Current Medicinal Chemistry, 2012, 19, 3967-3981
3967
Palladacycles as Antimicrobial Agents A.-S.S.H. Elgazwy*,1, N.S.M. Ismail2, S.R. Atta-Allah1, M.T. Sarg3, D.H.S. Soliman3, M.Y. Zaki4 and M.A. Elgamas1,2 1 Department of Chemistry, Faculty of Science, Ain Shams University, Cairo, Egypt; 2Department of pharmaceutical chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia 11566, Cairo, Egypt; 3Department of pharmaceutical chemistry, Faculty of Pharmacy (girls' branch), Al azahar University, Nasser city, Cairo, Egypt; 4National Organization for Drug Control & Research, P.O. Box: 29 Cairo, Egypt
Abstract: This review article deals with the structure activity relationship (SAR) for a variety of palladacycles in biomedical applications. Moreover, the types of antibacterial, antifungal, antimycobacterial and antiprotozoal (antiamoebic and antitrypanosomal) activities will vary considerably from one country to another. Therefore, all efforts will be required to face such a vast diversity of problems. This study gives an up to date overview of the antibacterial, antifungal, antimycobacterial and antiprotozoal chemistry of the palladium group elements with an emphasis on the new strategies used in the development of new antibacterial agents. Methodologies for application of bulky aromatic or aliphatic nitrogen ligands, chiral organic moieties, chelates containing other donor atoms than nitrogen, and biologically active ligands in the design of agents analogous to palladacycles are presented. Therefore, the use of palladacycles in medicinal chemistry is interesting as potential application in the biological properties with less toxic drugs compounds..
Keywords: Palladacycles, organopalladium complexes, anti-bacterial, anti-fungal, anti-mycobacterial, antiprotozoal, anti-trypanosomal, antiamoebic. 1. INTRODUCTION Palladium compounds containing chelating ligands with at least one palladium–carbon bond are commonly known as palladacycles [1-9]. There has been a significant number of papers related to palladacycles in recent years and therefore this has provided a timely review on this subject [10-15]. Herein, we try to provide a more comprehensive update of the pharmacological potentials of palladacyclic covering a wide range of possible applications upon antibacterial, antifungal, antimycobacterial and antiprotozoal activities. There are two distinct types of palladacycle where the ligand is either an anionic four-electron donor (1) or a six-electron donor (2). These types of compounds were first characterized in the 1965 [16-17] but became prominent in the 1995s when their potential as catalysts for crosscoupling reactions was highlighted by Herrmann's palladacycles (3) [18]. The compounds have high thermal stability, permitting them to be used with low cost, but poorly reactive, aryl chloride substrate. There are many variations on basic structural types as shown in structures 1 and 2, that differ in nature of supporting donor atom Y (nitrogen, phosphorus or sulfur) [19], and the size of chelate ring. So, compounds related to structure 1 with bridging ligands X such as chloride, or acetate are common dimeric and may be neutral or charged. These compound deals with the photophysical properties of palladacycles and interactions with biological systems [19]. Since then, palladacycles have also played an important role in medicinal chemistry [20]. C
X
C
Y
X (1)
Y
Pd
Pd
Pd C
P X
(2)
(OAc) O-tol 2
lot-O (3)
Herrmann's palladacycle (3): trans-di(m-acetato)bis-[O-(di-Otolylphosphino)benzyl]dipalladium(II). Fig. (1). The structures of palladacycles (1), (2) and Herrmann's complexes (3).
*Address correspondence to this author at the Department of Chemistry, Faculty of Science, Ain Shams University, Cairo, Egypt; Tel: +202-24831836; Fax: +202-24831836; E-mail:
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2. PALLADACYCLE COMPLEXES ANTIBACTERIAL PROPERTIES
EXHIBITING
As early as 1996, a mechanistic study of the antibacterial effect of palladacycles was conducted by Kidd et al. [21] which was meant to check the influence of [Pd(ptz)2Cl2], [Pd(cpzH)Cl3] and [Pd(pzH)Cl3] (where ptz = phenothiazine, cpz = chlorpromazine, pz = promazine) on bacterial plasmid replication. The common Inactive exhibited extensive biological activities by the organopalladium (II) complexes disturbing the normal structure of the cell membrane; it was shown to inhibit the plasmid transfer during the conjugation of Escherichia coli through pili. Thus, it was concluded that the strategy exploited against polyresistant bacteria as part of combinatorial chemotherapy. (complexes could inhibit the transmission of R-factor plasmid amongst a bacterial population). Later on 2001, the work of Kovala-Demertzi et al. [22] on testing the biological properties of Pt(II) and Pd(II) complexes with 2-acetylpyridine thiosemicarbazone (HAcTsc), against Gram(+) and Gram() bacteria found a lethal effect on Gram(+) bacteria , while the same complexes showed no bactericidal effect on Gram() bacteria. In year 2003, the same groups [23] studied the antibacterial activity of 2-acetyl pyridine N(4)-ethyl-thiosemicarbazones (HAc4Et) complexes of the same metals [Pd(Ac4Et)], [Pd(HAc4Et)2]Cl2, [Pd(Ac4Et)2] and DNA interaction of some selected complexes to our concern. Since the heterocyclic thiosemicarbazone, 2-acetyl pyridine 4N-ethyl thiosemicarbazone (HAc4Et), has been prepared as described by Klayman et al. method [24]. The complexes of palladium(II) and platinum(II) with (HAc4Et), [Pd(Ac4Et)], [Pd(HAc4Et)2]Cl2 and [Pd(Ac4Et)2], have been prepared using experimental methods as it has also been described in literature by Kovala-Demertzi et al. [25-26]. The most sensitive microorganisms of E. coli, B. subtilis, B. cereus and S. aureus of tested bacteria B. cereus of Pt(II) and Pd(II) complexes were documented and three Pd(II) complexes [Pd(Ac4Et)], [Pd(HAc4Et)2]Cl2 and [Pd(Ac4Et)2] being most effective with MIC value of 6–12 g/ml. In contrast, not one of the compounds affected E. coli growth at concentration 100 g/ml. The test pDNA integrity and electrophoretic mobility resulted in a concentration higher than 3 mM for [Pd(HAc4Et)2]Cl2. The factors have led to irrationalized used and eventually emergence of resistance to tetracycline [27], exhibiting superior broad-spectrum characteristic to their low toxicity, oral bioavailability and low cost. The main mechanism involving binding to bacterial 30S ribosomal subunits was © 2012 Bentham Science Publishers
3968 Current Medicinal Chemistry, 2012 Vol. 19, No. 23
OH
H3C CH3
NH
CH3 Cl O
OH
Elgazwy et al.
Pd
Cl
OH
Cl
H3C CH3
NH
CH3 Cl O
O
OH
O
OH
NH2 OH
(4)
O
OH
O
NH2
(5)
CH3 Cl O
O OH
NH
Pd Cl
OH
O
H3C
CH3
OH
O
OH
O
Pd Cl O
NH2
(6)
Fig. (2). Tetracycline (4), Chlortetracycline (5) and Doxycycline (6) palladium complexes.
prevented codon-anticodon interaction between tRNA and mRNA. Thus, prevented protein synthesis, existing in magnesium complex intracellular has proven to be essential for such binding [28]. Hitherto, the two most important resistance mechanisms identified were ribosomal mutation and Tc efflux mechanism [29]. The TetA was identified as a transmembranal antiporter of the monocationic magnesium-Tc for a single proton with transport rate depending on the metal-Tc complex stability [30]. This has evoked ChartoneSouza et al. [31] to study effect of Pt-Tc complex on Tetracyclineresistant strains that proved to be six folds more active. In continuation of the research group's work with Guerra et al. [32] three palladium complexes, as outlined in Fig. (2) were screened against two sensitive strains E. coli HB101 and E. coli ATCC25922 and in a resistant one E. coli HB101/pBR322. The results in Table (1) display clear importance of the proposed strategy as exemplified by the 16 fold increased in activity of the [Pd(Tc)Cl2] over tetracycline (4). The square planar of palladium (II) complexes [Pd(NS)2] (NS = uninegatively charged acetone Schiff bases of S-methyl- and Sbenzyldithiocarbazate) was prepared and screened for their antibacterial, antifungal and cytotoxic activities. In spite of the strong antibacterial activities exhibited by the schiff bases against B. subtilis (mutant defective DNA repair), methicillin-resistant S. aureus, B. subtilis (wild type) and P. aeruginosa of the corresponding complexes they have indeed shown to be inactive on contrary to the cytotoxicity screening results [33]. On their description of coordination behavior and biopotency of some semicarbazones and thiosemicarbazones complexes with Pd(II) complexes, Singh et al. [34] have assessed the antibacterial and antifungal activities of 5-chloro-1,3-dihydro-3-[2-(phenyl)ethylidene]-2H-indol-2-one-hydrazinecarbothioamide and 5-chloro1,3-dihydro-3-[2-(phenyl)-ethylidene]-2H-indol-2-onehydrazinecarboxamide of palladium (II) complexes and the activities were almost two folds higher than those of the free ligands. The complex of Pd(L)Cl2, (L = 1,3-bis(2-benzimidazyl)-2thiapropane) was tested against antibacterial and antifungal activities such as S. aureus, E. coli, E. aerogenes, K. pneumoniae, A. faecalis, C. freundii, S. pyogenes, P. vulgaris, P. mirabilis and E. faecalis the results were compared with those of ampicillin, ciprofloxacin, cefazolin, ofloxacin, and piperacillin antibacterial agents. Table 1.
Most cases of free ligand and Pd(II) complex show broadspectrum Gram (+) and Gram () activities that are either, more active or equipotent to the antibiotic and/or antifungal agents in the comparison tests [35]. In condensation product 2(diphenylphosphino)benzaldehyde and semioxamazide ligand of Pd(II) complex have proven to be more active against Staphylococcus aureus, E. coli and S. Enteritidis (MIC = 0.7, 0.77, 0.77 mM respectively)[36]. It was described by Mishra et al. [37] that the novel Pt(IV) and Pd(II) thiodiamine complexes of [Pt(L)2Cl2], [Pd(L)Cl2] (L = (cyclohexyl-N-thio)-1,2ethylenediamine or (cyclohexyl-N-thio)-1,3-propanediamine), (L = 1,1-diphenyl-2-thiosemicarbazide or (1,1-diphenyl-2-thio)-1,3propanediamine) [38], and (L = 1,1-diphenyl-2-thiosemicarbazide or (1,1-diphenyl-2-thio)-1,3-propanediamine)[39] have moderate antibacterial and antifungal activities. Through the research work of Shaheen et al. [40], the antibacterial and cytotoxic activity of six Pd(II) complexes such as [Pd(L)2] (L=piperidinedithiocarbamate (7), 4-methylpiperidinedithiocarbamate (8), N-methylbenzyldithiocarbamate (9), dibenzyldithiocarbamate (10), dicyclohexyldithiocarbamate (11) and N-cyclohexyl-N-methyldithiocarbamate (12) was investigated. The antibacterial activity of selected Pd(II) complexes has been determined against six strains of bacteria (E. coli, B. subtilis, S. flexenari, S. aureus, S. typhi, and P. aeruginosa) compared to the standard drug (imipenum), especially for complexes (9) and (12) with which clearly accreted the inhibition zone of imipenum for Salmonella typhi. The binuclear complexes of Pd(II) chloride, [(2-(L)PdCl]2·C2H5OH (L=1,6-bis(benzimidazol-2-yl)-3,4-dithiahexane) were synthesized and tested across ten bacterial and five fungal species, that boe a broad-spectrum property and activity close to equipotent pharmaceutical agent [41]. The monobasic bidentate Schiff base complexes of palladium(II) and platinum(II), derived from the parent ligands exist in the tautomeric forms of 1H-indol-2,3-dione-semicarbazone (L2H) (13) and 1H-indol-2,3-dione-thiosemicarbazone (L1H) (14), were prepared followed by the literature method [42]. A methanolic solution of PdCl2 was mixed with a nappropriate ligand in 1:2 molar ratio and that has been spectrally and biocidally studied as depicted in Fig. (4).and [43] The preparation of [Pd(LH)2]Cl2 and [Pd(L)2] (L = L1 or L2) against S. Aureus and E. coli was observed and screened by Biyala et al. The palladacycles showed inhibition zones slightly smaller than that of the standard drug (streptomycin) with a concentration dependent inhibition manner.
MIC Values for the Tetracyclines and their Corresponding Complexes [32].
Bacterial strain
MIC (M) Tc
[Pd(Tc)Cl2]
Dox
[Pd(Dox)Cl2]
Chlor
[Pd(Chlor)Cl2]
ATCC25922
4.16
2.08
8.23
4.16
2.08
4.16
HB101
2.08
2.08
2.08
2.08
2.08
4.16
HB101/pBR322
266.20
16.60
66.50
33.30
66.50
66.50
Palladacycles as Antimicrobial Agents
Current Medicinal Chemistry, 2012 Vol. 19, No. 23
S
S
N
Pd
N
S
S
S
S
Pd
N
(8)
Pd
Pd
N
N
N S
S
S
S
S
S
CH3
S
S H3C
N S
S
(7)
N
3969
(9) (10)
S
S Pd
N
H3C
N
S
S Pd
N
S
S
N S
S
CH3
(11) (12)
Fig. (3). The structures of the palladium dithiocarbamate complexes (7-12) [40].
OH
SH
H2N
H2N N
N
N
O
N
O N H
N H
(13)
(14)
Fig. (4). The structures of the palladium complexes of 1H-indol-2,3-dione semicarbazone (L2H) (13) and 1H-indol-2,3-dione thiosemicarbazone (L1H) (14).
More recently, palladium (II) bromide complexes of thioamides of [PdL2Br2] and [PdL4] Br2 (L= thiourea, methylthiourea, dimethylthiourea, tetramethylthiourea, Imidazolidine-2-thione, mercaptopyridine, mercaptopyrimidine and thionicotinamide) were synthesized and screened for their antibacterial effects against four strains of bacteria. The observed antibacterial activity of palladacycles compared to the standard drug (imipenum) with thiourea complex exhibited strongest activities against two bacteria, S. aureus and P. aeruginosa and methylthiourea complex was the least effective one. In general, It was observed that the complexes displayed more effective antibacterial activities than the free ligands except in the
case of mercaptopyridine [44]. Khan et al. [45-46] have synthesized six new steroidal thiosemicarbazone derivatives 15a-f, as shown in Fig. (5) on two separate studied palladium complexes tested against S. aureus, S. pyogenes, S. typhimurium, and E. Coli compared to the standard drug of amoxicillin. The activity of the organo palladium complexes reportedly was highest than the corresponding ligands. That study which exhibited broadness of spectrum of the results bearing much similitude which could be rendered to the similar ligand environments. The cyclopentyl-containing complex exhibitied a higher MIC value than amoxicillin against all tested species [46] and orthotoludine complex of E. coli [45]. As Rosu et al. [47] reported that the new complexes of Cu(II) and Pd(II) with 2-hydroxy-8-R-tricyclo-[7.3.1.0.2,7]tridecane-13one thiosemicarbazone (R = n-propyl, furyl), some of the copper complexes of the compounds exhibited a concentration dependant antiproliferative activity in the range of 1-10 M as well as good antibacterial activities. Trifunovic et al. [48] synthesized propyl, butyl and pentyl esters of the (S,S)-ethylenediamine-N,N"-di-2propanoic acid (H2-S,S-eddp) as a dihydrochoride are presented in Fig. (6). The esters are slightly soluble in water and in common organic solvents. Palladium(II) complexes [PdCl2(R2-S,S-eddp)] were synthesized by mixed aqueous solution of the K2[PdCl4] and corresponding alkyl esters. The obtained complexes were soluble in chloromethane, dichloromethane, trichloromethane and tetrachloromethane, methanol and ethanol, but not in water or other common organic solvents. The results of microanalysis data
H N
S
N
(15a-f)
R
R=
H
H
N
a
H
N
b
H N
N
c
Fig. (5). Ligand environments of the steroidal thiosemicarbazone complexes 15a-f.
d
H
N
e
H
N
f
3970 Current Medicinal Chemistry, 2012 Vol. 19, No. 23
confirmed the predicted content of the isolated complexes. The most important bands in the infrared spectra of the isolated dialkyl esters (L1, L2 and L3) of S,S-eddp ligand and corresponding palladium(II) complexes (C-1, C-2 and C-3) are given. The infrared spectra of the listed complexes confirmed the expected N–N coordination of the R2-S,S-eddp ligands to the palladium(II) ion. Indication to R2-S,S-eddp coordination via nitrogen ligand atoms can be proved by the presence of the bands for stereospecific ligands and their complexes. Cl H
Cl Pd
H
(S) N
N (S)
O
O
(S) RO
(S)
Elgazwy et al.
having less promising results and a few have proven highly efficacious. To the best of our knowledge the first standardsuperseding results were reported in 2005 by Agh-Atabay et al. [35] in which palladium as well as zinc complexes of the ligand: 1,3bis(2-benzimidazyl)-2-thiapropane were screened against bacterial species, as shown in Fig. (9). Although the complexes were not quite effective, they have realized very strong antifungal and penetrating activity on all three bacterial species (C. albicans, C. utilis, C. neoformans). It was suggested that the most favorable biomolecular target would be the zinc metalloenzyme phosphomannose isomeraze (PMI) which played an important role in organisms’ cell wall biosynthesis and was inhibited by silver sulfadiazine. Clinically, this complex was used as a topical antibacterial and antifungal agent, through binding of metal center with the cysteine in proteins [38].
OR
C2 (16) (S,S)
Fig. (6). The preparation of propyl, butyl and pentyl esters of (H2-S,S-eddp) and palladium (II) complexes of [PdCl2(R 2-S,S-eddp)] (16) where R = n-Pr, n-Bu and n-Pe.
Antimicrobial activity of palladium(II) complexes with some alkyl esters of (S,S)-ethylenediamine-N,N'-di-2-propanoic acid (H2S,S-eddp) has proven good micro-molar inhibitory and cidal values against eight different species that was indiscriminative against either of probiotics or pathogenic strains. Interestingly, they have shown to be extremely effective against Aspergillus spp., especially Aspergillus flavus, against which the three complexes proved approximately 1000-folds more active than fluconazole. It was noticed that the glycyl–glycine with several potential donor atoms could be a good choice to condense with ophthalaldehyde to develop binucleating Schiff-base Ligands. Geeta et al. [49] have synthesized, characterized and investigated the application of Pd(II) metal complexes as potential antibacterial agents and demonstrated [Pd2L] where L = 2-(2-[((E)-1-2-[(2[(carboxymethyl)amino]-2-oxoethylimino)methyl] phenyl methylidene)amino] acetylamino)acetic acid (CMAIPA), as shown in Fig. (7).
Fig. (8). MIC values (in g/mL) of complexes and standard drugs against different bacteria [49].
Taking into account the effects of high affinity of the palladium center with nitrogen atoms (such as in proteins and nucleobases), the mechanism of action of the metal center might be plausibly similar to that of the silver agent [50]. In continuation with the same team two years later have the binuclear complex [(2SCH2CH2NHNCC6H4)PdCl]2 against fourteen different organism compared to bacterial species and fungi was synthesized and assessed. Moderate to strong bactericidal activities were noticed superseding the standard (gentamycin) against S. aureus, M. smegmatis, L. monocytogenes and M. luteus. Meanwhile, the complex showed a more active antifungal activity than the standard nystatin against all tested species such as C. albicans, K. fragilis, R. rubra, H. guilliermondii, D. hansenii [51-53]. S
N
N
O
HN
O
NH
Pd Cl
O
O
O
Cl
N
N
Pd O
NH
HN
Pd
N Cl
(18)
N
S
N Pd
N
Pd S
Cl (19)
(17)
Fig. (7). The binuclear CMAIPA-Pd complex (17).
The compounds were screened for their antibacterial activity against two gram-positive and two gram-negative bacterial strains. Interestingly, the most potent activity was observed in Pd(II) complex against all tested strains when compared to respective standard drugs streptomycin and ampicillin, as described in Fig. (8) [49]. 3. PALLADACYCLES COMPLEXES EXHIBITING ANTIFUNGAL PROPERTIES In spite of brevity of the number of studies on antifungal activities of palladacycles, with the majority being negative and
Fig. (9). Palladium complexes of 1,6-bis(benzimidazol-2-yl)-3,4dithiahexane (18) and 1,3-bis(2-benzimidazyl)-2-thiapropane (19) [35,41].
Dialkyl (S,S)-ethylenediamine-N,N´-di-2-propanoic acid esters (n-Pr, n-Bu and n-Pe) of Pd(II) complexes further investigated which showed a moderate activity against antifungal and antibacterial agents.With respect to pathogenic and probiotic organisms of Aspergillus spp. compared to the tested fungi, the complexes showed a significant antifungal activity. All three complexes inhibited the growth of A. flavus at concentration of 0.49 g/mL which is approximately 1000-folds more active than fluconazole, while [PdCl2 (dpe-S,S-eddp)] complex affected A. fumigatus at low concentration (MIC was 7.8 g/mL than fluconazole at concentration MIC >500 g/mL). The MIC values
Palladacycles as Antimicrobial Agents
Current Medicinal Chemistry, 2012 Vol. 19, No. 23
O
O F
N
CO2H
N
N HN
HN
O
F
CO2H
Ciprofloxacin (20)
F
N O
N
H3C
CH3
O
O F
CO2H
N H3C
F
HN
CH3
Ofloxacin (22)
CO2H
N
N
O
F H3C
CO2H
N
Levofloxacin (21) NH2
3971
N
N
HN
CH3 Sparfloxacin (23)
OMe Gatrifloxacin (24)
Fig. (10). Fluoroquinolones (20-24) used as Ligands.
for yeast C. albicans were 125 g/mL for all three complexes, while the minimum fungicidal concentration (MFC) was 250 g/mL except for [PdCl2(dbu-S,S-eddp)] where it was 500 g/mL [51]. Palladium complexes of schiff bases derived from sulfanilamides or aminobenzothiazoles were screened against A. niger and A. flavus. However, only a single aminobenzothiazole revealed appreciable activity against both fungi [52]. The palladium complexes of pyridinecarboxaldimines have also been investigated as active antifungal agents against A. niger, A. flavus, C. albicans, and S. cerevisiae. Only the oleyl derivatives of the complex showed promising activity against all fungi tested in this study [53]. Palladium(II) complexes of 2-acetylpyridine N (4)-propyl, N(4)dipropyl- and 3-hexamethyleneiminylthiosemicarbazones were reported to have insignificant antifungal activities [54]. Also, more negative results have been reported on various chemical classes of the bis(N-arylsalicylaldiminato)palladium complexes [55], transbis(N-arylsalicylaldiminato)palladium complexes [56], binuclear palladium complexes[57] of [(3,5-dimethylpyrazole)2Pd2(-3,5dimethylpyrazolate)2(2,6-dipicolinate)](cyclohexyl-N-thio)-1,2ethylenediamine and (cyclohexyl-N-thio)-1,3-propanediamine as well as purine and pyrimidine thiolates tertiary phosphines palladium complexes. 4. PALLADACYCLES COMPLEXES ANTIMYCOBACTERIAL PROPERTIES
values for Rifampicin and Gatifloxacin (MIC = 1, 0.1 g/mL respectively) were taken as standards consideration. The most active complex being that of sparfloxacin at concentration (MIC = 0.31g/mL), while the ciprofloxacin palladium complex at concentration (MIC = 1.25 g/mL) has shown to be less active than rifampicin. In contrast the three other complexes showed the same level of activity at concentration MIC = 0.62 g/mL [60]. In continuation to the pursuit of new prepared palladium (II) compounds bearing thiourea-type ligands with promising biological activities [61]. Moro et al. [62] have reported antimycobacterial activities of [Pd(C2,N-dmba)(Br) (tu)] and [Pd(C2,N-dmba)(Cl)(tu)] (dmba = N,N-dimethylbenzylamine, tu = thiourea) as described in Fig. (11). The compounds were found to be less effective than isoniazide at concentration (MIC value of 0.03 mg/mL). On the other hand they showed to possess higher inhibitory activity than pyrazinamide at different concentration (MIC value of 50–100 mg/mL), while with bromido derivative being more active than its chlorido counterpart at concentration (MIC = 31.2, 23.0 g/mL) respectively [63]. CH3
H3C
Pd
The activity of the complexes against Mycobacterium tuberculosis virulent strain H37Rv was determined and the MIC
S NH2
Pd
Cl (25)
Vieira et al. [59] have exploited the utilities of five fluoroquinolones as ligands for both Pd(II) and Pt(II), in which the ligands have coordinated to palladium(II) through bidentate manner via carbonyl and carboxyl oxygens but the unlike platinum(II) which has occurred via the piperazine nitrogen atoms, as shown in Fig. (10).
NH2
N
S
EXHIBITING
Although there have been extensive efforts on the promising potential of Pd(II) complexes as anti-tubercular activity, the studies concerned with these activities are scarce and quite recent [58] due to the superiority of fluoroquinolones in terms of pharmacokinetic characteristics of antiparasitic and antimycobacterial. The broadness of spectrum and adopting the strategy of metal coordination to the biologically active molecules were aimed to enhance the activity or overcome the resistance.
CH3
H3C NH2
N
NH2 Br
(26)
Fig. (11). The tested chlorido (25) and bromido (26) derivatives of [Pd(C2,N-dmba)(X)(tu)].
More recently and in continuation of their research on biological chemistry of Pd(II) complexes, de Souza et al. [64] have synthesized and evaluated four Pd(II) complexes with general formula [PdX2(isn)2] (isn = isonicotineamide) for their antimycobacterial (see Table 2) and cytotoxic activity against murine tumor cell lines (LP07 and LM3). Following the strategy of replacing the labile halide ligand by pseudohalide (X = N3, SCN, NCO) palladium complexes enhanced the stability and biological activity [65]. All complexes proved to be more active than pyrazinamide as anti-tubercular agents. As it was expected of anionic ligand complexes they have shown significant effect of potency, with the azido derivative and the most active antitubercular activity, as shown in Table 2.
3972 Current Medicinal Chemistry, 2012 Vol. 19, No. 23
Table 2.
Elgazwy et al.
MIC Values of the isn (isn = Isonicotineamide) and their Palladium (II) Complexes Against M. tuberculosis H37Rv [63] and a Standard Drug [66] Compound
MWt
MIC (mol/L)
MIC (g/mL)
Isonicotinamide
122.12
>2047
>250
NaN3
65.01
599.9
39
NaSCN
81.08
>1542
>125
KNCO
81.11
>1541
>125
[PdCl2(CH3CN)2]
252.43
495.2
125
trans-[PdCl2(isn)2]
421.58
296.5
125
trans-[Pd(N3)2(isn)2]
434.72
35.89
15.6
trans-[Pd(SCN)2(isn)2]
466.83
267.8
125
trans-[Pd(NCO)2(isn)2]
434.70
287.5
125
Pyrazinamidea
123.11
406.1-812.2
50-100
S S N
N
N
N N H
S
2-Acpy-SMDT (27)
S N H
S N
2-Acpy-SBDT (28)
N
N H
NH2
2-Acpy-TSC (29)
Fig. (12): Structures of schiff bases (27-29) used as Ligands [75].
5. PALLADACYCLES COMPLEXES EXHIBITING ANTIPROTOZOAL PROPERTIES 5.1. Palladacycle Complexes Exhibiting Antiamoebic Properties The amoebiasis, caused by Entamoeba histolytica, an early branching eukarya, is one of the major threats to public health in much of the developing world. More than 50 million people worldwide are infected and up to 110,000 die every year due to amoebiasis [67]. It is the third most common parasitic disease in humans after malaria and schistosomiasis [68,69]. The metronidazole (MTZ, 1[2-hydroxyethyl]-2-methyl-5-nitroimidazole) was antibacterial and antiprotozoal drugs have been used for over 35 years. In the event of clinical resistance to metronidazole in aerobic protozoa and since there is no alternative treatment for invasive amoebiasis, the resistant strains have already been identified and their effectiveness in eliminating the parasite has been studied [70-74]. In year 2000, Azam et al. [75] were the first who reported strong effectiveness of anti-amoebic palladium complexes, the complexes were derived from S-methyl-dithiocarbazate, S-benzyldithiocarbazate and thiosemicarbazide ligands, as described in Fig. (12). The activities shown in Table 3 of palladium complexes have been potential activities of dithiocarbazate ligands around two folds more active than metronidazole. Noteworthy, the compounds have exhibited dose dependent inhibition against the trophozoites. Table 3.
In Vitro Activities of Ligands and their Complexes Against E. histolytica (HK-9) [75] Compound
Antiamoebic Activity (IC50 g/mL)
2-Acpy-SMDT
0.39
[Pd(2-Acpy-SMDT)Cl2]
0.19
2-Acpy-SBDT
0.38
[Pd(2-Acpy-SBDT)Cl2]
0.16
2-Acpy-TSC
0.33
[Pd(2-Acpy-TSC)Cl2]
0.33
Metronidazole
0.33
In year 2002, they have presented and documented in vitro and in vivo results of the metronidazolePd(II), Pt(II) and Cu(II) complexes [76]. Interestingly, the palladium complex of metronidazole showed the highest in vitro IC50 in the range of 0.085 – 0.148 M and 14-folds more active than metronidazole ligands. In vivo tests on hamsters with systematic experimental amoebic hepatic abscess reducing 71-92% in the EAHA score compared 4058% by metronidazole [76]. The same groups of two following studies focused on thiophene-2-carboxaldehyde thiosemicarbazones [77] (30) and 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones [78] (31) and their corresponding complexes, as shown Fig. (13). The outcomes of both studies were more or less similar as in two of them, the palladium complexes have proven to be more active than their respective activities (IC50 in the ranges 1.65-2.41 and 0.96-2.56 M). But it was most likely that inhibition of specific properties of acanthamoebae was a consequence of the initial amoebicidal-amoebistatic effects tended to interpret complexationenhanced activity on the basis of Tweedy's theory [79]. Chelation reduced the polarity of the central metal atom due to partial sharing of its positive charge with the ligand, which favors permeation of the complexes through the lipid layer of cell membrane. The presence of bulky groups at position N4 of the thiosemicarbazone moiety enhanced antiamoebic activity. Three groups of novel pyrazolinepalladium (II) complexes characterized by Azam et al. [80-84] were more active than their parent ligands. Table 4 displayed the IC50 values of the pyrazoline complexes (32), where six out of substituted compounds 1a-8a bore a higher activity than metronidazole mostly in submicromolar amounts [85]. More novel derivatives of 1-N-substituted thiocarbamoyl-3,5-diphenyl-2-pyrazoline complexes 1b-8b where further screened [83]. Interestingly compounds 1b-3b showed distinct difference in amoebicidal properties of ortho, meta and para isomers and the most active of them the para isomer of an IC50 in nanomolar range (IC50 = 0.05 M, S.D = 0.04) [83]. In addition to the antiamoebic activity the toxicity profiles against human kidney epithelial cells were assessed and the safety index (SI) for the 1-N-substituted 3-phenyl-2-pyrazoline palladium complexes (1c-10c). Besides their higher-than-standard activity the
Palladacycles as Antimicrobial Agents
Current Medicinal Chemistry, 2012 Vol. 19, No. 23
R= -NC4H8, R= -NC9H10, NH R= -NHC7H6Cl, S R R= -NHC6H3F2, R= -NH C6H3F2 (30)
N
Cl Pd Cl
NO2
S
S
N
Cl Cl
R= -NC7H14, R= -NC6H12, R= -NC12H16, R= -NC4H8, R= -NC4H10
NH
Pd S
R (31)
Fig. (13). Palladium complexes (30) and (31) [77,78]. Table 4.
Activities of Pyrazoline Derivatives Palladium Complexes Against HM1: IMSS strain of E. Histolytica. [76,83-86] Compound
#
Ph
1a
Substituent (R)
IC50 (M)
S.D.
2.24
0.05
1.44
0.06
0.70
0.15
0.42
0.05
2.08
0.06
0.77
0.06
0.83
0.09
0.90
0.05
4.58
0.08
HN
Ph
N
Pd Cl
N
Cl
S
R
1a 2
a
HN
(32)
(2a) 3
a
HN
(3a) 4
a
HN
(4a) 5
a
6
a
N (5a)
N (6a) 7a
N (7a)
8
a
N
(8a) 1
b
HN
(1b)
3973
3974 Current Medicinal Chemistry, 2012 Vol. 19, No. 23
Elgazwy et al.
(Table 4). Contd….. Compound
#
Substituent (R)
2b
IC50 (M)
S.D.
1.82
0.04
0.05
0.04
1.24
0.07
0.70
0.05
0.76
1.04
0.40
0.02
1.10
0.08
5.65
0.01
1.68
0.19
3.57
0.03
1.76
0.02
1.81
0.02
HN
(2b) 3
b
HN
(3b) 4
b
N H Cl (4b) 5
b
N (5b) 6
b
N
N (6b)
7
b
Ph
N
8b
N (8b) Cl
Cl
1
c
2
c
3
c
4
c
NH2
Pd S
(1c)
N N
N
R (33)
(2c) H
N (3c)
H
N (4c)
5c
HN
(5c)
Palladacycles as Antimicrobial Agents
Current Medicinal Chemistry, 2012 Vol. 19, No. 23
3975
(Table 4). Contd….. Compound
#
Substituent (R)
6c
IC50 (M)
S.D.
1.49
0.18
1.39
0.05
0.37
0.03
0.58
0.01
0.82
0.02
HN
(6c) 7c
HN
(7c) 8
c
N
N (8c)
9
c
HN
(9c) 10
c
Cl
NH (10c) [Pd(DMSO)2Cl2]
-
-
8.15
270.27), thus providing a very promising range of novel therapeutics [84]. Following the same trend of the researchers [86] who have investigated two groups of separate studies of novel Indole-3carboxaldehyde thiosemicarbazone Pd(II) complexes (34), as outlined in Table 5. [85-86] Expectedly, all of the complexes were more active than their thiosemicarbazone free ligands, five complexes of which (1d-7d) possessed higher activities than metronidazole [85]. Later on, aliphatic (1e-7e) and aromatic (8e-13e) 1-N-substituted 3-indole carboxaldehyde thiosemicarbazone complexes were tested with their ligands and their toxicity assessed against human kidney epithelial cells [87]. It was noticed that the positive relation between the bulkiness of the N4 position substituents and that the N1 aromatic-substituted compounds was more active than their alkyl-substituted counterparts in all of the former superseding metronidazoles (IC50 = 1.18 M, SI > 55.24) in terms of activity. Noteworthy, compound 12e was the most active amongst the other compounds as well as the least toxic (IC50 = 0.29 M, SI > 344.82) [87]. Regarding to the liability of thiosemicarbazones, Bernhardt et al. [88] have proposed that thiosemicarbazones from metallic complexes are displaced (dissociated) under physiological conditions. On the other hand, the metals act as lipophilic vehicles, facilitating the intracellular delivery of the metal-free thiosemicarbazones into cellular compartments. In light of these findings, it was supposed that the processes of precomplexation and dissociation play a pivotal role in determining
the pharmacological potency for the metallic complexes described by Bahl et al. [89] in their Structure–activity relationships (SAR). The mononuclear metal–thiosemicarbazone of antiplasmodial and antiamoebic activities was assessed for Pd(II) complexes as well as for other metals. Out of four, two of the palladium complexes exhibited the highest antiamoebic activity among the fourteen complexes of four transition metals of N4 furfuryl substituted thiosemicarbazones and metronidazole. Moreover, the complexes were found to interact with denatured DNA by findings of the UV-vis absorption spectra of agarose gel electrophoresis assays using pBR 322 plasmid DNA. The complexes of (Cu(II), Pd(II)) did not alter either the migration of plasmid DNA bands or other interaction processes (cleavage, for instance) to a significant degree at a concentration of 50 M. 5.2. Palladacycles Complexes Exhibiting Antitrypanosomal Properties In the light of the facts that trypanosomes possess an extraordinarily advanced antigenic variation capacity, the development of effective new vaccines against these parasites is at a standstill. While the chemotherapy still stands in a compromised position relying on rather obsolete drugs that were developed more than half a century ago and exhibiting established side-effects [90]. Some of the metallo-therapeutics development research was relevantly oriented. Inspired by the fact that trypanosomes require porphyrins for growth and the porphyrin pathway in the trypanosomatidae is a potentially important target for the development of new trypanocidal agents that selectively block the formation or
3976 Current Medicinal Chemistry, 2012 Vol. 19, No. 23
Table 5.
Elgazwy et al.
Activities of indole-3-aldehyde thiosemicarbazone palladium complexes (34) against HM1: IMSS strain of E. histolytica [85-86] Compound
#
Substituent (R)
1d
IC50 (M)
S.D.
0.98
0.02
0.62
0.02
1.18
0.08
2.32
0.02
0.47
0.06
1.85
0.03
0.78
0.08
3.57
0.02
4.06
0.02
1.44
0.11
2.78
0.08
1.24
0.13
2.22
0.08
2.14
0.08
1.30
0.09
0.58
0.02
0.52
0.07
HN
HN
2
d
HN
N
Cl
NH
Pd Cl
S
R
3
d
(34)
N
4d
N
5d
HN
6d
N
N
7d
N
NH2
1e 2e
H N
3e
H
N
4e
H
N
5e
Ph
H
N
6e
HN
7
e
N
8e
HN
9
e
HN
10e
HN
Palladacycles as Antimicrobial Agents
Current Medicinal Chemistry, 2012 Vol. 19, No. 23
3977
(Table 5). Contd….. Compound
#
Substituent (R)
11e
IC50 (M)
S.D.
0.74
0.02
0.29
0.03
0.62
0.01
Ph
N 12e
N H Cl 13e
F HN
F [Pd(DMSO)2Cl2]
-
-
8.00
0.34
Metronidazole
-
-
1.81
0.03
Fig. (14). Morphology of T. b. brucei (a) normal long slender and actively dividing forms (b) long slender but abnormally dividing cells in the presence of palladium(II) porphyrin (c) dead cells in the presence of palladium(II) porphyrin [94].
utilization of heme by the parasite [91]. Diamond et al. [92] found that hematoporphyrin D did enter the central nervous system (CNS) and the early studies by Meshnick et al. [93] clearly showed the trypanocidal potential of 2,4-disubstituted deuteroporphyrins like hematoporphyrin D, metalloporphyrin derivatives, and some mesotetrasubstituted porphyrins. Nyarko et al. [94] have in vitro studied toxicity of palladium(II) and gold(III) porphyrins and their aqueous metal ion counterparts on Trypanosoma brucei brucei growth. Unlike aqueous gold (III) solution and its respective porphyrin palladium (II) complex which exhibited a higher activity (IC50 = 4.8 106 M) than its aqueous Pd(II) ionic counterpart (IC50 = 1.3
105 M). Monomorphic strain bloodstream form was used for observing the morphological effects on the parasite, for cells treated with the palladium(II) porphyrin complexes were long slender and actively dividing cells but their nuclei were larger than in the controls. Other cells had unequal division of nuclei and so some of the daughter cells had more than one nuclei but the others had none at all and were disorientated, as shown in Fig. (14). The Electron Spin Resonance (ESR) measurements in HMI-9 medium for the complexes of free Au(III) and Pd(II) ions solutions led to the conclusion that free radical production in the medium in the presence of gold(III) ion contributed to the high toxicities of the
Cl
NO2
S RHN
Pd HN
RHN
Cl
O N
N
S n
O
NO2
N
n
Pd
[PdCl2(HL)2]
N n
(35) O R = -H, -Me, -Et, -Ph,; n = 0.1 O2N
Fig. (15). Thiosemicarbazone acting as a neutral (HL) or monodeprotonated Ligand (L) [97].
S
N NHR
[Pd(L)2] (36)
3978 Current Medicinal Chemistry, 2012 Vol. 19, No. 23
Elgazwy et al.
Fig. (16). One of the complexes showing 10% inhibition (a) at 150 M, (b) at 600 M and 300 M cyanide, (---) control [97].
gold(III) solutions to T. b. brucei than its gold(III) porphyrin complex and that the palladium(II) porphyrin and its free metal ion counterpart did not produce any free radicals [93]. The provided information is given by the trypanothione reducatase (TR), the trypanosomal counterpart of the mammalian glutathione reductase that rather acts on regenerating the reduced form of trypanothione and monoglutathionylspermidine through oxidizing NADPH which is a selective target for nitrofuran drugs [95]. The platinum complexes have shown to be irreversible inhibitors of TR[95] and the postulated metabolic similarities between tumor cells, trypanosoma cruzi and its proved ability to bind DNA as the main antitumoral mechanism of action. The two series of palladium nitrofurylthiosemicarbazones complexes (35) and (36) were synthesized and their various characteristics were measured, as outlined in Fig. (15) [96]. Most of the complexes proved to be active as the ligands, and they were up to 1.7-fold more active than nifurtimox (Nfx) at equal dosage. The compounds exhibited higher E1/2 values than Nfx, and higher capacity to be reduced; Electron Paramagnetic Resonance (EPR) experiments have consistently proved a correlation between free radical species concentration in T. cruzi and the observed IC50 values supporting the hypothesis around the radical species production. Due to the expected increase in parasitic oxygen uptake of involvement of the palladium complexes in intracellular redox cycling oxygen the uptake was measured for the complexes with and without mitochondrial inhibition by cyanide, most of the compounds increased oxygen consumption, and the effect was more obvious after inhibition of the parasite mitochondrial respiration as outlined in Fig. (16). The inhibition of TR showed an irreversible time-dependant inactivation of the palladium complexes [98] which was consistent with the previous studies on platinum complexes [99] and although Table 6.
the monoligand and biligand showed excellent binding properties with calf thymus DNA via base binding and intercalation mechanisms respectively, the main toxic trypanocidal effect was rather attributed to the oxidative stress caused by the complexes. Another trypanosomatid-selective target sought was fumarate reductase (FR), an enzyme that lacked in the mammalian cells and played a pivotal role in regenerating a major respiratory substrate; succinic acid, [86] 2-mercaptopyridine N-oxide (MPO) being an inhibitor of the former, it has shown low IC50 values against T. cruzi [91]. Accordingly, Vieites et al. [99] have extensively studied the physicochemical and biologically characteriz of [Pd(MPO)2] and [Pt(MPO)2] complexes. The activities against the epimastigotes of tulahuen 2 strain (Table 6) for palladium and platinum complexes were 115 and 39 fold that of Nfx with 3 fold enhancement in comparison with the parent ligand. In spite of that, the comparison of the anti-T.c efficacy and the cytotoxicity against normal cells (Table 6) revealed that platinum complex provided a higher selectivity. The organopalladium (II) complexes being preferentially toxic toward parasites besides that being less toxic to the normal cells than of free ligand. The DNA interaction investigation through gel electrophoresis and spectrometric analysis led to the conclusion of DNA and did not constitute an important target for the MPO complexes. Similarly, The mechanism-activity independencies were found of TR inhibition, free radical generation and scavenging capacities. Only the FR inhibition tests provided strong correlation to the nanomolar activity of the complexes and consequently evidence of the mechanism of action [98]. CONCLUSION It is apparent from the data reviewed that the ligand was a critical determinant of the biological targets and magnitude of
In vitro biological activity of the free ligand and its palladium and platinum complexes and comparison of values for the parasite and for macrophages (selectivity index = IC50 T. cruzi/ IC 50 macrophages) [98] Compound
IC50 (M) T. cruzi
IC50 (M) Macrophages
Selectivity Index 4.5
NaMPO
0.190 ± 0.015
0.85
[Pd(MPO)2]
0.067 ± 0.015
0.33
4.9
[Pt(MPO)2]
0.200 ± 0.018
>>2.0
>>10
Nifurtimox
7.700 ± 0.500
-
-
Palladacycles as Antimicrobial Agents
activities. Consequently, palladium complexes were emanated as unlike cisplatin versatile-target therapeutic agents that exploit protein and organelle-specific targets in addition to the conventional DNA modifying pathways. And since the binding modes with final destinations of this emerging range of therapeutics have not yet been subject to biochemical studies, the hope of systematization of the present data for the development of structurally enhanced members of presently active classes remains in computational QSAR models, especially those relying on CoMFA and QM descriptors, which could be the best described profound alterations in biological activities that are met by minuscule structural changes. It should be noted that much of the presented data have been supported recently by Hocharoen and Cowan [100] on which the activities of many of the complexes described above might be accounted. In the light of the new paradigm which has been described the ligand played an important role in recognition and binding to the biomolecular targets while the metal-binding domain executes a catalytic role, whether through oxidative cleavage or hydrolysis promotion and eventually destroying the targets. Finally, although a lot of in vivo experiments were conducted more than a preclinical stud the focus was mainly on pharmacodynamics and efficacy aspects with respect to the pharmacokinetic properties. The ADMETox profiling being the most critical filter for lead and drug-like compounds to enter clinical experiments, representative compounds from classes of structurally related complexes need to be screened for their tissuedistribution, elimination and toxicity against animal models to attract the interest of industrial research in hope of commercialization – which already holds promise based on superior safety indices obtained for many complexes compared to commercially available drugs.
Current Medicinal Chemistry, 2012 Vol. 19, No. 23
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CONFLICTS OF INTEREST/DISCLOSURE [22]
The authors report no conflicts of interest in this work. ACKNOWLEDGEMENTS [23]
The authors cordially thank Faculty of Science, Ain Shams University for providing facility and for carefully editing the manuscript and (Library) for relentless efforts to provide most of the articles cited in this review. Given the wide breadth of studies examining the effects of MB on biological systems, only the recent reviews and articles closely related to subjects discussed in this review have been cited in many instances and we apologize to those whose work may have been omitted due to space considerations. However, given the importance of the studies during the 21st century, we have also tried to cover the seminal studies of this era not covered by PubMed. REFERENCES [1]
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Received: December 09, 2011
Revised: February 05, 2012
Accepted: February 07, 2012
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