INTRODUCTION:

The sulpha drugs are drugs containing sulfonamide group (-SO₂NH-) and they are synthetic antimicrobial agents with a wide spectrum encompassing most gram-positive and gram-negative organisms.^1-8 These drugs were the first efficient treatment to be employed systematically for the prevention and cure of bacterial infections.^9-13 Their use introduced and substantiated the concept of metabolic antagonism. Sulfonamides, as antimetabolites, compete with p-aminobenzoic acid (PABA, 1) for incorporation into folic acid (2). PABA is an intermediate in the bacterial synthesis of folate. It has been referred to as Vitamin B_x.¹³ Some bacteria in the human intestinal tract such as E. coli require PABA. Humans require folate since we lack the enzymes to convert PABA to folate. Therefore, in humans PABA is not a vitamin and is considered nutritionally unimportant.

Sulfonamide drugs are structurally similar to PABA, and their antibacterial activity is due to their ability to interfere with the conversion of PABA to folate by the enzyme dihydropteroate synthetase (EC 2.5.1.15) (Figure 1). Thus, bacterial growth is limited through folate deficiency without effect on human cells. The action of sulphonamides illustrates the principle of selective toxicity where some difference between mammal cells and bacterial cells is exploited. All cells require folic acid for growth. Folic acid (as a vitamin is in food) diffuses or is transported into human cells. However, folic acid cannot cross bacterial cell walls by diffusion or active transport. For this reason bacteria must synthesize folic acid from p-aminobenzoic acid.

Figure 1: Action of sulphonamides

Till date, more than 15,000 sulfonamide derivatives, analogues, and related compounds have been synthesized, which are effective for diuretics, anti-malarial, leprosy and antithyroid agents and employed for other diseases.^14,15

The basic structure of sulfonamide cannot be modified if it is to be an effective competitive "mimic" for p-aminobenzoic acid. Essential structural features are the benzene ring with two substituents para to each other; an amino group in the fourth position; and the singly substituted 1-sulphonamido group. It has been observed that sulpha drugs show increased biological activity when administered in the form of metal complexes.^16,17

2. Synthesis and Bioactivity of Metallosulphadrugs:

The sulpha drugs and their condensation products with aldehydes, ketones or their derivatives are biologically very active and also have good complexing ability with various metals. A number of tin(IV) complexes have been synthesized by the reaction of dimethyltin dichloride with nitrogen donor ligands (Figure 2).

Figure 2

The ligands used in these studies were condensation products of dialdehydes / diketones and sulpha drugs. The monomeric and non-electrolytic nature of these complexes has been confirmed by their molecular weight determination, conductance measurements and other spectroscopic data.^18-26Some new coordination compounds of Sn(IV) have also been synthesized by reaction of dimethyltin dichloride with imines of sulphadrugs in 1: 1 molar ratio.^27,28 On the basis of different spectral data, a distorted octahedral geometry has been proposed for resulting coordination compounds.²⁷

Dibutyltin(IV) complexes of schiff bases (each of 2-hydroxy-1-naphthaldehyde, o-hydroxyacetophenone, and salicylaldehyde condensed with sulphanilamide or sulphamerazine) were also synthesized (Figure 3).

Figure 3

The molar conductometric data shows non-electrolytic nature of complexes. The bidentate nature of the ligands is inferred from IR and NMR spectral studies.²⁹

The reaction of triphenyltin chloride with schiff bases derived from sulpha drugs in a 1:1 molar ratio leads to the formation of a new series of organotin(IV) complexes.³⁰ The antimicrobial activities of the ligands and their tin complexes have been screened in vitro against the organisms Escherichia coli, Staphylococcus aureus, Proteus mirabilis, Bacillus thuringiensis, Penicillium chrysogenum, Aspergillus niger and Fusarium oxysporum.³⁰

The reaction of tin(II)methoxide with schiff bases derived by condensation of acetylacetone and ortho-hydroxyacetophenone with sulphaguanidine, sulphisoxazole and sulphathiazole in 1:2 molar ratio give tin(II) complexes of type SnL₂.^31,32 The schiff base formed by the condensation of indole-3-carboxyaldehyde, thiophene-2-aldehyde, 2-acetylfuran and 2-acetylthiophene with sulphaguanidine and sulphisoxazole also undergoes metalation with Sn(IV) chloride.^33-37 Their structures were determined from elemental analyses, IR, UV, ¹H NMR, ¹¹⁹Sn NMR and Mossbauer spectral studies.^33,34The coordination behavior of schiff bases (H₂L) derived from salicylaldehyde and some well known sulpha drugs, such as, sulphathiazole, sulphaphenazole, sulphadiazine, sulphaguanidine and 2-(p-aminobenzenesulphonamido)-4,5-dimethyloxazole, was systematically studied with Sn(OAc)₄.³⁸

The organosilicon complex of sulpha drugs was prepared by treating them with organosilicon derivatives. New hexacoordinated complexes of organosilicon(IV) have been synthesized by the reaction of diphenyldichlorosilane with the schiff bases derived from the condensation of heterocyclic ketones and aldehydes with a series of sulpha drugs (Figure 4).³⁹ The monomeric and non-electrolytic nature of these compounds has been confirmed by molecular weight determination method and conductance measurements. The schiff bases and their silicon complexes also have been screened for their antimicrobial activities against several fungi and bacteria and were quite active in this respect.³⁹

Figure 4

The synthesis, stereo chemical and biological activities such as antibacterial, antifungal, nematicidal and insecticidal behavior of organosilicon(IV) and organotin(IV) complexes of a biological potent ligands such as 2-acetylfuran-sulphaguanidine schiff base (NÇNH) were also performed.⁴⁰The unimolar and bimolar substitution products were characterized by elemental analyses, conductance measurements, molecular weight determination, and spectral studies. The data support the binding of the N atom to the metal atom in [R₃M(NÇN)], [R₂M(NÇN)₂] and [R₂M(NÇN)Cl], where [R = Me/Ph and M = Si(IV) and Sn(IV)] types of complex. Based on these studies, with coordination number five and six a trigonal bipyramidal and an octahedral geometry were proposed for the resulting derivatives.⁴⁰ The free ligand (NÇNH) and its respective metal complexes were tested in vitro against a number of microorganisms to assess their antimicrobial properties. These complexes also show good nematicidal and insecticidal properties.⁴⁰

The complexes of type R₂SiCl(SB) and R₂Si(SB)₂, (where R = CH₃ and C₆H₅ and SB = anion) of the schiff base of sulphonamide and Ph₃Si(SB) have been prepared by the reactions of schiff base SBH with metal chlorides.⁴¹ The mode of bonding and geometry of the complexes have been suggested on the basis of spectroscopic techniques. Schiff base and its silicon complexes have also been screened for their antibacterial activities, antifungal activities and nematicidal activities.⁴¹ The pathogenicity and virulence of certain microbial infections associated with ions of complexes have been found to be potent and broad-spectrum antibiotics. These results made it desirable to delineate a comparison between ligand and its silicon complexes.⁴¹

The lead complexes of sulpha drugs have been synthesized by the interaction of different lead salts with various sulphonamide derivatives. A number of lead(II) complexes of monobasic bidentate schiff base ligands derived from sulpha drugs and 2-acetylthiophene, 2-acetylfuran, indole-3-carboxaldehyde, and thiophene-2-carbaldehyde, were synthesized by reaction of Pb(OAc)₂ with the schiff bases in 1:2 molar ratio.⁴² The spectroscopic studies predicted their structures to be tetracoordination geometry. The complexes exhibit antibacterial and antifungal activities.⁴²

The reaction of triphenyllead chloride with schiff bases derived from sulpha drugs in a 1:1 molar ratio leads to organolead(IV) complexes.⁴³ The structures of these complexes were determined by elemental analyses, molecular weight determination method, conductometric measurements, UV, IR and multinuclear magnetic resonance (¹H and ¹³C) spectral studies. The IR spectra have been used efficiently to determine the complex formation.^44-50 A few representative complexes also were screened for their antibacterial and antifungal activity and are found to be quite active in this respect.⁴³

Four new azomethines of sulpha drugs have been prepared and six new organolead complexes and four pyridine adducts of the prepared complexes have been synthesized from these azomethines.⁵¹ Further, these complexes and adducts have been analyzed and IR and ¹H NMR spectra of a few representative complexes and thermogravimetric analyses of one of the lead complexes have been recorded.⁵¹

The reaction of bis(acetylacetonato)-dioxomolybdenum(VI) with the sulphonamide derivatives as ligands in ethanol leads to the formation of six new binuclear dioxomolybdenum(VI) complexes of [{MoO₂(OH)₂}₂(L)₂] type, where L = N-(4'-benzoylidene-3'-methyl-1'-phenyl-2'-pyrazoline-5'-one) sulphamethoxazole, N-(4'-benzoylidene-3'-methyl-1'-phenyl-2'-pyrazoline-5'-one) sulphadimidine, N-(4'-benzoylidene-3'-methyl-1'-phenyl-2'-pyrazoline-5'-one)sulphadiazine; N-(4'-benzoylidene-3'-methyl-1'-phenyl-2'-pyrazoline-5'-one)sulphanilamide, N-(4'-benzo-ylidene-3'-methyl-1'-phenyl-2'-pyrazoline-5'-one)sulphamerazine or N-(4'-benzoylidene-3'-methyl-1'-phenyl-2'-pyrazoline-5'-one)sulphadimethoxine.⁵²

Unsymmetrical imine dioxomolybdenum(VI) complexes like MoO₂(L)(L') with 2-formylthiophene thiosemicarbazone (LH) and sulfa drugs sulphapyridine and sulphaguanidine azomethines (L'H) were synthesized in 1:1:1 molar ratio in dry methanol (Figure 5).⁵³

Figure 5

The ligands are monobasic bidentate and the complexes are diamagnetic in nature. The ligands and the metal complexes were screened against several bacteria and fungi.⁵³

Imines derived from sulpha drugs and amino phenylthiazole with different aldehydes and ketones and their Mo(VI) complexes were synthesized.⁵⁴ The spectral studies revealed that sulpha drug schiff bases and benzothiazolines react with dioxobis (2,4-pentanedionato)Mo(VI) as chelating agents coordinating through NÇNH and NÇSH functional groups, having NÇN and NÇS donor systems, respectively in 1:1:1 ratio giving complexes MoO₂. Studies also indicated octahedral geometry for diamagnetic Mo(VI) mononuclear complexes. All the ligands along with their complexes were tested in vitro against a number of pathogenic fungi and bacteria to assess their growth inhibiting potential.⁵⁴

Imines derived from the sulpha drugs sulphathiazole, sulphaguanidine and sulphapyridine and the heterocyclic ketone 2-acetylfuran and their Mn(II) complexes were also synthesized. A high spin tetrahedral geometry for this Mn(II) is proposed from magnetic and spectral studies. The unimolar and bimolar reactions of hydrated manganese acetate and chloride with monobasic, bidentate heterocyclic ligands gave the colored solids, which are soluble in dimethylformamide (DMF) and dimethylsulphaoxide (DMSO). The molecular weight determination indicate them to be monomers and their conductometric measurements in dry DMF show them to be non-electrolytes. All the ligands and their corresponding complexes were screened for their fungicidal, bactericidal and nematocidal activities.⁵⁵

Some 1:1 and 2:1 Mn(II) complexes with sulphonamide imine derivatives from different sulpha drugs and heterocyclic ketones are also prepared.⁵⁶ The spectral data suggested that the ligands act in a monobasic, bidentate manner coordinating through nitrogen atoms. A high spin tetrahedral geometry around this metal is proposed from magnetic and spectral studies. The isolated products are colored solids, soluble in DMSO, DMF and methanol. All the complexes are monomeric in nature as indicated by their molecular weight determination and conductometric measurements in dry DMF show them to be non-electrolytes. All the ligands and their corresponding complexes are screened for their fungicidal, bactericidal and nematicidal activities.⁵⁶

Complexes of Cu(II), Ni(II) and Co(II) with schiff bases derived from 2-hydroxy-5-carboxyacetophenone and two sulpha drugs such as sulphamethoxazole and sulphisomidine, were prepared and characterized from their molar conductance, molecular weight, magnetic moment and IR spectral data.⁵⁷ Another set of the mixed complexes of the type M-A-L where M = Mn(II), Co(II), Ni(II), Cu(II), Ce(III), Th(IV), and UO₂(II); A = oxime and L = sulphamerazine or sulphadiazine have been synthesized and studied to determine the formation constants pH-metrically in 60 (v/v) ethanol-water mixture at 25 ^oC and constant ionic strength ([b.mu] = 0.1 M NaCl). The mode of chelation was ascertained by conductometric measurements. CuAL ternary solid complexes have been prepared and characterized on the basis of elemental analyses and IR spectroscopy. The thermal degradation of the prepared complexes are discussed in an attempt to assign the intermediate compounds formed.⁵⁸

Another set of metallosulpha drugs of the type [M₂LCl₂(OH₂)₆] where (M = Ni, Co, Cu; H₂L = 5-sulphadiazineazo-3-phenyl-2-thioxo-4-thiazolidinone and 5-sulphamethazineazo-3-phenyl-2-thioxo-4-thiazolidinone and [M₂L(OAc)₂(OH₂)₄]. 2H₂O were prepared and characterized by elemental analyses, IR, UV-visible, EPR spectroscopy and magnetic measurements. The visible and EPR spectral studies indicated that the Cu(II) complexes have distorted octahedral. The crystal field parameters for Co(II) and Ni(II) complexes are also calculated. The electronic absorption values are indicative for the beginning of tetragonal distortion. The complexes, however, have lower symmetries and the amount of distortion in terms of DT/Dp, applying NSH 'Hamiltonian Theory' was evaluated which indicate that the complexes are moderately distorted.⁵⁹

Some novel azo-sulpha drugs such as 3-methyl-N-azo-(4'-substituted heterocyclo-benzenesulphamoyl)quinoxalin-2-ones and 3-methyl-N-azo-(4'-substituted heterocyclo-benzenesulphamoyl)quinoxaline-2-thiones are synthesized by coupling the corresponding benzene diazonium acetates with 3-methyl-(1H)-quinoxalin-2-one and/or with 3-methyl-(1H)-quinoxaline-2-thione in acid medium. The corresponding Fe(III), Cu(II), and Hg(II) chelates were also prepared in a 1:1 metal-to-ligand ratio. The ligands and their chelates are characterized on the basis of microanalyses UV, IR, and ¹H NMR spectrometry and tested in vitro for their antibacterial and antifungal activities.⁶⁰

Eight substituted 4-(8-hydroxy-5-quinolylazo)benzenesulphonamides (HL) were prepared by coupling sulpha drugs with 8-hydroxyquinoline. Their metal complexes [ML₂(H₂O)₂] (M = Mn, Fe) were prepared and characterized by elemental analyses, IR spectra, and conductometric measurements. The Fe(II) complexes are more potent in their antibacterial activity than Mn(II) complexes or their corresponding ligands.⁶¹

4-Hydroxyacetophenone are reacted with cinnamonitrile derivatives to give 3-cyano-4-(substituted phenyl)-6-(p-hydroxyphenyl)-pyridines. Interaction of these compounds with 4'-substituted heterocyclo-benzenesulphonyl diazonium chloride gave the corresponding 3-cyano-4-(substituted phenyl)-6-(3'-azobenzene sulphonamido-4'-hydroxyphenyl)pyridines.⁶² The corresponding Fe(III), Cu(II) and Hg(II) chelates were also prepared in a 1:2 metal-to-ligand ratio. All the synthesized compounds were characterized on the basis of microanalysis, IR and ¹H NMR spectrometry.⁶²

Novel azo-dyes have also been synthesized by diazotization of 4-amino benzene-4'-(substituted heterocyclo)sulphonamide derivatives and coupling with 1-oxa-4-thia-spiro[4,4]nonan-2-one and/or with 1-oxa-4-thia-spiro[4,5]decan-2-one in acid medium to give the corresponding 3-azo-(4'-substituted benzenesulphonamido)-1-oxa-4-thia-spiro[4,4]nonan-2-one and/or 1-oxa-4-thia-spiro[4,5]decan-2-one as spiro-ligands. The reaction of these ligands with metal salts of Fe³⁺, Cu²⁺ and Hg²⁺ as chlorides in ethanolic solution furnished the corresponding metal chelates. The compounds were tested in vitro for antimicrobial activity to study the structure-activity relationship.⁶³Some other novel azo-sulpha drugs such as 3-methyl-N-azo-(4'-substituted heterocyclo-benzene-sulphamoyl) quinoxaline-2-ones and 3-methyl-N-azo-(4'-substituted heterocyclo-benzene-sulphamoyl)-quinoxaline-2-thiones were also synthesized by coupling 4'-substituted heterocyclo-benzene-sulphamoyl diazonium acetates with 3-methyl-N-(1H)-quinoxaline-2-one and/or with 3-methyl-N(1H) quinoxaline-2-thione in acid medium. The corresponding iron(III), copper(II) and mercury(II) chelates were also prepared in a 1:1 metal-to-ligand ratio. The ligands and their chelates were characterized on the basis of microanalysis, UV, IR and ¹H NMR spectrometry, and were tested in vitro for their antibacterial and antifungal activities.⁶⁴ Cyclodiphosph(V)azane therapeutic sulpha drug derivatives, 1,3-di(p-anisyl)-2,2,2,4,4,4-hexachlorocyclodiphospha(V)azane derivatives of sulphaguanidine, phthalylsulphathiazole and sulphametrole, were prepared and their chemical behaviors towards CuCl₂.2H₂O, CoCl₂.6H₂O, NiCl₂.6H₂O, FeCl₃.6H₂O, MnCl₂.4H₂O, CdCl₂.2 1/2H₂O and ZnCl₂ were studied. The structure of the isolated complexes is proposed from elemental analyses, IR, ¹H NMR, UV, Mossbauer spectra and conductometric titrations. All the prepared compounds showed a remarkable biological activity.⁶⁵

Sulphathiazole, phthalylsulphathiazole, and succinylsulphathiazole complexes with Cu²⁺, Co²⁺, Ag⁺, and Fe²⁺ were prepared and their toxicity was studied in mice.⁶⁶ The LD₅₀ values for the i.p. sulphathiazole complexes were 1.472-1.56 g/kg, for phthalysulphathiazole complexes 0.828-0.882 g/kg, and for succinylsulphathiazole complexes 5.814-6.156 g/kg. These LD₅₀ values did not differ from those of the respective parent sulphathiazoles.⁶⁶

The reactions of metal ions such as Cu(II), Co(II), Ni(II), and C(IV) with various sulphonamides on thin layer chromatographic (TLC) plates were examined to obtain a suitable reagent for the visualization of these drugs. A solution of copper acetate in methanol produces spots of varying colors, whereas an acidic solution of ceric sulphate gives yellow or purple spots with all the sulfonamides studies. Co(II) and Ni(II) are specific for a limited number of sulphonamides.⁶⁷

A series of novel azo-sulpha drugs of piperidino-, morpholino-, and mono- and bis-piperazino-N-dithiocarbamyl-azo dyes are synthesized via a reaction of 4-[(4'-heterocyclo-substituted) sulphamoyl and/or sulphonyl] benzenediazonium salts with N-piperidino-, N-morpholino-, mono-, and bis-N-piperazino-dithiocarbamate sodium salts in acid medium to afford the corresponding azo dye ligands. Interaction of these ligands with metal salts, Fe(III), Cu(II) and Hg(II) chlorides in ethanolic solution, afforded the corresponding metal chelates. The ligands and their metal chelates were screened in vitro for their antimicrobial activities. Chelation of ligands induces a remarkable increase in their antimicrobial activity.⁶⁸

Other form of metallosulpha drugs such as ML₂(H₂O)₄]SO₄ where M = Fe, Cu; and L = sulphaguanidine; [PbL(H₂O)₅](OAc)₂, [VOL(H₂O)₄]SO₄, [SnL(H₂O)₃Cl₂]Cl₂, NH₄[MoO₂L(OH)₃], and [SeO₂L(H₂O)₃] were prepared and characterized by different spectroscopy.⁶⁹ Binary, ternary, quaternary, and six-component separation schemes for different metal ions such as Co(II), Ni(II), Th(II), Fe(II), U(V), V(IV), Cu(II), As(III), Pb(II), Cd(II), Hg(II), Ag(I), Sb(III), Se(IV), Sn(IV), Ti(IV), Mo(VI), Pd(II) and Pt(IV) were developed by using sulphaguanidine as an impregnant on silica gel thin layers and by using the solvent system iso-PrOH/EtOAc/HOAc/H₂O/DMF in the ratios (60:30:5:10:5) and (60:30:5:10:3).⁷⁰ Potentiometric studies were carried out to establish the formation of complexes between sulphaguanidine and the different metal ions to decide the nature of bonding and to determine their stability constants in an attempt to correlate them with the chromatographic behavior.⁷⁰ Sulphaguanidine complexes with monovalent and divalent metals were more active than the parent drug against several pathogens.⁷¹

Other set of schiff’s bases were obtained from aromatic/heterocyclic sulphonamides and amino-sulphonamide derivatives⁷², such as sulphanilamide, homosulphanilamide, 4-aminoethylbenzenesulphonamide and 5-amino-1,3,4-thiadiazole-2-sulphonamide. Metal complexes of some of these schiff’s bases, incorporating Zn(II), Co(II), Ni(II) and Cu(II) ions (Figure 6), were also prepared and tested as inhibitors of the zinc enzyme carbonic anhydrase (CA)^73,74, and more specifically the red blood cell isozymes I and II. The schiff’s bases behaved as medium potency CA I and CA II inhibitors, whereas their metal complexes showed a highly enhanced potency, with several low nanomolar CA II inhibitors detected.^12,13

The complexes of sulphamethoxydiazine with Cu(II), Zn(II), Ni(II), Cd(II), Cr(III) and Fe(III) have been synthesized and characterized (Figure 7-9).⁷⁵ It is shown that sulphamethoxydiazine behaves as a bidentate ligand, binding the metal ion through the sulphonyl oxygen and sulphonamide nitrogen.

In vitro susceptibility tests of these complexes against Escherichia coli, Bacillus subtilis, Proteus vulgaris and Staphylococcus aureus were carried out.⁷⁵ The results show that the antibacterial activities of the complexes of Zn(II), Cu(II), Cr(III) and Fe(III) are, in general, stronger than that of sulphamethoxydiazine, while the complexes of Cd(II) and Ni(II) are less active. From the elemental analytic data and spectral studies of the sulphamethoxydiazine metal complexes, it was found that under alkaline conditions the sulphonamide NH group is deprotonated except in the case of Ni(II) and Cd(II) complexes. Sulphamethoxydiazine probably acts as a bidentate ligand, binding to the metal through the sulphonyl oxygen and sulphonamide nitrogen.⁷⁵

Mononuclear and binuclear Mn(II), Co(II), Ni(II) and Cu(II) complexes of new semicarbazone ligands derived from sulphonamide were synthesized and characterized by elemental analysis and IR spectra (Figures 10-13).⁷⁶ In mononuclear complexes, the semicarbazone behaves as a monoanionic terdentate or neutral terdentate ligand towards the metal ion. However, in binuclear complexes, it behaves as a monoanionic terdentate towards one of the bivalent metal ions and monoanionic bidentate ligand towards the other metal ion in the same complex.⁷⁶ Electronic spectra and magnetic susceptibility measurements of the solid complexes indicated octahedral geometry around Mn(II), Co(II) and Ni(II) and square planar around the Cu(II) ion. These geometries were confirmed by the results obtained from thermal analyses. The antifungus properties of the ligands and their complexes were investigated.⁷⁶

Figure 7

Figure 8

Figure 9

Figure 10: Octahedral structures of metal complexes: Y = H and CH₃, respectively; Z = a solvent molecule, H₂O and/or EtOH; X = Cl^- or NO₃^- (for m = 1) and SO₄^2- (for m = 2); M = Mn(II), Co(II), Ni(II) or Cu(II);

Figure 11: Octahedral structure of metal complexe

Figure 12: Octahedral structure of Co(II) complex

Figure 13: Square planer Cu(II) complex

3. Summery and Future Prospects

Sulpha drugs are widely used for the treatment of various infectious diseases. The condensation products of sulpha drugs with aldehydes, ketones or their derivatives are biologically very active and also have good complexing ability with various metals. The clinical application of complexes of various sulphadrugs in different therapy aroused interest in metal complexes of sulfa drugs. Since, the number of synthesized metal complexes of antibiotic sulfa drugs has been increasing, the interaction of metal ions with drugs administered for therapeutic reasons has become a subject of considerable importance.

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Received on 20.09.2010 Modified on 25.09.2010

Asian J. Research Chem. 4(3): March 2011; Page 339-347