connected cyclohexane rings, forming a cage-like structure.Although there are numbers of isomers with the formula C 10 H 16 , adamantane is the most stable one. 1 Moreover, it is peculiar since it is rigid considering its "armchair" configuration, but practically without strain.The lipophilic adamantyl group is interesting from the aspect of medicinal chemistry, since it is present in several compounds that are currently used for the treatment of neurodegenerative disorders, viral infections and type 2 diabetes. 2damantane polymers have been patented as antiviral agents against HIV. 3 It is important to emphasize that in many cases, the adamantyl group has improved the pharmacological properties of a parent compound, without increasing the toxicity.
Different derivatives of adamantane, such as memantine, dopamantine and rimantadine have been utilized as therapeutics.Amantadine (1-adamantanamine), which can be obtained in a well-established way from adamantane, [4][5][6] was used as an antiviral drug against different strains of influenza 7 and in the treatment of Parkinson's disease. 8,9t is well known that ligands having electron-donating atom(s) often show increased cytotoxicity due to their enhanced coordination capacity. 10,11Various research groups are devoted to development of novel coordination compounds that contain 1-adamantanamine as a ligand in order to improve the performances and potentially overcome the shortcomings of known therapeutics.3][14][15] For example, platinum(IV) complexes with adamantylamine were thoroughly tested for their biological activity and have the potential to provide a significantly improved therapy for many types of tumors. 13o the best of our knowledge, a complex of 1-adamantanamine with silver(I) has not been described, although some similar compounds could be found in the literature. 16In addition, in these complexes, 1-adamantanamine is the sole electron donor ligand.Since silver(I) ion is very well recognized for its antibacterial activity, 17 three novel silver(I) complexes with bulky, rigid 1-adamantanamine ligand were synthesized and characterized by spectroscopic measurements.The antifungal and antibacterial activities of these compounds were investigated and their minimum inhibitory concentrations were determined.EXPERIMENTAL An appropriate silver(I) salt was added dropwise during 30 min under stirring to a methanolic solution of 1-adamantanamine.The mixture was stirred for 2 h in total darkness.The mole ratio of the reactants was 2.1:1 in favor of the amine.The obtained clear solution was left to crystallize for 72 h in the dark.The formed photosensitive crystals were suction-filtered in the dark and dried in a light-protected desiccator.The synthetic procedure can be summarized by Scheme 1. Scheme 1. Overall synthesis of the silver(I) complexes.
Total silver content for the three novel compounds was determined by means of the atomic absorption method EPA 272.1, direct aspiration.The infrared (IR) spectra were recorded in the wavenumber range 4000-480 cm -1 on a Nicolet 6700 FT-IR instrument (Thermo Scientific) using the KBr technique.Available on line at www.shd.org.rs/JSCS/NEW SILVER(I) COMPLEXES WITH ADAMANTYLAMINE 701 instrument at 50 MHz.The agar-dilution method 18 was used for the determination of the minimal inhibitory concentration (MIC) values of the synthesized complexes.The microorganisms were prepared in nutrient-rich agar plates without the tested substances to obtain single cell colonies, which were then transferred into nutrient-rich agar plates containing the tested substances (10 μL, range: 0.02 to 50 μmol L -1 ).The inoculated agar-plates were incubated for 24 h and then the colonies were counted.
The infrared spectrum of 1-adamantanamine showed characteristic bands for primary amines: asymmetric and symmetric stretching bands (NH 2 group) at 3329.8 and 3252.7 cm -1 , respectively, N-H bend vibrations at 1587.7 cm -1 , C-N stretch (aliphatic amines) in the region of 1250-1020 cm -1 , located at 1098.8 cm -1 , and N-H wag vibration was found at 812.2 cm -1 .Moreover, in this spectrum two strong bands were observed at 2907.5 and 2848.7 cm -1 , presenting asymmetric and symmetric stretching bands, respectively (CH and CH 2 groups).In the IR spectrum of the synthesized complex of 1-adamantanamine with silver nitrate, the following bands were observed: 3435.2 cm -1 , wide stretching band; 1591.4 cm -1 , weak bending band that arises from the NH 2 group; 1348.1 cm -1 , strong stretching band of the NO 3 -ion; 2910.6 and 2847.1 cm -1 , strong stretching bands originating from the CH 2 groups and 1450.7 cm -1 , weak bending band, which is derived from the CH groups.In the IR spectrum of the synthesized complex of 1-adamantanamine with silver camphorsulfonate, the following bands were registered: 3457.1 cm -1 , wide stretching band; 1597.3 cm -1 , weak bending band originating from the NH 2 group; 2903.5 and 2846.5 cm -1 , strong stretching bands that originate from the CH 2 groups, 1451.6 and 1367.7 cm -1 , weak bending bands that originate from the CH groups; 1740.6 cm -1 , strong stretching band that comes from the C=O group; 1197.6 and 1047.0 cm -1 strong bands of the SO 3 -group.In the IR spectrum of the synthesized complex of 1-adamantanamine with silver perchlorate, the following bands were detected: 3426.0 cm -1 , wide stretching band; 1584.2 cm -1 , weak bending band that originates from the NH 2 group; 1097.0 and 621.5 cm -1 strong stretching bands that arise from ClO 4 -, 2906.7 and 2846.5 cm -1 , strong stretching bands that come from the CH 2 group and 1450.7 and 1363.6 cm -1 , weak bending bands originating from the CH group.Due to relatively low concentration of methanol, its IR bands were overlapped with the bands that belong to the NH 2 and CH 2 groups and counter ions.
In summary, two peaks assigned to stretching modes of NH 2 group (3329.8 and 3252.7 cm -1 ) in the non-coordinated ligand had become one broad peak located around 3440 cm -1 in the spectra of all the investigated complexes, indicating that the coordination to the metal ion was successful.
Evidence for complexation of silver(I) to l-adamantanamine could also be obtained from the NMR spectra.In the 1 H-NMR spectrum of l-adamantanamine, two broad signals of carbon-bound hydrogen atoms could be seen -one at 2.05 ppm, corresponding to the methine protons, and the other at 1.59 ppm, corresponding to the methylene protons.Upon complexation, the methine proton signals and the methylene proton signals from hydrogens at carbons 4, 6 and 10 remain at the same chemical shift (as in the ligand), while the methylene proton signals from the hydrogens at carbons 2, 8 and 9 are shifted downfield, to 1.66-1.70ppm (adequate numeration is shown in Fig. 2).
In the 13 C-NMR spectra, there is an important downfield shift of the quaternary carbon 1, from 47.2 ppm in the ligand to 48.8-50.1 ppm in the complex salts.This deshielding is the consequence of the electron-withdrawing effect of the silver(I) ion.________________________________________________________________________________________________________________________ (CC) 2018 SCS.
Available on line at www.shd.org.rs/JSCS/Determination of MIC values was performed and all obtained complexes showed activity to the tested microorganisms.The antifungal activities are comparable with those of the test compound nystatin.Unfortunately, 1-adamantanamine is not soluble in water.Therefore, MIC values for the ligand were not determined.
The diminished activity of the studied complexes (Table I) compared to simple silver(I) salts was expected, considering the lower concentration of free silver(I) ions due to complexation.On the contrary, only in one case, i.e.Aspergillus niger, MIC values determined for [Ag(1-AdNH 2 ) 2 ]CSA•2.5CH 3 OH showed significant increases in activity.Although the percentage of silver(I) in bis(1-adamantanamine)silver(I) D-camphor-10-sulphonate complex is lower than in nitrate and perchlorate analogues, [Ag(1-AdNH 2 ) 2 ]CSA•2.5CH 3 OH showed comparable activity in the case of Candida albicans.The increased activity of the camphorsulphonate complex was probably caused by the greater lipophilicity of the complex.The antiviral effect of adamantane amines is well known, as well as the antibacterial effect of silver(I) ions. 26The demonstrated antifungal and antibacterial activities of the newly synthesized complex compounds may have significance for their further application.

CONCLUSIONS
In this work, although being photosensitive, three novel compounds with a monodentate ligand, the almost completely rigid and bulky aliphatic amine (1-adamantanamine), were successfully prepared for the first time in a simple and low-cost way.All three compounds were characterized by atomic absorption, IR, and 1 H-and 13 C-NMR measurements.All three characterization methods evidenced that the complexation had been successfully achieved.Two characteristic bands that appear in the IR spectrum of the non-coordinated ligand became one broader peak positioned at higher energies in the spectra of the investigated complexes.In the NMR spectra, important downfield shifts were observed upon complexation.Since this amine is a bulky and rigid monodentate ligand, and silver(I) mostly forms linear compounds, the obtained complexes had coordination number 2. It should be noted that in these compounds, the amine ligand is the sole electron donor.The measured antifungal and antibacterial activities of the synthesized compounds, may have an impact on their further applications as therapeutics.Special attention should be paid to the nitrate and perchlorate complexes, although the lipophilic camphorsulphonate analogue gave satisfactory results despite having a lower percentage of silver(I).The obtained compounds are relatively unstable.However, these complexes could be observed as model systems in order to produce new derivatives with desired biological properties belonging to this class of compounds.
The 1 H-NMR spectra were recorded on a Varian Gemini 2000 instrument at 200 MHz and the 13 C-NMR spectra were recorded on a Bruker Avance III ________________________________________________________________________________________________________________________ (CC) 2018 SCS.