N-Containing Ag(I) and Hg(II) Complexes: A New

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N-Containing Ag(I) and Hg(II) Complexes: A New Class of Antibiotics Seyyed Javad Sabounchei* and Parisa Shahriary Faculty of Chemistry, Bu–Ali Sina University, Hamedan 65174, Iran Abstract: Several classes of antimicrobial compounds are presently available; microorganism’s resistance to these drugs constantly emerges. In order to prevent this serious medical problem, the elaboration of new types of antibacterial agents or the expansion of bioactivity of the naturally known biosensitive compounds is a very interesting research problem. The synthesis and characterization of metal complexes with organic bioactive ligands is one of the promising fields for the search. The biological activities of the metal complexes differ from those of either the ligand or the metal ion. The results obtained thus far have led to the conclusion that structural factors, which govern antimicrobial activities, are strongly dependent on the central metal ion. A review of papers dealing with the Ag(I) and Hg(II) complexes of N donor ligands is presented. These metal complexes of N-chelating ligands have attracted considerable attention because of their interesting physicochemical properties and pronounced biological activities. This review will mainly focus on the preparation procedures and antibacterial properties of free organic ligands and the corresponding complexes. Finally, a research about antimicrobial properties of new Hg(II) complexes with 5-methyl-5-(4-pyridyl)-2,4-imidazolidenedione (L) and various halogen ions, HgL2X2 (X = Cl¯ (49), Br¯ (50), and I¯ (51)), is reported. Noteworthy antimicrobial activities, evaluated by minimum inhibitory concentration, for these complexes were observed.

Keywords: Antimicrobial compound, Ag(I) complex, Hg(II) complex, N-chelating ligand, preparation procedure, 2,4-imidazolidenedione. INTRODUCTION The structural modification of promising lead compounds is still a significant approach in developing new therapeutic agents. It involves an intensive effort to condense the different pharmacophoric groups of bioactive active moieties into one compound, in the hope that the new compound may behave as a novel chemotherapeutic agents [1]. The interaction of metal ions with biologically active ligands, for instance in drugs, is a subject of great interest. Complexes containing N coordination functions have been designed to produce different kinds of transition metal complexes which exhibit biocidal (antibacterial, antifungal, and pesticidal) activities [219]. The enhanced activity of the complexes can be explained on the basis of Overtone’s concept [20] and Tweedy’s chelation theory [21]. According to Overtone’s concept of cell permeability, the lipid membrane that surrounds the cell favors the passage of only the lipid-soluble materials which makes liposolubility an important factor controlling the antimicrobial activity. On chelation, the polarity of the metal ion will be reduced to a greater extent due to the overlap of the ligand orbital and partial sharing of the positive charge of the metal ion with donor groups. Further, it increases the delocalization of -electrons over the whole chelate ring and enhances the lipophilicity of the complexes. This increased lipophilicity enhances the permeation of the complexes into lipid membranes and blocking of the metal binding sites in the enzymes of the microorganisms. These complexes also disturb the respiration process of the cell and *Address correspondence to this author at the Faculty of Chemistry, Bu–Ali Sina University, Hamedan 65174, Iran; Tel: 98-811-8282807; Fax: 98-811-8380709; Email: [email protected] 1873-5294/13 $58.00+.00

thus block the synthesis of the proteins thereby restricting further growth of the organism and resulting in the microorganism’s death. Some of the biologically active complexes do act via chelation according to the preferences dictated by the hard-soft theory of acids and bases, but for most, little is known about how metal coordination influences their activity [22-24]. Another mechanism of toxicity of these complexes to microorganisms may be due to the inhibition of energy production or ATP production, by inhibiting respiration or by the uncoupling of oxidative phosphorylation. The biological activity involves inhibition of DNA synthesis [25] by creating lesions in DNA strands by oxidative rupture and by binding the nitrogen bases of DNA or RNA, hindering or blocking base replication. The inhibition growth may be due to the effect on the biosynthesis of phospholipids in cell membrane and proteins [1]. So, the most successful compounds seem to be those that interfere with the construction of the bacterial cell wall, the process of protein synthesis, and replication or transcription of DNA. In this respect, the metal oxidation state, the type and the number of donor atoms, as well as their relative disposition within the ligand are major factors determining structure-activity relationship of metal complexes. The increased activity of the complexes can also be explained on the basis of their high solubility, fitness of the particles, size of the metal ion, and the presence of the bulkier organic moieties [1]. There are two main reasons for the current considerable interest in the coordination chemistry of coinage metal ‘silver(I)’: (i) silver has long been known to exhibit strong inhibitory and bactericidal effects as well as a broad spectrum biological and medicinal properties [2-17, 26-33]. Since ancient times, people have known that water can remain suit© 2013 Bentham Science Publishers

N-Containing Complexes as Effective Antimicrobial Agents

able for drinking for a long time if stored in silver jars. Colloidal silver and silver nitrate have been used safely in burn therapy, urinary tract infections, and central venous catheter infections [34]. (ii) silver(I) systems incorporate onto a wide range of medical and associated devices used in clinical settings. Silver has been proven as an effective antibacterial agent that can avoid defense mechanisms of bacteria (such as Pseudomonas aeruginosa) and prevent biofilm formation, which is the leading cause of acute infection [13]. In this regards, one of the applications of silver and its compounds is reduction of postoperative infections caused by implants [16]. The main aims of current research are the synthesis of compounds with Ag(I)–N, Ag(I)–S, Ag(I)–O, and Ag(I)–P bonds and the establishment of structural relationship of such complexes with antimicrobial activities [10]. It was suggested [3, 8-9] that one of the key factors determining the antimicrobial effects of silver complexes is the nature of the atom coordinated to Ag and its bonding properties, rather than the solubility, charge, chirality, or degree of polymerization of the complexes. For example, it has been speculated that the weak Ag(I)–N [3, 8] and Ag(I)–O [9] bond strengths might play an important role in exhibiting a wider spectrum of antimicrobial and antifungal activities. In general, Ag(I)– S complexes have been shown to have a narrower spectrum of antimicrobial activity than Ag(I)–N complexes [3]. In contrast, almost all compounds with Ag(I)–P bonds investigated thus far have shown no activity against bacteria [3, 8]. The antimicrobial activity of Hg(II) complexes containing N coordination ligands has been scarcely reported while nonessential mercury(II) is very soft acid with very high toxicity [15, 18-19]. Its salts have a long history of use as antibacterial agents. THE USE OF SILVER COMPLEXES AS ANTIMICROBIALS Background of Silver Antimicrobials The use of silver as an antimicrobial can be traced to ancient times. Metallic silver, silver salts (e.g. AgNO3), and silver complexes have been used in a variety of applications like water purification, wound management, eye drops, antiinfective coatings in medical devices, and in burn treatment because of their potent antimicrobial properties coupled with low human toxicity [35-46]. The antimicrobial properties of silver nitrate were well known long before the 1800s, and it was recognized as an antiseptic in wound care for more than 200 years [37]. However, the true revival of the use of silver antibiotics came with the discovery of silver sulfadiazine by Fox [47]. Silver sulfadiazine (Fig. 1) is used for the treatment of burn wounds, and was designed to combine the antibiotic sulfonamide, sulfadizine, with silver in order to obtain a broad spectrum antibiotic. Silver(I) sulfadiazine is a water insoluble polymeric compound [48] that releases silver ions very slowly. In contrast, water soluble silver nitrate releases silver ions very rapidly. However, the amount of ‘‘bioavailable’’ silver(I) from silver nitrate may be limited by the precipitation of AgCl when chloride ions are present in the solution (it is noteworthy that, moderate levels of chloride ions lead to the precipitation of AgCl, whereas at higher chloride concentrations, silver can return to the solution as AgCl2¯ (see references given in [39]). Silver sulfadiazine has

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been shown to be effective against a number of grampositive and gram-negative (especially against Pseudomonas aeruginosa) bacteria. It remains one of the most widely used antimicrobials for infections associated with burns [47].

H2N

O

Ag

S

N

N N

O

Fig. (1). Simplified drawing of the structure of silver sulfadiazine.

Mechanism of Action and Toxicity of Silver(I) The mechanism of antimicrobial activity in silver(I) complexes has been scarcely reported although three possible mechanisms for inhibition by the aqueous silver(I) ion have been proposed: (i) interference with electron transport, (ii) binding to DNA, and (iii) interaction with the cell membrane [49]. Almost all of the silver(I)-PPh3 complexes with AgNP2, AgNP3, AgSP2 and AgSP3 cores have shown no activity against bacteria [3-6, 50] whereas the antimicrobial activities by the Ag–N, Ag–S and Ag–O bonding complexes without PPh3 ligands depend upon the kind of coordinating donor atoms. For instance, the range of the antimicrobial activities observed in the Ag–S bonding compounds is narrower than that in the Ag–N bonding compounds. It was so far suggested that the coordination donor atoms to the silver(I) center and the ease of ligand replacement appear to be the key factors leading to a broad spectrum of antimicrobial activities, and the primary targets for the inhibition of bacteria by the silver(I) complexes are proteins as sulfur donor ligands, and not nucleic acids as N/O donors [3-4]. This concept has been applied to the molecular design of silver(I) complexes showing a broad spectrum of effective antimicrobial activities. Synthesis of Silver(I) Complexes and their Antimicrobial Properties In 1990, Ag(I) complex (Ag(EALDH)2NO3 ; 1) was obtained by conventional precipitation at solution pH resulting from addition of AgNO3 salt to a hot solution of the ligand E1-p-ethoxyphenyl-4-hydnomethyl imidazole (EALDH) [51] with ligand/metal ratio of 2 : 1 (Fig. 2) [2]. In this complex, the coordination takes place monodentately through the N3 atom of the imidazole. 1 showed antibacterial activity against some gram-negative bacteria, Pseudomonas aeruginosa and Escherichia coli, and also was active against Staphylococcus [2]. C2H5O

OC2H5

N

H

N C

N HO

N

Ag N

N

C

H

OH

Fig. (2). Proposed structure for 1 in [2].

In 1997, a neutral Ag(I)–N bonding compound, polymeric silver(I)-imidazolate [Ag(imd)]n (2), consisting of Ag+ : imd = 1 : 1 (Himd = imidazole, C3H4N2), was obtained from

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the reaction of imidazole and AgNO3 in water [3]. Herein the antimicrobial activities of the polymeric Ag(I)–N bonding compound (2), the monomeric Ag(I)–N bonding compound [Ag(Himd)2](NO3) (3) [52], and the mixed-ligand complex [Ag(imd)PPh3)3] (4) with both Ag(I)–N and Ag(I)–P bondings [53] together with those of the Himd ligand and aqueous AgNO3 in comparison with the previously reported for Ag(I)–S bonding compounds, {Na[Ag(Htma)]·0.5H2O}n (n = 24-34; H3tma = HO2CCH(SH)CH2CO2H)) (5) [54-55] and {Na[Ag(tsa)]·H2O}n (n = 21-27; H2tsa = o-HS(C6H4)CO2H)) (6) [56] have been reported (Fig. 3). Antimicrobial activity of the Himd ligand was estimated as 1600 g/cm3 or so for bacteria. Ag+ ion, as aqueous AgNO3, showed remarkable activities against gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and moderate activities against gram-positive bacteria (Bacillus subtilis). Complexes 2 and 3, on the contrary, showed remarkable and superior activities against wide spectra of bacteria. On the other hand, the mixed-ligand complex 4 showed no activity (> 1000 g/cm3). 2 also showed remarkable and superior activities against the infectious microbes [3]. Previous data showed also 5 and 6 had antimicrobial activities with different modes of action [54-56]. The spectra observed in the Ag(I)–S bonding compounds were narrower than those observed in the above Ag(I)–N bonding compounds 2 and 3. These results suggest that at least one of the key factors determining the antimicrobial effects and their bioactivity spectrum is the kind of atoms coordinated to silver(I) and the atoms bonding properties, rather than the polymerization degree of silver(I) complexes and the ligand charge. Thus, the Ag(I)–N bonding property with moderate strength, in these silver(I) complexes, plays an important role in showing the broad spectrum of antimicrobial activities. Additional bondings to the same silver(I) atom with other elements such as P and S, as observed in 4, may inhibit some ligand-exchange reactions with biological ligands, resulting in no activity. Silver(I) atom as a soft Lewis acid has a relatively low affinity for hard oxygen donors, high affinities for soft donors S, Se, P and As, and moderate affinities for nitrogen donors, and it usually forms two- or four-coordination complexes [57]. As for the bonding ability of silver(I) atom, experiments in ligand-exchange reactions have suggested the relative order of strength to be: Ag(I)–P > Ag(I)–S >> Ag(I)–C1 > Ag(I)– N >> Ag(I)–O [52, 54, 56]. So, it can be proposed that for bacteria the inactivation targets of the silver(I) complexes are not nucleic acids as N/O donor ligands, but rather the proteins as S donor ligands, which include the proteins indispensable to the survival of the microbes [3]. Synthesized complexes [Ag(1,2,3-L)]n (1,2,3-L = 1,2,3triazole) (7) and [Ag(1,2,4-L)]n (1,2,4-L = 1,2,4-triazole) (8) (HL = triazole) in 1998 [5], a colorless powders insoluble in most solvents with molar ratios of AgI : L¯ = 1 : 1, were Ag(I)–N bonding polymers just as the reported [Ag(imd)]n (Himd = imidazole) [3] and [Ag(pz)]n (Hpz = pyrazole) [5859]. The synthetic conditions presented here using AgNO3 : HL : NaOH are crucial factors in determining the yields and purities of 7 and 8. The PPh3 derivatives, [Ag(1,2,3L)(PPh3)2]n (9) and [Ag(1,2,4-L)(PPh3)2]n (10), helical mixed polymers with both Ag(I)–N and Ag(I)–P bondings and molar ratios of AgI : L¯ : PPh3 = 1 : 1 : 2, were prepared using the molar ratio of [Ag(L)]n (7 or 8) : PPh3 = 1 : 3 in dichloromethane [5]. Antimicrobial activities of 1, 2, 3- and 1,

Sabounchei and Shahriary

2, 4-HL (Fig. 4) were estimated as >1000 g/cm3 for bacteria (Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and Pseudomonas aeruginosa), suggesting that they do not show any activity. The polymer 8, on the contrary, showed a broad spectrum of remarkable and superior activity against bacteria, whereas the other polymer 7 showed only limited activities for three organisms of bacteria (Escherichia coli, Bacillus subtilis, and Pseudomonas aeruginosa). On the other hand, other polymeric PPh3 derivatives 9 and 10 showed no activity (>1000 g/cm3, except 500 g/cm3 for Staphylococcus aureus by 10) [5], thus confirming the previous results [3]. Since the silver(I)–N bound ligand can easily exchange with stronger donors such as S and P atoms, it should play an important role in showing the wide spectra of antimicrobial activities. Ionic species such as [Ag(PPh3)4]+ L¯ and [Ag(PPh3)2]+ L¯, if they are present in solution as dominant species generated from 9 and 10 by dynamic exchange, will not show any activity, because the noncoordinating L¯ does not show any activity [5]. H N N

Himd + N

HN

P(C6H5)3

NH N

Ag N

Ag N

N

N Ag P(C6H5)3 P(C6H5)3

n 2

3

4

R = OOCCH2CHCOO-

R

5

Ag

S

n

COO-

6

R=

Fig. (3). Structure of ligand and complexes in [3].

5

H N

H N N N

4 1, 2, 3-HL

5

N N

3 1, 2, 4-HL

Fig. (4). Structure of ligands in [5].

Synthesis of novel light- and thermally-stable coinage Ag(I)-triphenylphosphine complex with a heterocyclic ligand, [Ag(tetz)(PPh3)2]n (11) (Htetz = tetrazole) (Fig. 5) , from a reaction of the precursor complex [Ag(tetz)]n with 3 equiv. of PPh3 in dichloromethane, was reported in 2000 [6]. Complex 11 is composed of a helical polymer, formed by a bridged tetrazolate of an AgNP2 core in the solid-state, but it was present as a monomer in solution. For synthesis of precursor complex, molar ratios AgNO3 : Htetz : NaOH = 1 : 2 : 1 were used [6]. The free Htetz ligand showed only poor activities against gram positive bacteria (Bacillus subtilis and Staphylococcus aureus). On the other hand, the precursor [Ag(tetz)]n has shown effective activities against grampositive and -negative bacteria. Antimicrobial activities of 11 were estimated as >1000 g/cm3 for bacteria, showing no activity. These facts are consistent with the observed results; the polymeric silver(I) complexes without a PPh3 ligand have shown effective antimicrobial activities while almost


all of their triphenylphosphine derivatives have shown no activity [3, 5]. These facts have been attributed to the restricted ligand exchange ability of the Ag–P bonding complexes [3-5]. From a viewpoint of metal-based drug design, no activity of the PPh3 derivatives is also crucial and can be utilized. H N N N

N

Tetrazole Fig. (5). Structure of ligand in [6].

Two other silver(I) complexes, synthesized in 2000, were water-insoluble, DMSO-soluble yellow powder [Ag(Hmna)]6·4H2O (12) and water-soluble, yellow powder {Na[Ag(mna)]·H2O}n (13) in which 2-mercaptonicotinic acid (H2mna = 2-HS(C5H3N)CO2H) (Fig. 6), with pyridine N, thiol S, and carboxylic O donor atoms, acts as a polyfunctional ligand [7]. Structure determination was successful only for 12. The molecular structure of 12 consists of a discrete, hexanuclear silver(I) cluster with the two silver(I) triangles linked by the mercaptonicotinate anions, the geometry around each silver(I) atom being constructed by one aromatic nitrogen atom and two -S atoms and the two weak silver(I)–silver(I) interactions. Complex 13 was synthesized from the reaction of Ag2O : H2mna : NaOH with molar ratios = 1 : 2 : 2. Addition of sulfuric acid resulted in the formation of 12. These two complexes were interconverted on changing the acidity of the solution. The syntheses of 13 and 12 are represented in eqn. (1) and (2), respectively [7]. (1)

Ag 2 O + 2H 2 mna + 2NaOH (2/n){Na[Ag(mna)]}n + 3H 2 O 13

(2)

(6/n){Na[Ag(mna)]}n + 3H 2SO 4 [Ag(Hmna)]6 + 3Na 2SO 4 12 13 COOH

N

SH

H2mna

Fig. (6). Structure of ligand in [7].

Antimicrobial activities of the free ligand were estimated as >1000 g/cm3 for four bacteria (Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and Pseudomonas aeruginosa), showing a lack of activity against all test organisms. Complex 12 showed a broad spectrum of effective activities against four bacteria. On the other hand, 13 showed effective activities against two gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) but no activity against two gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus). Since 12 and 13 contain extra Ag–N bonds compared with Ag–S bonded complexes [56], their antimicrobial activities, different from those, should be interpreted by taking into account the bonding factor (the ease of ligand replacement) [7]. The other Ag(I)–N complex, with a broad spectrum of effective antibacterial activities, introduced in 2000, was com-


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plex {[Ag(Hhis)]·0.2EtOH}2 (14 ; H2his = L-histidine) (Fig. 7), as dimer and polymer in aqueous solution and solid state, respectively [8]. Reaction of H2his with Ag2O in water gives the corresponding complex. Physicochemical data showed that the dimeric core of 14 was formed through Ag– N bonds. Crystallization of 14 by slow evaporation and/or vapor diffusion give water-insoluble crystals of [Ag(Hhis)]n (15). X-ray crystallography revealed that 15 was a lefthanded helical polymer consisting of a bent, 2-coordinate silver(I) atom bonding to the Namino atom of one Hhis¯ ligand and the N atom of a different Hhis¯ ligand, of particular note is the fact that Ocarboxyl atoms do not participate in the coordination. Antimicrobial activities of the free ligand, H2his, was estimated as >1000 g/cm3 for bacteria, showed no activity. The complex 14 showed remarkable and excellent activities against a broad spectrum of gram-negative and -positive (Bacillus subtilis and Staphylococcus aureus) bacteria, similar with those of complex 3 [8]. A broad spectrum of antimicrobial activities of 14 and 3 is reasonable because the ligand replacement with biological ligands in the compounds with the weak Ag–N and Ag–O bonds is further possible [8]. Complex 15 showed a broad spectrum of modest activities. These activities mostly correspond to those of the previous silver(I)–S bonding complexes 5 and 6 . The modest activities of 15 cannot be simply attributed to its low solubility in water because both 5 and 6 show effective activities despite quite different solubilities in water [8].

HOOC

NH2 H2 C C H

N NH

H2his


From the viewpoints of (1) model complexes for silver(I)-protein interaction, (2) the anticipated wider spectrum of antimicrobial activities and (3) structure–activity correlation, silver(I)–N complexes with three amino-acid ligands with both N and O donor atoms and without an S atom were prepared by Nomiya et al. in 2002 [9]. Complexes {[Ag(gly)]2·H2O}n (Hgly = glycine) (16) and [Ag(L-asn)]n (Hasn = asparagines) (17) (Fig. 8) were obtained from the addition of a stirred suspension of Ag2O in water to a solution of Hgly in water and solid L-Hasn, respectively. In the synthesis process, when D-Hasn was used and vapor diffusion with EtOH as an external solvent was carried out, colorless needle crystals of [Ag(D-asn)]n (Hasn = asparagines) (18) were obtained. Silver(I) complexes formed by aminoacids with N and O donor atoms and without an S atom can be classified into four types (I–IV) based on the bonding modes of the silver(I) center. Type I which contains only Ag–O bonds (complex 1 in [9]), type II in which the twocoordinate O–Ag–O and N–Ag–N bonding units are alternately repeated (complex 16), type III in which the twocoordinate N–Ag–O bonding units are repeated (complexes 17 and 18), type IV which contains only Ag–N bonds (complexes in [8]). Antimicrobial activities of the free amino-acid ligands, Hgly and D- and L-Hasn were estimated as >1000 g/cm3 for bacteria, thus showed no activity. Silver(I)amino-acid complexes tested here showed a broad spectrum


of effective activities against gram-negative (Escherichia coli and Pseudomonas aeruginosa) and -positive (Bacillus subtilis and Staphylococcus aureus) bacteria. The difference in the magnitude of antimicrobial activity may come from the structural factor of the silver(I) complexes [9].

H2N

O H2 C C

O H2N

OH

H2 C C

C

H2N

glycine (Hgly)

H COOH

L-asparagine (L-Hasn) Fig. (8). Structure of ligands in [9].

The synthesis of a water-soluble anionic silver 2mercaptonicotinate complex having effective antibacterial properties was described in 2003 [10]. Different salts of this complex ({Na[Ag(mna)]}6·nH2O (19), {K[Ag(mna)]}6 ·nH2O (20), and {Cs[Ag(mna)]}6·nH2O (21) were obtained according to the previously reported method [7] in 90.0% yield by a reaction in an aqueous solution of Ag2O : H2mna : NaOH = 1 : 2 : 4 molar ratio, followed by crystallization by vapor diffusion of a water/acetone system. Hexameric cluster [Ag(mna)]66- has a Ag6S6 core and an overall shape of twisted hexagonal cylinder with six sulfur atoms and six silver atoms alternating on a puckered drum-like surface, almost the same hexanuclear core structure as that of the previously reported, neutral complex [Ag(Hmna)]6 [7]. Each Ag atom is trigonally coordinated by one N and two S ligands. Surprisingly, these two silver(I) complexes have shown a different spectrum of antimicrobial activities while it was proposed that for metal complexes with the same or similar core structures the magnitudes of their antimicrobial properties are related to the ease with which they participate in ligand-exchange reactions [60]. The neutral complex has shown activity against both gram-negative and -positive bacteria [7], while the anionic complex has shown activity against only gram negative bacteria. The most remarkable difference is found with the gram-positive bacteria Bacillus subtilis and Staphylococcus aureus; the neutral complex is active while the salt complex is not. Because both complexes are active against the gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the permeability [61] of the outer membrane of the gram-negative bacteria cannot be a factor. The results would suggest a mechanism for the antimicrobial function, which is determined not only by the structure of the anion and its conjugate acid but also by solubility and transport phenomena and by ligand exchange equilibria. So it can be concluded that, rather than the geometries of the silver(I) clusters, hydrophobicity or hydrophilicity of the clusters may account for observed differences in antimicrobial activity [10] in addition to the mentioned factors. In 2006, highly fluorinated tris(pyrazolyl)borate ligand [HB(3,5-(CF3)2Pz)3]¯ has been used in the isolation of airand light-stable silver complex, [HB(3,5-(CF3)2Pz)3] Ag(OSMe2) (OSMe2 = dimethyl sulfoxide) (22), a monomeric tetrahedral silver complex with an O-bonded dimethylsulfoxide ligand [11]. The silver(I) complex [HB(3,5(CF3)2Pz)3]Ag(THF) (THF = tetrahydrofuran) (23) was prepared using the corresponding sodium salt as described pre-


viously [62-63]. The complex 22 can be obtained by treating 23 with OSMe2 in hexane. Both silver(I) complexes, with Ag(I)–N and Ag(I)–O bondings, showed very similar antibacterial activity, and both showed greater activity against Staphylococcus aureus than silver nitrate or silver(I) sulfadiazine. The similar activity observed for 22 and 23 is not surprising since 23 to 22 conversion would be facile in the presence of OSMe2 [11]. A novel neutral tetrameric silver(I) cluster [Ag(mtsc)]4 (24) was obtained in 2007 from reactions of a tridentate 4Nmorpholyl 2-acetylpyridine thiosemicarbazone ligand (N´-[1(2-pyridyl)ethylidene]morpholine-4-carbothiohydrazide, Hmtsc) (Fig. 9) and silver(I) sources containing Ag–O bonds (Ag2O, Ag(OAc), silver(I) 2-pyrrolidone-5-carboxylate silver(I) 5-oxo-2-tetrahydrofura{[Ag(Hpyrrld)]2}, ncarboxylate {[Ag(othf)]2}, and silver(I) complexes with camphanic acid {[Ag(ca)]} and {[Ag(ca)(Hca)]}) [12]. A reaction of the Hmtsc and {[Ag(Hpyrrld)]2} in a 4 : 1 CH2Cl2/EtOH solvent, followed by crystallization from CHCl3, produced orange crystals of [Ag(mtsc)]4·2CHCl3. Even if an excess amount of Hmtsc or {[Ag(Hpyrrld)]2} was mixed, the isolated product was always complex 24. When water-soluble and light-stable silver(I) sources ({[Ag(othf)]2}, {[Ag(ca)]}, and {[Ag(ca)(Hca)]}) were used instead of {[Ag(Hpyrrld)]2} during the preparation, the carboxylate and carbonyl groups of the ligands (Hpyrrld, othf, and ca) disappeared in 30 min. These four watersoluble silver(I) complexes with Ag–O bonds produced the tetramer quantitatively over a short period of reaction time at room temperature, the resulting product was easily purified by washing with water. When a light-unstable silver material (Ag(OAc)) which was sparingly soluble in water was used, the reaction also completed within 30 min. When waterinsoluble Ag2O was used in the reaction, more than several hours were required to produce the tetramer quantitatively. The using of AgNO3 in the reaction was led to the formation of complicated mixtures containing silver(I), mtsc¯ ligand, and NO3¯ so that it was not possible to isolate the light-stable silver(I) complex after numerous trials. When 2acetylpyridine thiosemicarbazone (Hatsc) (Fig. 9) was used during the preparation, instead of Hmtsc, a light-unstable product was formed that contained both H2pyrrld (Fig. 9) and Hatsc ligands. These preparations indicated that the 4Nmorpholine group in mtsc¯ played an important role in the formation of the light-stable cluster. The obtained silver(I) cluster with an Ag4S4N4 core is a novel example of a lightstable AgI cluster with a tridentate thiosemicarbazone ligand. The free ligand (Hmtsc) showed a broad spectrum of moderate to effective antimicrobial activities against the test organisms (Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Candica albicans, Saccharomyces cerevisiae, Aspergillus niger, and Penicillium citrinum). The MIC values of the tetrameric cluster for the selected bacteria in water suspension were larger than 1000 g/cm3, which indicated no antimicrobial activity. When the tetramer was dissolved in CHCl3 and added to the test culture, it showed modest activities for bacteria. The tetramer did not inhibit the selected microorganisms when contacted in the solid state. The lack of activity in the water-suspension system could be attributed to the extraordinary stability or the low solubility of this complex [12].

N-Containing Complexes as Effective Antimicrobial Agents Me

Me N N


H N

N S

N

O N

Hmtsc

H N

H N S

Hatsc

O

O

N H

COOH

S-H2pyrrld


The synthesis, characterization, and plasma deposition of a novel organo-silver compound for the prevention of the growth of Pseudomonas aeruginosa on both polystyrene surfaces and polypropylene non-woven fabrics was reported in 2009 [13]. The problem of infection and colonization of medical devices by bacteria is gaining increasing publicity with stories of so-called hospital ‘superbugs’ now common in the media. Though receiving less publicity, Pseudomonas aeruginosa has been recognized as an emerging opportunistic nosocomial pathogen of clinical relevance [64]. Pseudomonas aeruginosa has become notorious for its resistance to antibiotics, in part due to permeability barrier afforded by its gram-negative outer membrane. Also, its tendency to colonies surfaces in a biofilm form makes the cells impervious to therapeutic concentrations of antibiotics [64-65]. These issues make the development of new antibiotics, or the generation of materials for which biofilm formation is inhibited, a significant challenge for both the materials chemistry and clinical medicine communities [66]. Silver has been proven as an effective antibacterial agent that can avoid defence mechanisms of such bacteria and prevent biofilm formation, the cause of acute infection. Most current technologies using silver require the silver to be included into the polymer matrix [13]. These approaches, while fairly effective, have two principal difficulties [67]: firstly, such coatings are expensive, pushing up the cost of medical devices such as catheters. Secondly, in some clinical situations, silver may have a retarding effect on cell growth, for example in burns [68]. Plasma deposition offers a low cost, highly industrially upscalable, and solvent free method for depositing thin polymer like films on surfaces [13]. It has the advantage of deposition taking place at near to room temperature, avoiding potential substrate melting which could take place in chemical vapour deposition (CVD), and the control of chemical group functionalities by altering the input energy [69]. Moreover, it allows for the straightforward coating of complex three dimensional objects such as tubes and fabrics. The phosphine-stabilized silver maleimide complex, [(Ph3P)2Ag(Mal)] (Mal = maleimide) (25), with a central three coordinate silver atom coordinated by the phosphorous atoms of two triphenylphosphine groups and the nitrogen of the maleimide group in a trigonal arrangement, was prepared by the reaction of silver nitrate with sodium maleimide (prepared in situ), in the presence of triphenylphosphine [13]. In that communication, the effectiveness of the complex in its monomer form was far greater than many other silver based small molecules such as silver sulfadiazine and after plasma deposition was an effective way of conferring antimicrobial properties to polymeric materials, especially otherwise hard to treat textiles. The films appear not to affect the growth of sensitive mammalian cells and to be particularly effective against Pseudomonas aeruginosa [13]. Binuclear complexes of Ag(I), Ag2(-L)2-type (L = 8-(2pyridinylmethylthio)quinoline ligand)) (Fig. 10), in which the ligand bridges two anion binding and Ag–Ag bonded

3031

ions, were reported in 2010 [14]. For obtaining the complexes, methanol solution of AgClO4 and AgNO3 was very slowly layered on top of the chloroform/acetone solution of ligand, the tube was sealed with film, and put in the dark for several days. Both complexes, [Ag2(L)2(ClO4)2] (26) and [Ag2(L)2(NO3)2] (27), are isostructural with different coordinated anions. The binuclear structure of 26 is composed from two Ag+ ions, two ligands and two ClO4¯ anions. The ligand serves as a bridge in complex, therefore, each silver(I) ion is coordinated by one quinoline N atom and one S atom from one ligand as well as one pyridine N atom from the other ligand. The remaining coordination site for Ag+ with the largest angle of about 151° involving the strongest bonding Npyridyl and S atoms is occupied by Nquinoline and an O atom from ClO4¯, resulting at first in a distorted 4-coordinate environment (2+2) coordination [70]. For 27 a monodentate nitrate ligand replaces the perchlorate. Biological activity studies showed that the ligand itself does not have obvious efficiency in restraining bacteria. Comparatively, these two complexes were most effective against gram (+) bacteria (S. u and Staphylococcus aureus), which may be related to the binuclear structures of these two complexes or to the provision of Ag+ [14].

N

N S


Synthesis of other new bioactive Ag(I) complex of four schiff bases prepared by condensation of 2-amino-pyridin-3ol with 3,4-dihydroxy-benzaldehyde (I), 2-hydroxybenzaldehyde (II), 5-bromo-2-hydroxybenzaldehyde (III), and 4dimethylaminobenzaldehyde (IV) (Fig. 11), Ag+-I (28), -II (29), -III (30), and -IV (31), was reported in 2010 [15]. The solid chelate of stoichiometric ratios (1 : 1) (M : L) for metal chelate was prepared by mixing the metal ion solution with a hot alcoholic solution of ligands, synthesized according to the recommended method for schiff base compounds [71]. As about ligand I, III, and IV, the data reflected that these three schiff base ligands have an activity in comparison with I, did not exhibit any remarkable activity against all the organisms (Gram-negative bacteria, Escherichia coli and Agrobacterium sp., and gram-positive bacteria, Staphylococcus aureus, Bacillus subtlus, and Bacillus megatherium). The complexes 28, 29, and 31 have moderate activity with different degrees whereas 30 showed no activity [15]. One of the applications of silver and its compounds, reported in 2010, is reduction of postoperative infections caused by implants [16]. The number of patients requiring an internal fixation device or artificial joint has grown rapidly. Bacterial infection induced by an implant placement is a significant rising complication and is associated with considerable morbidity and costs [72]. These device-related infections caused by Pseudomonas aeruginosa are usually acute and extremely difficult to treat [73-75]. Even immediate device replacement and long-term administration of high-dose antibiotics are often ineffective [76-77]. Clinical practice has shown that systemic antibiotics are unable to provide



OH H

H N

C

N

OH

C N

N

HO OH

OH

2-(1,2-Dihydroxybenzyldiaminomethyl)pyridine-3-diol (I)

2-(2-Hydroxybenzlideneamino)pyridine-3-ol (II)

Br H

H N

N

C

CH3

C

N

N

N OH

2-(5-Bromo-2-Hydroxybenzlideneamino)pyridine-3-ol (III)

CH3 HO

HO OH

2-[(4-Dimethylamino-benzylidene)-amino]-pyridine-3-ol (IV)


effective treatment for implant-associated infections. At the present time, only a high dose of antibiotics applied locally at the bone-implant interface can prevent such bacterial infections. However, this treatment causes a number of side effects, such as increased bacterial resistance to antibiotics, allergic reactions, and microbial flora depletion. Due to the rapid increase in use of artificial implants, it is critical that new infection-preventing strategies are developed, and in particular, antibacterial agents. Therefore, it is important to identify and study new metal-based compounds that will meet these demands. Pure organic compounds cannot meet these criteria, but some water-insoluble metal complexes, for example silver(I) compounds, can. Thus, intrinsically low toxicity silver compounds were loaded into several implant materials [78-80]. In this regard, ten silver(I) cyanoximates were synthesized [16]. Cyanoximes, compounds with the general formula HO–N=C(CN)–R, represents a new and special class of biologically active molecules [81] that are also capable of binding to different metal ions [82-84]. The presence of the CN-group significantly increases their acidity and makes them better ligands for binding metal ions as compared to conventional monoximes [16]. The complexes 2-(oximido)-2-benzoxazoleacetonitrile silver(I), Ag(BOCO) (32), silver(I) nitrosodicyanomethanide, Ag(CCO) (33), silver(I) -oximido-(acetamide)acetonitrile, Ag(ACO) (34), silver(I) -oximido-([n,n-dimethylamine]acetamide) acetonitrile, Ag(DCO)·0.5MeOH (35), silver(I) -oximido(ethylacetoxy)acetonitrile, Ag(ECO) (36), silver(I) oximido-(2-pivaloyl)acetonitrile, Ag(PiCO) (37), silver(I) oximido-(2-benzoyl)acetonitrile, Ag(BCO) (38), silver(I) oximido-(2-pyridyl)acetonitrile, Ag(2PCO) (39), silver(I) oximido-(2-[n-methyl]benzoimidazolyl)acetonitrile, Ag(BIMCO)·0.5H2O (40), and silver(I) -oximido-(2benzothiazolyl)acetonitrile, Ag(BTCO)·1.5H2O (41) are obtained from the reaction of L : K2 CO3 : AgNO3 = 2 : 1 : 2 in EtOH/water solvents, for abbreviation and structure of ligands see Fig. 12. All of these compounds represent coordination polymers of different complexity in which the metal center is covalently bound to ligands such as Ag–O and Ag– N. All studied AgL complexes are sparingly soluble in water and are thermally stable to 150 ºC. Synthesized compounds demonstrated remarkable insensitivity toward visible light and UV-radiation, which was explained based on their polymeric structures with multiple covalent bonds between bridging cyanoxime ligands and Ag(I) centers [16]. All 10 cyanoximates exhibited antimicrobial activity against the

tested infection agents (Escherichia coli, Klebsiella pneumoniae, Proteus sp., Pseudomonas aeruginosa, Streptococcus mutans, Staphylococcus aureus, Enterococcus hirae, Mycobacterium fortuitum, and Candida albicans). The lowest MIC value was detected for Ag(DCO) and Ag(PICO), which indicated their highest activity. These data suggested that hydrophobic methylated cyanoximes (Fig. 12) showed stronger inhibitory effect possibly due to their interactions with cell membranes which may help in complexes’ intracellular uptake. Investigated compounds soluble in DMF were remarkably more effective against clinical isolates from nosocomial infections (K. pneumonia 244, P. aeruginosa 2314, AMA, Enterococcus faecium VRE (vancomycinresistant), Streptococcus pneumoniae PCI, S. aureus MRSA (methicillin-resistant), and S. aureus MRSC (coagulasenegative methicillin-resistant) than to strains from the Collection of Microorganisms. However, the solubility of silver(I) cyanoximates in DMSO and DMF was limited, and, therefore, there was a need in conducting experiments with solid samples of synthesized AgL. Seven cyanoximates (32, 33, 35, 36, 37, 38, and 40) exhibited antimicrobial activity in the solid state as well, but their efficiency was strain dependent. All seven tested silver(I) cyanoximates inhibit bacterial growth and can be used as agents to prevent infections and biofilm formations [16]. The crystal structure and antibacterial activity of the first metal complex of 2-aminophenoxazine-3-one (L) also was reported in 2010 [17]. This silver(I) complex (42) is an important biological molecule and showed that the binding mode was through the phenoxazine ring nitrogen. 2Aminophenoxazine-3-one is a naturally occurring heterocycle and a core part of the well-known polypeptide antibiotic Actinomycin D, the first antibiotic shown to have anticancer activity, and has the good potential for coordination through the ring and/or terminal nitrogen donors [85-86]. 2aminophenoxazine-3-one and 2,3,5,6-tetrachloro-1,4hydroquinone co-crystallized in a 2 : 3 ratio by reacting o-aminophenol with p-chloranil under aerobic conditions in ethanol (Scheme 1). 2-Aminophenoxazine-3-one was reacted with AgNO3 in 1 : 1 acetonitrile/ethanol to yield dark red colored crystals of [Ag-2-aminophenoxazine3-one(NO3)]. The silver(I) is 6-coordinate with an unusual pentagonal pyramidal geometry, each nitrate ion chelating two adjacent silver ions. The base of the pyramid around the [Ag]+ is completed by the phenoxazine nitrogen.


Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 24 CH3

H2N

CN

O

N

H3C NC

N

NC

N

OH

NC

O

NC

N

OH

H(ACO)

O

C2H5O

N

OH

H(CCO)

NC

O

CH3

H3C

C

H3C

O

NC

N

OH

H(DCO)

H(ECO)

S

N

O

N

NC

3033

OH

H(PiCO)

N

N

NC

OH

OH

NC

OH H(BCO)

N

N

N

NC

N

N

H(2PCO)

N OH

OH

H(BTCO)

CH3

H(BOCO)

H(BiMCO)

Fig. (12). Abbreviation and structure of ligands in [16]. O Cl

OH

2

+ NH2

OH Cl

N

NH2

O

O

Ethanol

3 Cl

Cl O

Cl

Cl

+ Cl

Cl OH

L

Scheme 1. Synthesis of L in [17].

3-Aminophenoxazine-2-one has previously been shown to be inactive towards gram(-) Escherichia coli [87-88] and the silver complex have no activity towards this microbe. In contrast, 42 shows enhanced activity against gram(+) Staphylococcus aureus compared with free ligand, may be due to dissociation of the complex and release of silver ions in the cell [17]. The absence of activity of both ligand and complex towards Escherichia coli may be due to the greater challenges of penetrating the double layer cell wall in the gram(-) bacterium and it may be that neither L or 42 passes through in a DMSO solution [17]. THE USE OF MERCURY COMPLEXES AS ANTIMICROBIALS Synthesized Mercury(II) Complexes and their Antimicrobial Properties To the best of our knowledge, there are three reports of Hg(II)–N bonding complexes with antimicrobial activity. Synthesis of complex HgL(Cl2) (L = 2,6-bis(benzimidazol-2-yl)pyridine) (43) (Fig. 13), with penta-coordinated central ion surrounded by N3Cl2 environment, adopting a distorted trigonal bipyramidal geometry, was reported in 2007 [18]. The ligand is tridentate, via three nitrogen atoms to metal centre and two chloride ions lie on each side of the distorted benzimidazole ring. The corresponding complex was obtained from the reaction of ligand and HgCl2 in EtOH. Inhibition zone values (25, 29, and 30 mm) of the complex on Escherichia coli (gram negative), Staphylococcus aureus (gram positive), and Proteus vulgaris (gram negative) organisms are exceptionally effective compared with most of the reference antibiotics. Surprisingly, this complex have either

very weak or no effect under the given experimental conditions on Mycobacterium smegmatis and Listeria monocytogenes microorganisms. The inhibition activity seems to be governed in certain degree by the facility of coordination at the metal centre, and therefore the complexes show stronger activity against the tested microorganisms, compared to the free ligands. This supports the argument that some type of bimolecular binding most probably occurs to the metal ions causing the inhibition of biological synthesis and preventing the organisms from reproducing [18]. In classifying the antibacterial activity as gram positive or gram negative, it would generally be expected that a much greater number would be active against gram positive than gram negative bacteria. In this study, the compounds are active against both types of the bacteria, which may indicate broad spectrum properties [18].

N

N

N NH

HN


Synthesis of new bioactive Hg(II) complex of four schiff bases prepared by condensation of 2-amino-pyridin-3-ol with 3, 4-dihydroxy-benzaldehyde (I), 2-hydroxybenzaldehyde (II), 5-bromo-2-hydroxybenzaldehyde (III), and 4dimethylaminobenzaldehyde (IV) (Fig. 11), Hg2+-I (44), -II (45), -III (46), and -IV (47), was reported in 2010 [15]. The solid chelate of stoichiometric ratios (1 : 1) (M : L) for metal chelate was prepared by mixing the metal ion solution with a



hot alcoholic solution of ligands, synthesized according to the recommended method for schiff base compounds [71]. As about ligand I, III, and IV, the data reflected that these three schiff base ligands have an activity in comparison with I, did not exhibit any remarkable activity against all the organisms (Gram-negative bacteria, Escherichia coli and Agrobacterium sp., and gram-positive bacteria, Staphylococcus aureus, Bacillus subtlus, and Bacillus megatherium). The complexes 44, 45, and 47 have moderate activity with different degrees whereas 46 showed no activity [15].

pharmacological activity of the so-formed complexes [96101]. We have been interested in the structure-biological activity correlation of the different metal complexes [102106]. In this regard, since there is almost no data about mercury complexes of hydantoin derivatives, we devoted this study to the elucidation of the nature of hydantoin complexes with Hg halides in an attempt to illuminate the potential of these compounds. Recently, we have presented the preparation, spectroscopic, structural characterization, and theoretical studies of mercury(II) complexes with 5-methyl-5-(4-pyridyl) hydanroin (L) [107]. Room temperature reactions of HgX2 (X = Cl, Br and I) with L (1 : 2 M ratio) in CH3OH gave the mononuclear complexes 49–51 (Scheme 3). Based on X-ray analysis, complex 50 has a pseudotetrahedral mononuclear Hg(II) atom coordinated with two pyridine’s nitrogen atoms of the ligands and two bromides. Comparing the experimental and theoretical results have shown by exploring noncovalent interactions a very distorted tetrahedral structure with the smallest N–Hg–N, observed so far, and 3D network were constructed for this complex [107].

Antimicrobial agent schiff base Hg(II) complex (48) of (E)3-(2-(furanylmethylene)hydrazinyl)-3-oxo-N-(thiazol-2yl) propanamide (H2FH), containing N and O donor sites, have been synthesized in 2012 [19]. This ligand was prepared by heating a mixture of 3-hydrazinyl-oxo-N-(thiazole-2)propanamide and furfural under reflux in absolute ethanol (Scheme 2). The complex 48 was obtained by mixing equimolar amounts of H2FH with ethanolic and/or aqueous solution of chloride salt of Hg(II). In this complex, H2FH acts as a binegative tetradentate ligand coordinating via deprotonated enolized carbonyl oxygens (=C–O¯)1, (=C–O¯)2, azomethine nitrogen (C=N)1 and furfuryl oxygen (O–C–O)f. Their activity is greatly enhanced at the higher concentration [89]. The activity of the complexes against Clostridium sp., and Escherichia coli has been compared with the activity of a common standard antibiotic Ampicillin [19].

Antibacterial Study Test Organisms The standard strains of the following microorganisms were used as test organisms: Staphylococcus aureus (ATCC 6633), Staphylococcus saprophyticus (ATCC 15305), Escherichia coli (Lio), Proteus vulgaris (Lio), Serratia marcescens (PTCC 1330), and Bacillus cereus (ATCC 7064). Some microorganisms were obtained from Persian Type Culture Collection, Tehran, Iran and others locally isolated (Lio). The organisms were sub-cultured in nutrient broth and nutrient agar (Oxiod Ltd.) for using in experiments while diagnostic sensitivity test agar (DST) (Oxoid Ltd.) was used in antibiotic sensitivity testing.

Mercury(II) Complexes of 5-Methyl-5-(4-Pyridyl)-2,4Imidazolidenedione Synthesis and Structural Characterization The profound interest on different hydantoin derivatives stems from the well-established medical applications of some of them as antiepileptic drugs [90-91]. Recently, possible application for HIV-1 therapy has also been suggested [92-93]. It is well established that the type of the substituents at 5th position in the hydantoin ring is of crucial importance for the pharmacological action of the corresponding compounds [94-95]. On the other hand, their ability in formation of metal complexes with different coordination modes has also been extensively exploited, again with respect to the

H N

N S

C

H2 C C

O

O

H

O

N

C

NH2 + H

Sensitivity Testing For bioassays, suspension of approximately 1.5 108 cells per cm3 in sterile normal saline was prepared as described by Forbes et al. [108]. The sensitivity testing was

H N

N

O

S

C

H2 C C

O

O

H N

H N

O

Scheme 2. Synthesis of H2FH in [19]. X

O HN

Hg NH

O

N

O

HgX2 (X= Cl, Br, I) CH3OH, r.t. N

N

HN

NH HN

O

O

X=Cl (49), Br (50), I (51)

Scheme 3. Synthesis of HgL2X2 complexes in [107].

O

X NH

C



determined using the agar-well diffusion method [109]. In each disk of 30 dm3 of L and complexes 49-51were loaded. The bacterial isolates were first grown in nutrient broth for 18 h before use. The inoculum suspensions were standardized and then tested against the effect of the chemicals at amounts of 30 dm3 for each disk in DST medium. The plates were later incubated at 37 ± 0.5 ºC for 24 h after which they were observed for zones of inhibition. The effects were compared with that of the standard antibiotic Chloramphenicol at a concentration of 1 mg/cm3 [110]. The minimum inhibitory concentration (MIC) of chemicals was also determined by tube dilution techniques in MuellerHinton broth (Merck) according to NCCLS [111]. The experiments were repeated at least three to five times for each organism and the data are presented as the mean ± SE of 3-5 samples. Antibacterial Results and Discussion Herein we report the antimicrobial activities of the recently prepared Hg(II)–N bonding compounds (49-51), in comparison with those of a common standard antibiotic, Chloramphenicol. Antibacterial activity of chemicals was studied against both types of the bacteria ‘gram-positive and -negative’ (Staphylococcus aureus, Staphylococcus saprophyticus, Escherichia coli, Proteus vulgaris, Serratia marcescens, and Bacillus cereus) (Table 1). All prepared chemicals inhibited the growth of bacterial strains producing a zone diameter of inhibition from 20.0 to 40.0 mm, depending on susceptibility of the tested bacteria. The results indiTable 1.

Inhibition zones

Chemicals

Staphylococcus aureus

Staphylococcus saprophyticus

Escherichia coli

Proteus vulgaris

Serratia marcescens

Bacillus cereus

DMSO

–

–

–

–

–

–

HgCl2

–

–

–

–

–

–

HgBr2

–

–

–

–

–

–

HgI2

–

–

–

–

–

–

L

20 ± 4

–

–

–

–

–

49

40 ± 5

40 ± 4.5

34 ± 2.5

28 ± 2

40 ± 3

30 ± 2

50

40 ± 5.5

40 ± 5

26 ± 3

24 ± 2

40 ± 6

32 ± 4

40 ± 6

40 ± 3.5

26 ± 2

23 ± 2.5

34 ± 4

28 ± 2.5

25 ± 3.5

23 ± 5

24 ± 4.3

35 ± 8

22 ± 5

18 ± 2.5

L

12 (0.062)b

–

–

–

–

–

49

2 (0.003)

2 (0.003)

6 (0.009)

6 (0.009)

2 (0.003)

10 (0.015)

50

2 (0.002)

2 (0.002)

10 (0.013)

10 (0.013)

2 (0.002)

10 (0.013)

51

4 (0.004)

2 (0.002)

10 (0.011)

10 (0.011)

6 (0.007)

12 (0.014)

STD

2 (0.006)

4 (0.012)

8 (0.024)

4 (0.012)

4 (0.012)

1 (0.003)

51 STD

a

a

Chloramphenicol standard MIC values in mM unit Each datum represents the means ± SE of 4-5 samples. b

cate that the complexes show more activity and L does not have any activity against same microorganisms (except against Staphylococcus aureus) under identical experimental conditions. With comparing the antibacterial activities of complexes with those of reference antibiotic, Chloramphenicol, it is clear that all complexes have remarkable inhibitory potencies. As can be seen in Table 1, complex 49 has more inhibitory activity against the most bacteria than the other two complexes. Thus, it can be concluded that the decrease of Hg–X bond strength (as Hg–Cl > Hg–Br > Hg–I) leads to the reduction of antibacterial activity in most cases [102103]. This would be suggested that the strong chelation (with more polar bonds) could facilitates the ability of a complex to cross a cell membrane and can be explained by Tweedy’s chelation theory [21]. Chelation considerably reduces the polarity of the metal ion because of partial sharing of its positive charge with donor groups and possible electron delocalization over the whole chelate ring. Such a chelation could enhance the lipophilic character of the central metal atom, which subsequently favors its permeation through the lipid layer of the cell membrane [112]. The highest minimum inhibitory concentration (MIC) was evaluated for L (12 g/cm3) against Staphylococcus aureus, for 49 (2, 6, and 2 g/cm3) against Staphylococcus saprophyticus, Escherichia coli, and Serratia marcescens, respectively, for 50 (2 g/cm3) against Staphylococcus saprophyticus and Serratia marcescens, and for 51 (2 g/cm3) against Staphylococcus saprophyticus, which is stronger even than those of Chloramphenicol in this cases. The above-mentioned results indi-

Inhibition Zones (mm) and Minimum Inhibitory Concentration (g/cm3) of Ligand and Complexes Against Bacterial Strains.

Bacterial strains

MIC

3035


cate the studied complexes may be useful in the treatment of diseases caused by the bacteria tested. Further studies are needed to evaluate the in vivo potential of these compounds using experimental in animal models.

Sabounchei and Shahriary [2]

[3]

SUMMARY The antibacterial use of topical complexes containing N coordination functions is well established. Several silver(I) and mercury(II) complexes have been reported in order to attain this goal. It is confirmed that the complexes show stronger activity against the microorganisms than the free ligands. The enhanced activity of the complexes can be explained on the basis of Overtone’s concept and Tweedy’s chelation theory. In relation to the present review/research paper, we know in fact that the presence of lipophilic and polar substituents is expected to enhance the bacterial toxicity. It also has been observed that some moieties such as heteroaromatic nucleus introduced into such compounds exhibit extensive biological activities that may be responsible for the increase in hydrophobic character and liposolubility of the molecules in crossing the cell membrane of the microorganism and enhance biological utilization ratio and activity of complexes. The antimicrobial activity of Hg(II) complexes containing N coordination ligands has been scarcely reported than silver(I). For this reason, little is known about the mechanism of antimicrobial activity in mercury(II) complexes. Results suggest that at least one of the key factors determining the antimicrobial effects of silver(I) complexes is the kind of atom coordinated to the silver(I) center and their bonding properties, rather than their polymerization degree and whether or not the ligand is neutral. Since the silver(I)– N bound ligand can easily exchange with stronger donors such as S and P atoms, it should play an important role in showing the wide spectra of antimicrobial activities. From a viewpoint of metal-based drug design, no activity of the PPh3 derivatives is crucial and can be utilized. So, it can be proposed that for bacteria the inactivation targets of the silver(I) complexes are not nucleic acids as N/O donor ligands, rather but proteins as S donor ligands, which include the proteins indispensable to the survival of the microbes. In the silver(I) clusters, rather than the geometries of the clusters, hydrophobicity or hydrophilicity may account for observed differences in antimicrobial activity. In short, the potential use of silver(I) and mercury(II) complexes as effective antimicrobials has been introduced as a new area of research.

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

CONFLICT OF INTEREST The author(s) confirm that this article content has no conflicts of interest.

[14]

ACKNOWLEDGEMENTS We are grateful to Bu-Ali-Sina University for financial support.

[15]

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Received: July 16, 2013

Revised: August 29, 2013

Accepted: September 07, 2013

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