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Synthesis and characterization of sulfonamide metal complexes as antimicrobial agents
Journal Pre-proof Synthesis and Characterization of sulfonamide metal complexes as antimicrobial agents.
Muhammad Pervaiz, Aqsa Riaz, Anfal Munir, Zohaib Saeed, Shah Hussain, Ayoub Rashid, Ahmad Adnan PII:
S0022-2860(19)31393-6
DOI:
https://doi.org/10.1016/j.molstruc.2019.127284
Reference:
MOLSTR 127284
To appear in:
Journal of Molecular Structure
Received Date:
31 March 2019
Accepted Date:
23 October 2019
Please cite this article as: Muhammad Pervaiz, Aqsa Riaz, Anfal Munir, Zohaib Saeed, Shah Hussain, Ayoub Rashid, Ahmad Adnan, Synthesis and Characterization of sulfonamide metal complexes as antimicrobial agents., Journal of Molecular Structure (2019), https://doi.org/10.1016/j. molstruc.2019.127284
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Journal Pre-proof 1 Review articleSynthesis and Characterization of sulfonamide metal complexes as antimicrobial agents. . Muhammad Pervaiz a, Aqsa Riaza, Anfal Munira, Zohaib Saeeda, Shah Hussaina, Ayoub Rashida , Ahmad Adnana aDepartment
of Chemistry, Government College University, Lahore, Pakistan
Abstract The sulfa drug ligands and their derivatives retain well-thought-out as pre-eminent compounds in the field of synthetic as well as pharmaceutical chemistry. The transition metal complexes of 4-amino-N-(5-methyl-3-isoxazolyl)benzene sulfonamide are synthesized by reaction of 4-amino-N-(5-methyl-3-isoxazolyl)benzene sulfonamide with metals like Mn(II), Co(II), Fe(II), Fe(III),Cr(III),Ni(II),Cu(II) and Zn(II).The synthesized metal complexes of sulfa drugs have been engaged for biological (as anti-bacterial &antifungal entities) as well as catalytic activity as example Olefin Polymerization. Due to broad spectrum range, the sulfa drug derived complexes are found to be very imperative in pharmaceutical and medical chemistry. Being borne in mind the worth of sulfa drug based transition metal complexes, the review has recapitulated the synthesis, characterization and antimicrobial activities of 4-amino-N-(5-methyl-3-isoxazolyl) benzene sulfonamide metal complexes. Key words: Transition Metals, Sulfa drugs, Spectroscopy, Biological activity. Corresponding
author Address: Department of Chemistry, Government College
University, Lahore, Pakistan. Tel/Fax: +00924237164058 E-mail Address: [email protected] (Dr.M.P. Bhatti) [email protected] (Prof.Dr.Ahmad Adnan)
1
Journal Pre-proof 2 1. Introduction Due to the increase in the proportion of life threatening infections, the aim is to find better chemical compounds with more efficient and coherent anti-microbial activities. Sulfamethoxazole [4-amino-N-(5-methyl-3-isoxazolyl) benzene sulfonamide is a sulfonamide, where sulfonamide is a class of chemical compounds that contain the -SO2N group in its structure. It includes several groups of drugs that are involved in antibacterial and antifungal activities. A variety of sulfonamide drugs have been synthesized due to their extremely efficient antimicrobial nature [1-3](Described in Table.2 labeled as characteristics of SMX metal complexes or sulfonamide drugs), though they also present some serious hazards due to their allergic properties. Somehow their applications have become limited because of the development of resistance in bacterial strains against them. Paul Gelmo synthesized the first sulfonamide in 1908 while doing his research in azo dyes. Later on Hoerlien et al discovered dyes that contain sulfonyl group and that had affinity for proteins of silk and wool fiber. This lead to the discovery of “chrysolidine” by Eisenberg in 1913. Until 1930 the medicinal properties of sulfonamides were not known Domagk et al however found that prontosil has antibacterial properties but later it was investigated and found that it was not the prontosil but sulfanilamide that was formed by the reduction of prontosil in cell [4]. The data for binding of hydrogen sulfide (H2S) to a zinc porphyrin complex and the stabilization of the related zinc hydrosulfido adduct have been reported [65]. Sulfamethoxazole has been shown to form complexes with Cr (II), Mn (II), Fe(III), Ni(II),Cu(II) and Zn(II).All of these complexes are of solid physical nature. Sulfamethoxazole is monobasic as it contains only one hydrogen ion for acid base reaction resulting in the formation of coordination compounds. It is bi-dentate as it binds with the 2
Journal Pre-proof 3 metal through its deprotonated sulfonamide nitrogen and sulfonyl oxygen or isoxazolyl ring nitrogen. The stability of the complexes formed can be explained on the basis of Pearson’s principle. The complex that is formed by the coordination of the ligand base groups will be more stable when both the donor and the acceptor atoms are either soft acids and soft bases or hard acids and hard bases. The lewis base groups of SMX i-e sulfonamide nitrogen, sulfonyl oxygen and isooxazolyl ring nitrogen act as soft bases because of their greater polarizibilty. As a result they prefer to combine with soft acids as example transition metals in low oxidation states(Cu(I) , Zn(II) , Co(II), Ag(I), Fe(II) and Ni(II). The salen and salalen Fe (III) complexes have been synthesized in order to check their catalytic activity for CO2/ epoxide reactions [66]. The main feature that led to the discovery of sulfamethoxazole complexes was the administration of sulfamethoxazole for the treatment of urinary tract infection. It remained intact in human blood and was able to interact with many biologically active metal ions like Cu (II), Zn (II) etc. present in human body [5-7].
The salen Ruthenium complexes have been synthesized for direct
transformation of aldehydes into nitriles and amines [67]. The metal complexes has been studied by using spectroscopic tools (UV-Visible. IR & NMR) in order to elucidate the structures of the synthesized compounds. The assignment was made on the basis of earlier reported works [52-54]. The metal complexes has been applied as fluorescent probes for sensing biologically relevant gas molecules [60]. The complexes of sulfa drugs with the transition metals enhanced their range of applications against the isolated bacterial and fungal strains (Reported in Table.3 and Table.4 labeled as Anti-bacterial activity data of SMX metal complexes and Anti-Fungal activity data of SMX metal complexes respectively). They possess special attention as they are widely used against the broad
3
Journal Pre-proof 4 spectrum of bacterial diseases [8, 51]. The metal complexes have been used for detection of some biomolecules [61]. Sulfamethoxazole is one of the most important sulfonamides that contains various donor atoms (S, N&O) at different positions in its structure. These donor atoms are responsible for the chelating behavior of sulfamethoxazole with different metal ions. Many drugs are administrated in the form of metal complexes. These complexes are more efficient to work as compared to the ligand used alone. Organic compounds used as drugs do not have a simply natural method of activity. They are bio-transformed by metal ions by forming chelates with them. On chelation the polarity of the metal ion will be decreased to a more prominent degree because of the overlap of the ligand orbital and fractional sharing of the positive charge of the metal ion with donor groups. Further it builds the delocalization of the electrons over the entire chelate ring and upgrades the lipophilicity of the complexes. This extended lipophilicity upgrades the entrance of complexes in to the lipid films and hindering the metal binding sites in the enzymes of bacteria thus eliminating them.[9-11] In metal-Sulfamethoxazole complexes, the antimicrobial activity of heavy metals and the antibacterial activity of sulfamethoxazole makes them an important field of research. The synthesis and reactivity of alkyldisulfanido complexes with transition metals have been carried out and their reactivity was studies against different compounds [63]. The synthesis and reactivity of organometallic sulfur complexes of hydrogen sulfide anion have been carried out [64]. Besides anti-bacterial activity, sulfamethoxazole also exhibit anti-fungal activity. In order to investigate the antifungal activity of SMX, SMX dissolved in methanol at an initial concentration of 10ug/mL was added to C-limiting agar medium and PDA medium separately in order to obtain
the
final
concentration
at
100ug/ml.
Suspensions
of
Aspergillus
4
Journal Pre-proof 5 species(A.Fumigatus, A.oryzae, A.niger) and two Candida species(C.albicans , C.parapsilosis) were prepared and inoculated on to the plates. A.niger has been found to be resistant to SMX in PDA medium but sensitive to SMX in C-limiting agar medium. SMX has also shown sensitivity against A.fumigatus and A.oryzae. While in case of Candida species both the fungal strains were insensitive to SMX in PDA medium.SMX has shown anti-fungal activity against C.albicans in C-limiting agar medium[68].Thus they reinforce paramount applications in the field of medicine. Sulfamethoxazole and its derivatives interact with the p-amino benzoic acid that is involved in the synthesis of tetra hydro folic acid, the essential growth factor required for the growth of certain metabolic processes of bacteria, thus it acts as an anti-bacterial agent [12-14]. Transition metals have also been used as H2S sensor after biding with sulfur as CuS and ZnS [62].The complexes of sulfa methoxazol possesses wide range of applications in the field of pharmaceuticals. 2.
Synthesis of ligand Sulfamethoxazole is a sulfonamide, where sulfonamide is a group of chemical
compounds that contain the SO2N group. It includes several groups of drugs which are involved in the antimicrobial activity. It was prepared at room temperature by the reaction of 3-amino-5-methylisoxazol with p-acetamidobenze sulfonyl chloride. Its yield comes to be 80.4% [15, 39].
H3C H2N
O C
O S O NH
NH H2N
N O O S
O
N O
Cl 3-amino-5-methlyisoxazol
p-acetamido benzene sulfonyl chloride
sulfamethoxazole
5
Journal Pre-proof 6 Sulfamethoxazole acted as a ligand in forming the complex with Fe (II), Ni (II) and Mn(II).The complexes have been synthesized by the reaction of basic solution of ligand with that of metal salts solution[5,26,48]. In forming the complex with Ag(I) the ligand has seen to coordinate with the metal through the nitrogen of 5-membered ring and through the nitrogen of sulfonamide group. The ligand has been observed to form dimeric structure with Ag (I) [13]. Cobalt –SMX has been prepared by the reaction of the basic solution of ligand with that of metal salt. The ligand coordinated through the nitrogen of heterocyclic ring, sulfonyl oxygen atom and through the nitrogen atom of the sulfonamide group [16, 20, 38]. SMX acted as a mixed ligand with Imidazole in forming the complex with copper. The ligand coordinated through the nitrogen of the amine group of benzene ring, sulfonyl oxygen, through the nitrogen of heterocyclic ring and through the nitrogen of imidazole nitrogen [17, 22]. In forming the complex with Hg (II) the ligand solution was prepared by the reaction of sulfamethoxazole with salicylaldehyde in methanol and water. The precipitate of SMX-SD then formed complex with Hg (II) [10, 24].The Ca, Au and Zn complexes of sulfamethoxazole were prepared by heating and refluxing the solution of ligand and metal salts. In [Au(SMX)(Cl2)]Cl complex the ligand coordinated through the Iso-oxazole nitrogen and sulfonyl oxygen, while in [Ca(SMX)Cl2].8H2O and [Zn(SMX)Cl2].2H2O the ligand coordinated through sulfonamide nitrogen and sulfonyl oxygen[11]. 3. Synthesis of metal complexes The complexes of [Fe(III),Cr(III),Mn(II)&Ni(II) were prepared when 1.27 g of sulfamethoxazole were dissolved in 25 mL of water in the presence of basic media. Then solution of ligand was poured into 10 mL aqueous solution of metal salts [Fe (III), Cr (III),
6
Journal Pre-proof 7 Mn (II),and Ni(II)] with constant stirring. The precipitate that was obtained was filtered washed and dried. The complexes that were formed were characterized by spectral studies (UV-Visible, IR& H NMR), magnetic and thermal studies The yield of metal complexes in these reactions was found to be in the range 60-80%..[5,27,40]. Table.1 IR spectral data of SMX and its metal complexes Ligand-
Fe(III)
Mn(II)
Ni(II)
Cr(III)
Assignment
3400
3460
3500
3600
O-H (H2O)
3100b
3100b
3100b
3200b
3467
3466
3449
3422
3480
Aniline
3378
3398
3378
3356
3418
NH2)
3300
-
-
-
-
SMX -
(sulfonamide NH) 1620
1620
1625
1620
1620
C=N
of
isoxazolyl ring 1320
-
1315
1320
1320
1310
1310
1300
-
1305
SO2
The absence of vibrational bands at 3300cm-1 in metal complexes show that sulfonamide NH group was deprotonated during the complex formation. The vibrational band at 1620cm-1 may be assigned to isoxazolyl ring C-N stretching vibration of ligand and this 7
Journal Pre-proof 8 remain un-shifted in the metal complexes. The un-shifted vibrational bands due to sulfonyl oxygen in case of Fe(III) suggest little bonding between sulfonyl oxygen and metal.[5] Sulfamethoxazole has been shown to form a complex with Ag (I) where co-ordination occurred through the Nitrogen atom of the sulfonamide group and also through the Nitrogen atom of the 5-membered N-heterocyclic ring. The complex formed a dimeric structure. The complex was formed by the reaction of 5.0 mL aqueous solution containing 0.1015 g of SMX and 1.0 mL aqueous solution contacting 0.0476 g of KOH with 1.0 mL aqueous solution containing 0.0685 g of AgNO3. The stirring was carried at room temperature. The white precipitate that was obtained was filtered, washed and dried. The yield
of
the
synthesis
was
90
%.
Fig. 1. FT- IR spectrum of SMX and Ag-SMX The complexes were characterized by CHN, NMR and IR spectroscopic techniques [13].
8
Journal Pre-proof 9 CH3 O
Ag
H2N
S O
N
O O
N
N N Ag
O
S O
NH2
H3C
Fe(II) and Ni(II) formed complexes [Fe(SMX)2Cl2].2H 2O and [Ni(SMX)2CL2] .2H2O respectively sulfamethoxazole when 0.5 mmol Aqueous solution of metal salts in 5 mL of distilled water was added drop wise to the alkaline solution of sulfamethoxazole at pH 9,the pH of the solution dropped to 6.2. The mixture was stirred magnetically for some hours, under nitrogen until the color change was observed. The precipitate was filtered, washed and dried. The yield of Iron complex was found to be 69 % and that of Nickel complex 75 %. These complexes were characterized by conductivity measurement, UVvisible spectra, magnetic measurements, FTIR and HNMR [12, 29, 36]. H3C
NH2
O N O
Cl O
NH
M
S O
NH
S
O
Cl N O
CH3
NH2
(M=Fe, Ni)
9
Journal Pre-proof 10 Cobalt has been shown to form complex with sulfamethoxazole [Co(SMX)2 .3H2O] when 0.4 mmol of CoSO4.7H2O was dissolved in 20 mL of water was then added to the ligand solution prepared by 0.8 mmol of SMX in water in the presence of basic media. The pink precipitate formed was filtered, washed (with 5 mL of water 3 times) and dried at room temperature. The structure was characterized by using different spectroscopic techniques, UV-visible, IR and EPR. The yield of the complex was 42 %.[16,23]. Copper formed mixed ligand complex with sulfa methaoxazol(Cu(SMX)(Imi) when 0.005 mol of copper acetate in 20 mL of water and 0.01 mol of Imidazole in 10 mL of water were mixed with0.005 mol of SMX dissolved in20 mL of ethanol. The mixture was heated and stirred for 3-4 hours. The product was then filtered, washed and dried over silica gel. The metal ligand ratio was 1:1:2.The complexes that were formed were characterized by IR and UVVisible spectroscopic technique. The yield of the complex was 55.72 %[17,32]. O H2N
S
CH3
H N
N O
O M
N
H2O
N
N H
N H
(M= Cu, Zn, Mn ,Co)
The complexes of Hg (II) &Cu (II) with SMX-Salicyladimine were synthesized when 0.2532 g of SMX and 0.12 mol of salicylaldehyde ere dissolved in methanol and 10
Journal Pre-proof 11 water mixture (1:1) separately and refluxed for about four hours. The precipitates formed of SMX-SD was filtered and washed with 50%methanol-water mixture and then dried and weighed.0.02 mol of ligand solution was prepared in 60% of acetone-water solvent. It was then refluxed with 0.01 mol solution of metal salt for about four hours. Green solid crystal of C34H32N6O10S2Cu in the solution were filtered, washed and dried. The yield of copper complex was 62 % and that of Mercury complex was 51 %. The synthesized complexes were characterized by elemental analysis, NMR and IR spectral studies [11, 19, 31]. CH3 O N HN
O S
O O N
Hg
N O
O O
N
S NH
O
H3C
Cobalt and Cadmium has also been shown to form complexes with sulfamethoxazole when 2 mmol of SMX was dissolved in hot water in the presence of basic media. Then this solution was mixed with 1 mmol solution of Cobalt acetate and cadmium acetate separately with constant stirring. The compound formed was filtered, washed with distilled water and dried at room temperature. The prepared complexes were characterized by IR spectral studies [9,21,41]. 11
Journal Pre-proof 12
Fig. 2. FT-IR spectrum of a) SMX, b)Cd(SMX)2 &Co(SMX)2 Sulfamethoxazole was treated with Au (III), Pd(II) and Pt(IV) in the presence of alcoholic media in order to prepare a series of new metal complexes. The complexes were characterized by FTIR, UV-Visible, elemental analysis, conductivity and magnetic measurements [8]. The mixture of metal salts (NaAuCl4.2H2O, CaCl2 and ZnCl2) and
12
Journal Pre-proof 13 sulfamethoxazole were heated at 60-700C and refluxed for 3 hours with constant stirring. precipitate
obtained
were
filtered,
washed
1.2
3.5
1.0
3.0
with
methanol
and
dried.
2.5
0.8
Abs.
Transmittance, %
The
0.6
2.0 1.5
0.4
0.0 4000
1.0
SZ Ca(II) Zn(II) Au(III)
0.2
3500
3000
2500
0.5
Zn(II) Au(III)
0.0
2000
1500
Wavenumbers, cm
1000
200
500
400
600
800
1000
1200
λ , nm
-1
Fig. 3. The IR-Spectra of the corresponding complexes The complexes[Ca(SMX)Cl2].8H2O, [Zn(SMX)(Cl)2].2H2O, [Au(SMX)(Cl)2]Cl were characterized by the spectroscopic techniques IR, H-NMR, molar conductance and elemental analysis. The yield percent of the products collected were about 70–80%. [11,34,43] O O H2N
S
H N
O
CH3 N O
N O
Zn
.2H2O
.8H2O
Ca Cl
S O
H2N
CH3
H N
Cl
[Ca(SMX)Cl2].Cl.8H2O
Cl
Cl
[Zn(SMX)Cl2].2H2O
13
Journal Pre-proof 14 O
H N
S N O
O
H2N
CH3 .Cl
Au Cl
Cl
[Au(SMX)Cl2].Cl
Table 2.Characteristics of sulfamethoxazole metal complexes
14
Sr. No
Ligan
Metals used
Complex
Geometry
Color
d
1
SMX
Fe(III)
[Fe(SMX)2Cl].H2O
Octahedral
Brown
Reaction
Characterizat
Biological
conditions
ion
Activity
Stirring
UV/Vis, IR,
Anti-bacterial
HNMR 2
SMX
Ag(I)
Ag(SMX)
Linear
White
Stirring, room
References
15
Kanagaraj et al., 1992
HNMR
Anti-bacterial
Nunes et al.,2015
UV/Vis, IR,
Anti-bacterial
Mondelli et al.,
temperature 3
SMX
Co(II)
Co(SMX)2.3H2O
Slightly
Pink
Stirring
tetrahedron,
EPR
2013
distorted octahedral 4
SMX
Fe(II)
[Fe(SMX)2Cl2].2H2
Octahedral
Yellow
Stirring (3-4 h)
O
FTIR, H-
Anti-bacterial
Bouchoucha et al.,
NMR, UV-
&Anti-fungal
2013
Anti-cancer
Al-Khodir et al.,
Visible 5
SMX
Ca(II)
[Ca(SMX)Cl2].8H2
Square
O
planer
White
Refluxed (3 h)
60oC
IR, NMR, Molar
2015
conductance. 6
SMXSalicyl
Cu(II)
SMX-SD-Cu
-----------
Green
Refluxed (4 h)
NMR, IR
----------
Bharti jain et al.,2013.
adimin e
15
16
7
SMX
Zn(II)
Zn(SMX)(Imi)2
Octahedral
White
Refluxed (3 h)
and
IR, UV-
Anti-bacterial
Visible
& anti-fungal
Anti-cancerous
Samuel et al.,2017
Imidaz ole 8
SMX
Au(III)
[Au(SMX)Cl2].Cl
Square planer
Yellowi
Refluxed (3 h)
IR, H-NMR,
sh green
60o-70oC
Molar
Al-khodir et al.,2015
conductance 9
SMX
Cr(III)
[Cr(SMX)2(NO3)].2
Octahedral
H2O 10
SMX
Zn(II)
[Zn(SMX)2Cl2].2H2
Grey
Stirring
green Octahedral
White
SMX
Ni(II)
[Ni(SMX)2Cl].2H2 O
---------
HNMR Stirring
O 11
UV/Vis, IR,
HNMR,
al.,1992 Anti-bacterial
UV/Vis, IR Octahedral
Blue
Stirring (3-4 h)
FTIR, HNMR, UV/Vis
Kanagaraj et
Al-Khodir et al.,2015
Anti-bacterial
Bouchoucha et al., 2013
16
Journal Pre-proof 17
4. Anti-Bacterial activity. Sulfonamides interacts with p-aminobenzoic acid that is involved in the biosynthesis of Tetra-hydrofolic acid which is the fundamental developmental factor basic for the metabolic procedure of microbes. Considering the previous knowledge it could suggest that one purpose behind the higher action of complex might be because of higher lipophilicity in connection with the free sulfonamide. Because of their multi-targeting mode of action the complexes of silver with sulfonamide are capable to overcome bacterial resistance. The differential behavior of gram negative and gram positive strains in relation to the test compounds should be assigned to the different morphology of these classes of bacteria. The complex cellular walls of gram negative strain implement different penetration to the test compounds. The silver complexes of SMX were synthesized and their antimicrobial activity was determined by minimum inhibitory concentration against gram positive S. aureus and S. enterica and gram negative P. strains. The complex showed MIC for gram positive at 13.9 mmolL-1 and for gram negative at 1.74 mmolL1.
They appeared to be more active against gram negative strains [13, 25, 51,55].The
antimicrobial activity of cobalt sulfamethoxazole complex was studied against M. tuberculosis. The MIC was found to be higher than 25ug/ml. The low activity of cobalt complexes against M. tuberculosis was probably due to their low lipophilicity as these compounds cannot penetrate the hydrophobic cell wall of mycobacteria. The behavior of cobalt complex in eukaryotic macrophages cells were studied in order to understand its biological activity as macrophages are the first cells that respond to mycobacterial
17
Journal Pre-proof 18 invasion. The results showed that the tested compound exhibit low cytotoxicity as it bear bacteriostatic effect. [20,16,47,49, ]. The antimicrobial activity of iron complex of sulfamethoxazole against different bacterial strains S. aureus, B. subtilis, P. aeruginosa, K. pneumonia and E.coli were studied. It showed remarkable activity against S. aureus with minimum inhibitory concentration 6.25ug/ml and least activity against K. pneumoniae. [Ni (SMX)2Cl].2H2O has also been observed to show highest activity
against
S.aureus
[12,46,35,44,56].
Fig.4. Antibacterial Analysis of metal compleces with SMX Cu (SMX)2 (H2O)4.3H2O and Cu(SMX)2.H2O were prepared and their antimicrobial activity against different bacterial strain were studied. The MIC values for the aforesaid complexes were found to be 4ug/ml for S. aureus and 32ug/ml for E. coli of the Cu (SMX)2 H2O complex and 16ug/mL for S. aureus and E.coli of the Cu(SMX)2.H2O complex. Although both the complexes were active against bacteria but the activity was different due to different stoichiometric ratio [18, 33, 45,51, 56].The antimicrobial activity of [Au 18
Journal Pre-proof 19 (SMX) Cl2] was investigated. Its cytotoxic activity was performed on human colon carcinoma cell line and human hepatocellular carcinoma cell line in the presence of standard drug Doxorubicin. From the results obtained it was found that the complex was more effective against hepatocellular carcinoma cell line [11]. Table.3 Antibacterial activity data for SMX metal complexes. Sr. No. 1
2
Complex
Bacterial strain
MIC
Reference
[Fe(SMX)2Cl2].2H2O
S. aureus
6.25(u g/ml)
Bouchoucha et al., 2013
Bacillus subtilis
12.5(u g/ml)
P. aeruginosa
100(u g/ml)
K. pneumonia
25(u g/ml )
E.coli
25(u g/ml)
S. aureus
4(u g/ml)
E.coli
32(u g/ml)
Cu(SMX)2(H2O)4.3H 2O
Borthagaray et al., 2016
3
Co(SMX)2.3H2O
M. tuberculosis
>25(u g/ml)
Mondelli et al.,2013: Blasco et al 1996.
4
Cu(SMX)2.H2O
S. Aureus E.coli
16(u g/ml) 16(u g/ml)
Borthagaray et al., 2016
5
Ag-SMX
S. aureus Salmonella P. aeruginosa
13.9(mmol/L) 13.9(mmol/L) 1.74(m mol/L)
Nunes et al., 2015
6
[Ni(SMX)2.Cl].2H2O
S. aureus
25(u g/ml)
Bouchoucha et al., 2013
E. coli
100(u g/ml) 19
Journal Pre-proof 20 P. aeruginosa
>200(u g/ml)
K. pneumoniae
25(ug/ml)
B. subtilis
12.5(ug/ml)
2. Anti-fungal activity: Metal complexes additionally exasperate the breath procedure of the cell and in this manner hinder the amalgamation of proteins, which limits further development of the organism. Finally, it is proposed that the explanation behind this higher antimicrobial viability could be identified with the hindrance of a few basic catalysts that assume a key job in fundamental metabolic pathways of the microorganisms[50]. In view of the huge natural and pharmacological properties that the sulfamethoxazole has, another class of such mixes was accounted for by consolidating the science of sulfonamides with first row transition metals and to investigate their organic exercises with the point of acquiring progressively powerful anti-fungal compounds.[40].SMX alone showed no activity against fungal strains but the complex of SMX-Fe showed a little activity against different fungal strains S. cerivisiae, A. fumigatus, A. niger while no activity against C. albicans and C. tropicalis. The complex of [Ni (SMX)2Cl].2H2O has not shown any activity against any type of fungal strains[12,28,37]. The complexes of Manganese, Lanthanum and Neodymium with SMX
having the formula [Mn (SMX)2Cl2].2H2O,
[La(SMX)2Cl3].3H2O & [Nd(SMX)2Cl3].2H2O were synthesized and their antifungal 20
Journal Pre-proof 21 activity was studied against the two fungal strains A. fumigatus and A. flavus. The complex of La with SMX showed the highest activity against the two aforesaid fungal strains [50, 30, 35,57-59]. Table 4. Antifungal activity data of SMX metal complexes: Sr. Complex No
Fungal strain
MIC
Zone of inhibition( mm)
[Fe(SMX)2Cl2].H2O
C. tropicalis
>200 -----
[Ni(SMX)2.Cl2.2H2O
Cndiada ----- -----albicans Saccharomyces ------ ------cervisiae
Reference
1
2
A. fumigatus,
-----
------
C. tropicalis
-----
------
A.fumigatus
-----
27
A.flavus
------ 35
Bouchoucha et al., 2013
Bouchoucha et al.,2013
3 [La(SMX)2Cl2].2H2O
[Nd(SMX)2Cl2].2H2 O
Yasmin et al.,2017
A.fumig ------ 26 atus A.flavus
------ 36
A.fumigatus
-----
22
[Mn(SMX)2Cl2].2H2O
21
Journal Pre-proof 22 A.flavus
-----
25
Conclusion The structural geometry of the synthesized transition metal complexes with sulfa drugs permits them to rupture the cell wall of bacteria and fungi which enhance their applications in pharmaceutical and synthetic chemistry. Literature justifies that sulfa drug based metal complexes of transition metals have been found excellent in field of research and development now a day, that is why sulfa drug metal complexes synthesis is getting more and more attention of modern researchers. So, it has been concluded from the review that transition metal complexes of sulfa drug derivatives have beneficial prospective against numerous syndromes so there is a dire need for the exploration of these types of complexes in the field of pharmaceutical and pharmacological processes. Future prospects. The pharmaceutical scope of sulfa drug metal complexes have enriched the attention of researchers so, in future the project can also be boosted up to homo bimetallic and hetero bimetallic transition metal complexes of sulfa drugs which may act as strong antibacterial and antifungal agents.
22
Journal Pre-proof 23
References: 1. L.L. Marques, O.D.G., Manzoni, E.S. Lang, C.D. Anraku, L.R.S Gris. New gold(I) and
silver(I)
characterization
complexes and
of
sulfamethoxazole:
microbiological
synthesis,
activities
of
X-ray
structural
triphenylphosphine
(sulfamethoxazole-N2) gold(I) and (sulfamethoxazolato)silver(I).Inorganic chemistry communications,10:10 (2007) 83-1087. 2. W. Byarugaba,, H.W. Rudiger, T. Koske-Westphal, W. Wöhler, E.Passarge..Toxicity of antibiotics on cultured human skin fibroblasts. Humangenetik, 28: (1975) 263–267. 3. M.F.Mahdi, R.F, Al-Smaism, Z.M.Al-Khaliq..2015.Synthesis ,Characterization and antibacterial activity of new series of sulfamethoxazole derivatives. World journal of pharmacy and pharmaceutical sciences,4 (10): (2015)284-293 4. R.Bentley. Different roads to discovery; Prontosil (hence sulfa drugs) and penicillin (hence beta-lactams).journal of Indian microbiological and biotechnology, 36 (6): (2009)775-786. 5. G.Kanagaraj, G.N. Rao, Synthesis and characterization of some first row transition metal complexes of 4-amino-N-(5-methyl-3-isoxazolyl)benzenesulfonamide. Synthesis and reactivity in inorganic and metal-organic chemistry,22 (1992) 559-574. 6. Z.Guo, P.J Sadler.Metals in medicine.Angewandte chemie international,38(11) (1999)1512-1531. 7. S.S.AShah, G.Rivera, Ashfaq. M. Recent advances in medicinal chemistry of sulfonamides. Rational design as anti-tumoural, antibacterial and anti-inflammatory agents. Mini Rev Med Chemistry,13(1): (2013)70-86.
23
Journal Pre-proof 24 8. M.F. Alias, M.M.Abdulhassan..Synthesis and Characterization of Some Metal Complexes with their Sulfamethoxazoleand 4,4'-dimethyl-2,2'-bipyridyl and study Cytotoxic Effect on Hep-2 Cell Line. Baghdad Science Journal ,12(4)( 2015) 740-752. 9. B.Kesimli, A. Topacli,A. Infrared studies on Co and Cd complexes of sulfamethoxazole. Spectrochimica Acta Part A ,Molecular biomolecular spectroscopy.57: (2001) 1031–1036. 10. B.Jain, S. Malik, N.Sharma,S. Sharma. Synthesis, physico-chemical and spectral studies of Hg(II) and Cu(II) complexes with sulfamethoxazole schiff base.
Der Chemica
Sinica, 4(5)( 2013) 40-45. 11. F.A.I. Al-Khodir. Ca(II), Zn(II) and Au(III) Sulfamethoxazole Sulfa-drug Complexes: Synthesis, Spectroscopic and Anticancer Evaluation studies.Oriental journal of chemistry,31(3)( 2015)1277-1285. 12.
A.Bouchoucha,
A.
Terbouche,
M.Zaouani,
F.
Derridj,
S.Djebbar.
Iron and Nickle complexes with heterocyclic ligands:stability,synthesis,spectral characterization,antimicrobial activity,acute and sub-acute toxicity.Journal of trace elements in medicine and biology 27 ( 3) (2013): 191-202. 13. J.H.N Bromio, R.F.E. Paiva,, A.Cuin, W.Lustri, P.P. Corbi. Silver complexes with sulfathiazole
and
sulfamethoxazole:synthesis,spectroscopic
characterization,crystal
structure and antibacterial assays,Polyhedron,85: (2015)437-444. 14. W. Baran,, E. Adamek, J. Ziemianska, Sobczak. Effects of the presence of sulfonamides in the environment and their influence on human health. Journal of Hazardous Materials,196 (2011)1–15.
24
Journal Pre-proof 25 15.
Bozkurt,
A.,
Basci,
N.E.,
Isimer,
A.,
Tuncer,
M.,
Erdal,
R.
and
Kayaalp,S.O.1990.Sulfamethoxazole acetylation in fast and slow acetylators. International journal of clinical pharmacology, therapy and toxicology, 28:164-166. 16.M.Mondelli, F.Pavan, P.C. Souza, C.Q.Leite, J. Ellena, O.R. Nascimento, G.,Facchin, M.H.Torre. Study of series of cobalt sulfonamide complexes; synthesis, spectroscopic characterization, microbiological evaluation against M.tuberculosis .crystal studies of [Co(SMX)22H2O].H2O.Journal of molecular structure,1036(2013)180-187.
17. A. Samuel, O. Oladpo, O. Olukemi, B.Oladayo. Spectroscopic Studies of Mixedligand Complexes of Cu(II), Co(II), Mn(II) and Zn(II) with Sulfa Drug and Heterocyclic Compound. Der Pharma Chemica , 9(10): (2017)55-58. 18. G. Borthagaray, M. Mondelli, M.H.Torre. Essential transition metal ion complexes as strategy to improve the antimicrobial activity of organic drugs.Journal of infectious diseases and epidemiology,2(2). 2014 10.23937/2474-3658/1510014 19..M.A.El-Nawawy. Synthesis,spectroscopic,
R.S.Farag, Thermal
studies
I..Sabbah, and
Biological
I.A.A.M.Abu-Yamin, activity
of
a
new
sulfamethoxazole Schiff base and its copper complexes.International journal of pharmaceutical sciences and research,2(12): (2011) 3143-3148. 20. Z.H. Chohan, K Mahmood-ul-Hassan, K.M. Khan.C.T. Supuran. Invitro antibacterial,sntifungal and cytotoxic properties of sulfonamidederived schiff’s basesand their metal complexes.Enzyme Inhib.Med.chem, 20(2)( 2005)183-188.
25
Journal Pre-proof 26 21. T. Arora, A. K. Mehta, V. Joshi, K. D. Mehta, N. Rathor, P. K. Mediratta, K. K. Sharma. Substitute of Animals in Drug Research: An Approach Towards Fulfillment of 4R’sIndian journal of pharmaceutical sciences, 73 (1): (2011)1-6. 22. M.H.Torre, S. Calvo, H. Pardo, A.W. Mombru. Synthesis, spectroscopic characterization and crystal structure of disulfamethoxazole and diaquo Ni(II) monohydrate.Journal of coordination chemistry,58(6):( 2005)513-520. 23. F.R.Pavan, D.N. Sato,C.Q.F. leite. An approach to the search for new drugs against Tuberculosis.doi:10.5772/31618 (2010). 24. A. Rani, M. Kumar, R. Khare, H.S.Tuli. Schiff bases as antimicrobial agent. A review. Journal of biological and chemical sciences, 2(1): ( 2015)62-91. 25. S. Eckhardt, P.S. Brunetto, J.Gagnon, P. Magdalene. B.Giese. Nanobio silver ;its interaction with peptides and bacteria and its uses in medicine.Chem.Review, 113(7): (2013)4708-4754. 26.
K.K.Nrang.
Sulfadrugs
complexes
of
Zinc(II),Cadmium(II)
and
Mercury(II).Transition metal chemistry,2(11): (1977)181-183. 27.
K.K.Nrang,
J.K.Gupta.
Cu(II)
Complexes
of
sulfanilamide,
sulfaguanidine,sulfathiazole,sulfamerazine,sulfadiazine and sulfapyridine.Indian.Journal of chemistry,13(1975)705. 28. Z.H.Chohan, S.H.Sumrra, M.H.Youssoufi, T.B.Hadda. Metal based biologically active compounds:design ,synthesis and antibacterial/antifungal/cytotoxic properties of triazolederived Schiff bases and their oxovanadium(IV) complexes.European journal of medicinal chemistry,45(2010)1189-1199.
26
Journal Pre-proof 27 29. S. Djebbar, O.B. Baitich, J.P. Deloume. Synthesis, characterization , electrochemical behavior and catalytic activity of manganese(II) complexes with linear and tripodal tetradentate ligands derived from Schiff bases.Transition metal chemistry,23(4)( 1998)443-447. 30 G..Karthikeyan, k.Mohanaraj, K.P.Elango, K.Girishkumar. Synthesis and spectral characterization of lanthanide complexes with sulfamethoxazole and their antibacterial activity. Russian journal of coordination chemistry,32(2006.)380-385.
31. G.M. Gehad, M.O.Mohammad, M.H. Ahmed. Metal complexes of Schiff bases: preparation characterization and their biological activity. Turkish journal of chemistry,30: (2006)361-382. 32. J. Joseph, B.G.Janaki, K. Nagashri. Novel metal based anti- tuberculosis agent: synthesis, characterization, catalytic and pharmacological activities of copper complexes. European journal of medicinal chemistry, 49 (2012)151-163. 33. C.T.Supuran, F.Minicione, A. Scozzafav, F. Briganti, G. Minicinone, M.A. Ilises. Metal complexes of heterocyclic sulfonamides:a new class of strong topical intraocular pressure-lowering agents in rabbits. European journal of medicinal chemistry, 33(1998.)247. 34. ,F.A .Saad. Elaborated molecular docking and DFT/B3LYP studies for novel sulfa drugs complexes, spectral and antitumor investigations. Journal of thermal analysis and calorimetry,129(1):( 2017) 425-440. 35.
B.A.A.Oluwatoosin,
M.S.
Wakil.
A.A.Osowole.
Synthesis,
Spectroscopic
Characterization and Antimicrobial Activities of Some Mixed Drug Metal (II) Complexes
27
Journal Pre-proof 28 of Sulfamethoxazole and Paracetamol. Journal of Research & Developments in Chemistry. (2014) DOI: 10.5171/2014.400324 36. M.E.Moustafa. Synthesis and structural and biological activity studies on some lanthanide chelates with O- and N-containing ligands. Spectroscopy letter,38(1): (2005)2334.
37. P.J.Sadler, Zijien. Metal complexes in medicine, Designed and Mechanism of Action. Journal of Pure and Applied Chemistry, 70( 4): (1998) 863-871. 38. M.F.Melina, P.Fernando, C. Paula, Q.L.Clarice, E.Avier, R.N. Otaciro, Gianella,F. H.T.Maria. Study of a series of cobalt(II) sulfonamide complexes: synthesis, spectroscopic characterization, and microbiological evaluation against M.Tuberculosis. Journal of molecular structure,1036: (2013)180-187. 39. B.C. Rudy, B.Z. Senkowski. Sulfamethoxazole.Profile of drug substances excipients and related methodology, doi:10.1061/S0099-5428(08)60051-9 1st edition (1973) 562. 40. P. Edder, A. Cominoli, C. Corvi. Analysis of residues of sulfonamides in foods of animal origin (liver, kidney, meat, fish, eggs, milk) by liquid chromatography with prederivatization and fluorimetric detection. Mitt. Geb. Lebensmittelunters. Hyg, 88(1997) 554–569. 41. J. Koch-Weser, V.W. Sidel, M. Dexter, C. Parish, D.C. Finer, P. Kanarek. .Adverse reactions to sulfisoxazole, sulfamethoxazole, and nitrofurantoin. Arch. intern. Med, 128 (1971) 399–404. 42. F. Blasco, L. Perello, J. Latorre, J. Borras, S. Garcia-Granda, J. Inorg. Cobalt(II), Nickel(II), and Copper(II) Complexes of Sulfanilamide Derivatives: Synthesis,
28
Journal Pre-proof 29 Spectroscopic
Studies,
and
Antibacterial
Activity.
Crystal
Structure
of
[Co(sulfacetamide)2(NCS)2]. Journal of Inorganic Biochemistry, 61(1996)143-154.
43. S. Ramesh, Y.Yamgar, N.Satish, M.Mustapha, R.G.Atram.S.S.Sudhir. Novel Zinc(II) Complexes of Heterocyclic Ligands as Antimicrobial Agents: Synthesis, Characterisation, and
Antimicrobial
Studies.Bioinorganic
Chemistry
and
Application,(2014)
doi.org/10.1155/2014/276598 44. M. Rizzotto.2013 Metal complexes as antimicrobial agents, InTechoPen (2013). 45. R.N.Patel, P.V. Sondhiya, k.K. Shukla, D.K.Patel, V.P.R. Singh. Design, synthesis, and characterization of a series of biologically active copper(II) Schiff-base coordination compounds. Journal of Indian Chem, 89(2012)1085-1092. 46.S.Ghosh, B. Jain, S, Malik, S.A.Iqbal. Synthesis, characterization, antimicrobial and diuretic study of Mg(II), Mn(II), Fe(II) and VO(II) complexes of chemotherapeutic importance.Journal of Saudi Chemical Society,16(2): (2012)137–143. 47. S. Ahmad, A. Anvarhusein. A. Isab, R.Abdul. Perspectives in bioinorganic chemistry of some metal based therapeutic agents Polyhedron ,25 (2006) 1633–1645. .48.S.S.A.Shah, M.Ashfaq, T. Najam, M.M.Ahmed, R.Tabassum, S.Abida. Synthesis of Sulfonamides, Metal Complexes and the Study of In vitro Biological Activities. Current bioactive compounds, 9(3): (2013): 211-220. 49. K. Palaniappan, R.A. Holley. Use of natural antimicrobials to increase antibiotic susceptibility of drug resistant bacteria. International journal of food microbiology, 140 (2010)164-168.
29
Journal Pre-proof 30 50.M.S.Yasmin, M.A.Al-Maqtari,M.K.Al-Qadasi. Ligational and spectroscopic on some sulfamethoxazole metal complexes as antimicrobial agents. European
journal of
pharmaceutical and medical research,4(7): (2017) 95-105. 51 M. Pervaiz, I. Ahmad, M.Yousaf, S. Kirn, A.Munawar, Z. Saeed, A. Adnan, T. Gulzar, T. Kamal, A. Ahmad, A.Rashid. Synthesis, spectral and antimicrobial studies of amino acid derivative Schiff base metal (Co, Mn, Cu, and Cd) complexesSpectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 206 (2019) 642–649. 52. R. Tabaraki , E. Heidarizadi.
Spectrophotometric determination of phenol and
chlorophenols by salting out assisted liquid-liquid extraction combined with dispersive liquid-liquid microextraction. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 25 (2019). 405-409. 53. M. Pervaiz, M. Yousaf, M. Sagir, M. Mushtaq, M.Y. Naz, S. Ullah, R. Mushtaq, Synthesis and characterization of bimetallic post transition complexes for antimicrobial activity, Synth. React. Inorg., Met.-Org., Nano-Met. Chem. 45 (2015) 546–552. 54. K. Meena, K. Muthu, V. Meenatchi, M. Rajasekar, G. Bhagavannarayana, S. Meenakshisundaram. "Spectrochimica acta part A: molecular and biomolecular spectroscopy." Spectrochim Acta Part A 124 (2014): 663-669. 55. L.H. Abdel-Rahman, R.M. El-Khatib, L.A.E. Nassr, A.M. Abu-Dief, F.E.-D. Lashin, Design, characterization, teratogenicity testing, antibacterial, antifungal and DNA interaction of few high spin Fe(II) Schiff base amino acid complexes, Spectrochim. Acta A. Mol. Biomol. Spectrosc. 111 (2013) 266–276. 56. M.Pervaiz. Muhammad Yousaf, Ameer Fawad Zahoor, Abdullah Ijaz Hussain, Muhammad Kaleem Khan Khosa, Sadia Ashraf, Muhammad Sagir, Ashar-uz-Zaman,
30
Journal Pre-proof 31 KhurramShehzad, Synthesis, characterization and biological studies of Bis-{μ-2,2¢[ethane-1,3-diyl-bis(nitrilomethylidyne)]diphenolato}dicopper(II) using triple component solvent system, Asian J. Chem. 25 (2013) 521–524. 57. A.-U. Zaman, I. Ahmad, M. Pervaiz, , S. Ahmad ,S. Kiran, M. A. Khan, T. Gulzar, T. Kamal. A novel synthetic approach for the synthesis of pyrano[3,2-c]quinolone3carbaldehydes by using modified Vilsmeier Haack reaction, as potent antimicrobial agents Journal of Molecular Structure 1180 (2019) 227e236 58. M. Pervaiz, M. Yousaf, A. Jabbar, A. F. Zahoor, T. H. Bokhari, A. Anjum, M. Sagir, M.A. Khan, K. G. Ali, S. Ahmad, M. Z. Rehman, S. Ashraf, K.S. Qeureshi, Synthesis, characterization
and
biological
studies
of
bis{m-2,2'-[N,N'-diylbis
(nitrilomethylidyne)]diphenolato}dicobalt(II) using triple component solvent system, Asian J. Chem. 25 (2013) 2161e2164. 59. M. Pervaiz, M. Yousaf, M. Sagir, A. Pervaiz , M. Y. Naz.. Novel preparation and spectral investigation of a series of schiff base derivatives monometallic transition metal complexes as bacteria and fungus inhibitors. Main Group Chemistry, 13 (2014)129-145. 60. Strianese M, Pellecchia C. Metal complexes as fluorescent probes for sensing biologically relevant gas molecules. Coordination Chemistry Reviews.1(318) (2016) 318:16-28. 61. Ma, Dik-Lung, Modi Wang, Chenfu Liu, Xiangmin Miao, Tian-Shu Kang, and ChungHang Leung. "Metal complexes for the detection of disease-related protein biomarkers." Coordination Chemistry Reviews 324 (2016): 90-105.
31
Journal Pre-proof 32 62. Kaushik, Rahul, Amrita Ghosh, and D. Amilan Jose. "Recent progress in hydrogen sulphide (H2S) sensors by metal displacement approach." Coordination Chemistry Reviews, 347 (2017): 141-157. 63. Galardon, Erwan, Alain Tomas, Mohamed Selkti, Pascal Roussel, and Isabelle Artaud. "Synthesis, characterization, and reactivity of alkyldisulfanido zinc complexes." Inorganic chemistry 48, no. 13 (2009): 5921-5927. 64. Strianese, Maria, Silvia Mirra, Valerio Bertolasi, Stefano Milione, and Claudio Pellecchia. "Organometallic sulfur complexes: Reactivity of the hydrogen sulfide anion with cobaloximes." New Journal of Chemistry 39, no. 5 (2015): 4093-4099. 65. Strianese, Maria, Marina Lamberti, and Claudio Pellecchia. "Chemically reversible binding of H 2 S to a zinc porphyrin complex: towards implementation of a reversible sensor via a “coordinative-based approach”." Dalton Transactions 46, no. 6 (2017): 18721877. 66. Cozzolino, Mariachiara, Vincenza Leo, Consiglia Tedesco, Mina Mazzeo, and Marina Lamberti. "Salen, salan and salalen iron (iii) complexes as catalysts for CO 2/epoxide reactions and ROP of cyclic esters." Dalton Transactions 47, no. 37 (2018): 13229-13238. 67. Borase, Pravin N., Pranila B. Thale, and Ganapati S. Shankarling. "Ru (Cl)‐Salen Complex: Solvent Selective Homogeneous Catalyst for One‐Pot Synthesis of Nitriles and Amides." ChemistrySelect 3, no. 20 (2018): 5660-5666. 68. Hida.S, Yoshida M, Nakabayashi I, Miura NN, Adachi Y, Ohno N.(2005) “Antifungal activity of sulfamethoxazole toward Aspergillus species” Biol Pharm Bull,28(5):773-778
32
Journal Pre-proof 33 69. Zhang.Y., Cao.Y., Leng. X., Chen.C & Huang.Z.(2014). Cationic Palladium(II) Complexes of Phosphine-sulfonamide Ligands: Synthesis, Characterization and catalytic ethylene oligomerization. Organomettalics. 33(14); 3738-3745.
33
Journal Pre-proof
Highlights.
Being borne in mind the worth of sulfa drug based transition metal complexes, the review has recapitulated the synthesis, characterization and antimicrobial activities of sulfonamide metal complexes.
Due to broad spectrum range, sulfa drug derivatives have beneficial prospective against numerous syndromes so there is a dire need for the exploration of these complexes in the field of pharmaceutical and pharmacological processes.
In future, the project can also be boosted up to homo/hetro bimetallic metal complexes of sulfa drugs which may act as strong antimicrobial agents.
Muhammad Pervaiz, Aqsa Riaz, Anfal Munir, Zohaib Saeed, Shah Hussain, Ayoub Rashid, Ahmad Adnan PII:
S0022-2860(19)31393-6
DOI:
https://doi.org/10.1016/j.molstruc.2019.127284
Reference:
MOLSTR 127284
To appear in:
Journal of Molecular Structure
Received Date:
31 March 2019
Accepted Date:
23 October 2019
Please cite this article as: Muhammad Pervaiz, Aqsa Riaz, Anfal Munir, Zohaib Saeed, Shah Hussain, Ayoub Rashid, Ahmad Adnan, Synthesis and Characterization of sulfonamide metal complexes as antimicrobial agents., Journal of Molecular Structure (2019), https://doi.org/10.1016/j. molstruc.2019.127284
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Journal Pre-proof 1 Review articleSynthesis and Characterization of sulfonamide metal complexes as antimicrobial agents. . Muhammad Pervaiz a, Aqsa Riaza, Anfal Munira, Zohaib Saeeda, Shah Hussaina, Ayoub Rashida , Ahmad Adnana aDepartment
of Chemistry, Government College University, Lahore, Pakistan
Abstract The sulfa drug ligands and their derivatives retain well-thought-out as pre-eminent compounds in the field of synthetic as well as pharmaceutical chemistry. The transition metal complexes of 4-amino-N-(5-methyl-3-isoxazolyl)benzene sulfonamide are synthesized by reaction of 4-amino-N-(5-methyl-3-isoxazolyl)benzene sulfonamide with metals like Mn(II), Co(II), Fe(II), Fe(III),Cr(III),Ni(II),Cu(II) and Zn(II).The synthesized metal complexes of sulfa drugs have been engaged for biological (as anti-bacterial &antifungal entities) as well as catalytic activity as example Olefin Polymerization. Due to broad spectrum range, the sulfa drug derived complexes are found to be very imperative in pharmaceutical and medical chemistry. Being borne in mind the worth of sulfa drug based transition metal complexes, the review has recapitulated the synthesis, characterization and antimicrobial activities of 4-amino-N-(5-methyl-3-isoxazolyl) benzene sulfonamide metal complexes. Key words: Transition Metals, Sulfa drugs, Spectroscopy, Biological activity. Corresponding
author Address: Department of Chemistry, Government College
University, Lahore, Pakistan. Tel/Fax: +00924237164058 E-mail Address: [email protected] (Dr.M.P. Bhatti) [email protected] (Prof.Dr.Ahmad Adnan)
1
Journal Pre-proof 2 1. Introduction Due to the increase in the proportion of life threatening infections, the aim is to find better chemical compounds with more efficient and coherent anti-microbial activities. Sulfamethoxazole [4-amino-N-(5-methyl-3-isoxazolyl) benzene sulfonamide is a sulfonamide, where sulfonamide is a class of chemical compounds that contain the -SO2N group in its structure. It includes several groups of drugs that are involved in antibacterial and antifungal activities. A variety of sulfonamide drugs have been synthesized due to their extremely efficient antimicrobial nature [1-3](Described in Table.2 labeled as characteristics of SMX metal complexes or sulfonamide drugs), though they also present some serious hazards due to their allergic properties. Somehow their applications have become limited because of the development of resistance in bacterial strains against them. Paul Gelmo synthesized the first sulfonamide in 1908 while doing his research in azo dyes. Later on Hoerlien et al discovered dyes that contain sulfonyl group and that had affinity for proteins of silk and wool fiber. This lead to the discovery of “chrysolidine” by Eisenberg in 1913. Until 1930 the medicinal properties of sulfonamides were not known Domagk et al however found that prontosil has antibacterial properties but later it was investigated and found that it was not the prontosil but sulfanilamide that was formed by the reduction of prontosil in cell [4]. The data for binding of hydrogen sulfide (H2S) to a zinc porphyrin complex and the stabilization of the related zinc hydrosulfido adduct have been reported [65]. Sulfamethoxazole has been shown to form complexes with Cr (II), Mn (II), Fe(III), Ni(II),Cu(II) and Zn(II).All of these complexes are of solid physical nature. Sulfamethoxazole is monobasic as it contains only one hydrogen ion for acid base reaction resulting in the formation of coordination compounds. It is bi-dentate as it binds with the 2
Journal Pre-proof 3 metal through its deprotonated sulfonamide nitrogen and sulfonyl oxygen or isoxazolyl ring nitrogen. The stability of the complexes formed can be explained on the basis of Pearson’s principle. The complex that is formed by the coordination of the ligand base groups will be more stable when both the donor and the acceptor atoms are either soft acids and soft bases or hard acids and hard bases. The lewis base groups of SMX i-e sulfonamide nitrogen, sulfonyl oxygen and isooxazolyl ring nitrogen act as soft bases because of their greater polarizibilty. As a result they prefer to combine with soft acids as example transition metals in low oxidation states(Cu(I) , Zn(II) , Co(II), Ag(I), Fe(II) and Ni(II). The salen and salalen Fe (III) complexes have been synthesized in order to check their catalytic activity for CO2/ epoxide reactions [66]. The main feature that led to the discovery of sulfamethoxazole complexes was the administration of sulfamethoxazole for the treatment of urinary tract infection. It remained intact in human blood and was able to interact with many biologically active metal ions like Cu (II), Zn (II) etc. present in human body [5-7].
The salen Ruthenium complexes have been synthesized for direct
transformation of aldehydes into nitriles and amines [67]. The metal complexes has been studied by using spectroscopic tools (UV-Visible. IR & NMR) in order to elucidate the structures of the synthesized compounds. The assignment was made on the basis of earlier reported works [52-54]. The metal complexes has been applied as fluorescent probes for sensing biologically relevant gas molecules [60]. The complexes of sulfa drugs with the transition metals enhanced their range of applications against the isolated bacterial and fungal strains (Reported in Table.3 and Table.4 labeled as Anti-bacterial activity data of SMX metal complexes and Anti-Fungal activity data of SMX metal complexes respectively). They possess special attention as they are widely used against the broad
3
Journal Pre-proof 4 spectrum of bacterial diseases [8, 51]. The metal complexes have been used for detection of some biomolecules [61]. Sulfamethoxazole is one of the most important sulfonamides that contains various donor atoms (S, N&O) at different positions in its structure. These donor atoms are responsible for the chelating behavior of sulfamethoxazole with different metal ions. Many drugs are administrated in the form of metal complexes. These complexes are more efficient to work as compared to the ligand used alone. Organic compounds used as drugs do not have a simply natural method of activity. They are bio-transformed by metal ions by forming chelates with them. On chelation the polarity of the metal ion will be decreased to a more prominent degree because of the overlap of the ligand orbital and fractional sharing of the positive charge of the metal ion with donor groups. Further it builds the delocalization of the electrons over the entire chelate ring and upgrades the lipophilicity of the complexes. This extended lipophilicity upgrades the entrance of complexes in to the lipid films and hindering the metal binding sites in the enzymes of bacteria thus eliminating them.[9-11] In metal-Sulfamethoxazole complexes, the antimicrobial activity of heavy metals and the antibacterial activity of sulfamethoxazole makes them an important field of research. The synthesis and reactivity of alkyldisulfanido complexes with transition metals have been carried out and their reactivity was studies against different compounds [63]. The synthesis and reactivity of organometallic sulfur complexes of hydrogen sulfide anion have been carried out [64]. Besides anti-bacterial activity, sulfamethoxazole also exhibit anti-fungal activity. In order to investigate the antifungal activity of SMX, SMX dissolved in methanol at an initial concentration of 10ug/mL was added to C-limiting agar medium and PDA medium separately in order to obtain
the
final
concentration
at
100ug/ml.
Suspensions
of
Aspergillus
4
Journal Pre-proof 5 species(A.Fumigatus, A.oryzae, A.niger) and two Candida species(C.albicans , C.parapsilosis) were prepared and inoculated on to the plates. A.niger has been found to be resistant to SMX in PDA medium but sensitive to SMX in C-limiting agar medium. SMX has also shown sensitivity against A.fumigatus and A.oryzae. While in case of Candida species both the fungal strains were insensitive to SMX in PDA medium.SMX has shown anti-fungal activity against C.albicans in C-limiting agar medium[68].Thus they reinforce paramount applications in the field of medicine. Sulfamethoxazole and its derivatives interact with the p-amino benzoic acid that is involved in the synthesis of tetra hydro folic acid, the essential growth factor required for the growth of certain metabolic processes of bacteria, thus it acts as an anti-bacterial agent [12-14]. Transition metals have also been used as H2S sensor after biding with sulfur as CuS and ZnS [62].The complexes of sulfa methoxazol possesses wide range of applications in the field of pharmaceuticals. 2.
Synthesis of ligand Sulfamethoxazole is a sulfonamide, where sulfonamide is a group of chemical
compounds that contain the SO2N group. It includes several groups of drugs which are involved in the antimicrobial activity. It was prepared at room temperature by the reaction of 3-amino-5-methylisoxazol with p-acetamidobenze sulfonyl chloride. Its yield comes to be 80.4% [15, 39].
H3C H2N
O C
O S O NH
NH H2N
N O O S
O
N O
Cl 3-amino-5-methlyisoxazol
p-acetamido benzene sulfonyl chloride
sulfamethoxazole
5
Journal Pre-proof 6 Sulfamethoxazole acted as a ligand in forming the complex with Fe (II), Ni (II) and Mn(II).The complexes have been synthesized by the reaction of basic solution of ligand with that of metal salts solution[5,26,48]. In forming the complex with Ag(I) the ligand has seen to coordinate with the metal through the nitrogen of 5-membered ring and through the nitrogen of sulfonamide group. The ligand has been observed to form dimeric structure with Ag (I) [13]. Cobalt –SMX has been prepared by the reaction of the basic solution of ligand with that of metal salt. The ligand coordinated through the nitrogen of heterocyclic ring, sulfonyl oxygen atom and through the nitrogen atom of the sulfonamide group [16, 20, 38]. SMX acted as a mixed ligand with Imidazole in forming the complex with copper. The ligand coordinated through the nitrogen of the amine group of benzene ring, sulfonyl oxygen, through the nitrogen of heterocyclic ring and through the nitrogen of imidazole nitrogen [17, 22]. In forming the complex with Hg (II) the ligand solution was prepared by the reaction of sulfamethoxazole with salicylaldehyde in methanol and water. The precipitate of SMX-SD then formed complex with Hg (II) [10, 24].The Ca, Au and Zn complexes of sulfamethoxazole were prepared by heating and refluxing the solution of ligand and metal salts. In [Au(SMX)(Cl2)]Cl complex the ligand coordinated through the Iso-oxazole nitrogen and sulfonyl oxygen, while in [Ca(SMX)Cl2].8H2O and [Zn(SMX)Cl2].2H2O the ligand coordinated through sulfonamide nitrogen and sulfonyl oxygen[11]. 3. Synthesis of metal complexes The complexes of [Fe(III),Cr(III),Mn(II)&Ni(II) were prepared when 1.27 g of sulfamethoxazole were dissolved in 25 mL of water in the presence of basic media. Then solution of ligand was poured into 10 mL aqueous solution of metal salts [Fe (III), Cr (III),
6
Journal Pre-proof 7 Mn (II),and Ni(II)] with constant stirring. The precipitate that was obtained was filtered washed and dried. The complexes that were formed were characterized by spectral studies (UV-Visible, IR& H NMR), magnetic and thermal studies The yield of metal complexes in these reactions was found to be in the range 60-80%..[5,27,40]. Table.1 IR spectral data of SMX and its metal complexes Ligand-
Fe(III)
Mn(II)
Ni(II)
Cr(III)
Assignment
3400
3460
3500
3600
O-H (H2O)
3100b
3100b
3100b
3200b
3467
3466
3449
3422
3480
Aniline
3378
3398
3378
3356
3418
NH2)
3300
-
-
-
-
SMX -
(sulfonamide NH) 1620
1620
1625
1620
1620
C=N
of
isoxazolyl ring 1320
-
1315
1320
1320
1310
1310
1300
-
1305
SO2
The absence of vibrational bands at 3300cm-1 in metal complexes show that sulfonamide NH group was deprotonated during the complex formation. The vibrational band at 1620cm-1 may be assigned to isoxazolyl ring C-N stretching vibration of ligand and this 7
Journal Pre-proof 8 remain un-shifted in the metal complexes. The un-shifted vibrational bands due to sulfonyl oxygen in case of Fe(III) suggest little bonding between sulfonyl oxygen and metal.[5] Sulfamethoxazole has been shown to form a complex with Ag (I) where co-ordination occurred through the Nitrogen atom of the sulfonamide group and also through the Nitrogen atom of the 5-membered N-heterocyclic ring. The complex formed a dimeric structure. The complex was formed by the reaction of 5.0 mL aqueous solution containing 0.1015 g of SMX and 1.0 mL aqueous solution contacting 0.0476 g of KOH with 1.0 mL aqueous solution containing 0.0685 g of AgNO3. The stirring was carried at room temperature. The white precipitate that was obtained was filtered, washed and dried. The yield
of
the
synthesis
was
90
%.
Fig. 1. FT- IR spectrum of SMX and Ag-SMX The complexes were characterized by CHN, NMR and IR spectroscopic techniques [13].
8
Journal Pre-proof 9 CH3 O
Ag
H2N
S O
N
O O
N
N N Ag
O
S O
NH2
H3C
Fe(II) and Ni(II) formed complexes [Fe(SMX)2Cl2].2H 2O and [Ni(SMX)2CL2] .2H2O respectively sulfamethoxazole when 0.5 mmol Aqueous solution of metal salts in 5 mL of distilled water was added drop wise to the alkaline solution of sulfamethoxazole at pH 9,the pH of the solution dropped to 6.2. The mixture was stirred magnetically for some hours, under nitrogen until the color change was observed. The precipitate was filtered, washed and dried. The yield of Iron complex was found to be 69 % and that of Nickel complex 75 %. These complexes were characterized by conductivity measurement, UVvisible spectra, magnetic measurements, FTIR and HNMR [12, 29, 36]. H3C
NH2
O N O
Cl O
NH
M
S O
NH
S
O
Cl N O
CH3
NH2
(M=Fe, Ni)
9
Journal Pre-proof 10 Cobalt has been shown to form complex with sulfamethoxazole [Co(SMX)2 .3H2O] when 0.4 mmol of CoSO4.7H2O was dissolved in 20 mL of water was then added to the ligand solution prepared by 0.8 mmol of SMX in water in the presence of basic media. The pink precipitate formed was filtered, washed (with 5 mL of water 3 times) and dried at room temperature. The structure was characterized by using different spectroscopic techniques, UV-visible, IR and EPR. The yield of the complex was 42 %.[16,23]. Copper formed mixed ligand complex with sulfa methaoxazol(Cu(SMX)(Imi) when 0.005 mol of copper acetate in 20 mL of water and 0.01 mol of Imidazole in 10 mL of water were mixed with0.005 mol of SMX dissolved in20 mL of ethanol. The mixture was heated and stirred for 3-4 hours. The product was then filtered, washed and dried over silica gel. The metal ligand ratio was 1:1:2.The complexes that were formed were characterized by IR and UVVisible spectroscopic technique. The yield of the complex was 55.72 %[17,32]. O H2N
S
CH3
H N
N O
O M
N
H2O
N
N H
N H
(M= Cu, Zn, Mn ,Co)
The complexes of Hg (II) &Cu (II) with SMX-Salicyladimine were synthesized when 0.2532 g of SMX and 0.12 mol of salicylaldehyde ere dissolved in methanol and 10
Journal Pre-proof 11 water mixture (1:1) separately and refluxed for about four hours. The precipitates formed of SMX-SD was filtered and washed with 50%methanol-water mixture and then dried and weighed.0.02 mol of ligand solution was prepared in 60% of acetone-water solvent. It was then refluxed with 0.01 mol solution of metal salt for about four hours. Green solid crystal of C34H32N6O10S2Cu in the solution were filtered, washed and dried. The yield of copper complex was 62 % and that of Mercury complex was 51 %. The synthesized complexes were characterized by elemental analysis, NMR and IR spectral studies [11, 19, 31]. CH3 O N HN
O S
O O N
Hg
N O
O O
N
S NH
O
H3C
Cobalt and Cadmium has also been shown to form complexes with sulfamethoxazole when 2 mmol of SMX was dissolved in hot water in the presence of basic media. Then this solution was mixed with 1 mmol solution of Cobalt acetate and cadmium acetate separately with constant stirring. The compound formed was filtered, washed with distilled water and dried at room temperature. The prepared complexes were characterized by IR spectral studies [9,21,41]. 11
Journal Pre-proof 12
Fig. 2. FT-IR spectrum of a) SMX, b)Cd(SMX)2 &Co(SMX)2 Sulfamethoxazole was treated with Au (III), Pd(II) and Pt(IV) in the presence of alcoholic media in order to prepare a series of new metal complexes. The complexes were characterized by FTIR, UV-Visible, elemental analysis, conductivity and magnetic measurements [8]. The mixture of metal salts (NaAuCl4.2H2O, CaCl2 and ZnCl2) and
12
Journal Pre-proof 13 sulfamethoxazole were heated at 60-700C and refluxed for 3 hours with constant stirring. precipitate
obtained
were
filtered,
washed
1.2
3.5
1.0
3.0
with
methanol
and
dried.
2.5
0.8
Abs.
Transmittance, %
The
0.6
2.0 1.5
0.4
0.0 4000
1.0
SZ Ca(II) Zn(II) Au(III)
0.2
3500
3000
2500
0.5
Zn(II) Au(III)
0.0
2000
1500
Wavenumbers, cm
1000
200
500
400
600
800
1000
1200
λ , nm
-1
Fig. 3. The IR-Spectra of the corresponding complexes The complexes[Ca(SMX)Cl2].8H2O, [Zn(SMX)(Cl)2].2H2O, [Au(SMX)(Cl)2]Cl were characterized by the spectroscopic techniques IR, H-NMR, molar conductance and elemental analysis. The yield percent of the products collected were about 70–80%. [11,34,43] O O H2N
S
H N
O
CH3 N O
N O
Zn
.2H2O
.8H2O
Ca Cl
S O
H2N
CH3
H N
Cl
[Ca(SMX)Cl2].Cl.8H2O
Cl
Cl
[Zn(SMX)Cl2].2H2O
13
Journal Pre-proof 14 O
H N
S N O
O
H2N
CH3 .Cl
Au Cl
Cl
[Au(SMX)Cl2].Cl
Table 2.Characteristics of sulfamethoxazole metal complexes
14
Sr. No
Ligan
Metals used
Complex
Geometry
Color
d
1
SMX
Fe(III)
[Fe(SMX)2Cl].H2O
Octahedral
Brown
Reaction
Characterizat
Biological
conditions
ion
Activity
Stirring
UV/Vis, IR,
Anti-bacterial
HNMR 2
SMX
Ag(I)
Ag(SMX)
Linear
White
Stirring, room
References
15
Kanagaraj et al., 1992
HNMR
Anti-bacterial
Nunes et al.,2015
UV/Vis, IR,
Anti-bacterial
Mondelli et al.,
temperature 3
SMX
Co(II)
Co(SMX)2.3H2O
Slightly
Pink
Stirring
tetrahedron,
EPR
2013
distorted octahedral 4
SMX
Fe(II)
[Fe(SMX)2Cl2].2H2
Octahedral
Yellow
Stirring (3-4 h)
O
FTIR, H-
Anti-bacterial
Bouchoucha et al.,
NMR, UV-
&Anti-fungal
2013
Anti-cancer
Al-Khodir et al.,
Visible 5
SMX
Ca(II)
[Ca(SMX)Cl2].8H2
Square
O
planer
White
Refluxed (3 h)
60oC
IR, NMR, Molar
2015
conductance. 6
SMXSalicyl
Cu(II)
SMX-SD-Cu
-----------
Green
Refluxed (4 h)
NMR, IR
----------
Bharti jain et al.,2013.
adimin e
15
16
7
SMX
Zn(II)
Zn(SMX)(Imi)2
Octahedral
White
Refluxed (3 h)
and
IR, UV-
Anti-bacterial
Visible
& anti-fungal
Anti-cancerous
Samuel et al.,2017
Imidaz ole 8
SMX
Au(III)
[Au(SMX)Cl2].Cl
Square planer
Yellowi
Refluxed (3 h)
IR, H-NMR,
sh green
60o-70oC
Molar
Al-khodir et al.,2015
conductance 9
SMX
Cr(III)
[Cr(SMX)2(NO3)].2
Octahedral
H2O 10
SMX
Zn(II)
[Zn(SMX)2Cl2].2H2
Grey
Stirring
green Octahedral
White
SMX
Ni(II)
[Ni(SMX)2Cl].2H2 O
---------
HNMR Stirring
O 11
UV/Vis, IR,
HNMR,
al.,1992 Anti-bacterial
UV/Vis, IR Octahedral
Blue
Stirring (3-4 h)
FTIR, HNMR, UV/Vis
Kanagaraj et
Al-Khodir et al.,2015
Anti-bacterial
Bouchoucha et al., 2013
16
Journal Pre-proof 17
4. Anti-Bacterial activity. Sulfonamides interacts with p-aminobenzoic acid that is involved in the biosynthesis of Tetra-hydrofolic acid which is the fundamental developmental factor basic for the metabolic procedure of microbes. Considering the previous knowledge it could suggest that one purpose behind the higher action of complex might be because of higher lipophilicity in connection with the free sulfonamide. Because of their multi-targeting mode of action the complexes of silver with sulfonamide are capable to overcome bacterial resistance. The differential behavior of gram negative and gram positive strains in relation to the test compounds should be assigned to the different morphology of these classes of bacteria. The complex cellular walls of gram negative strain implement different penetration to the test compounds. The silver complexes of SMX were synthesized and their antimicrobial activity was determined by minimum inhibitory concentration against gram positive S. aureus and S. enterica and gram negative P. strains. The complex showed MIC for gram positive at 13.9 mmolL-1 and for gram negative at 1.74 mmolL1.
They appeared to be more active against gram negative strains [13, 25, 51,55].The
antimicrobial activity of cobalt sulfamethoxazole complex was studied against M. tuberculosis. The MIC was found to be higher than 25ug/ml. The low activity of cobalt complexes against M. tuberculosis was probably due to their low lipophilicity as these compounds cannot penetrate the hydrophobic cell wall of mycobacteria. The behavior of cobalt complex in eukaryotic macrophages cells were studied in order to understand its biological activity as macrophages are the first cells that respond to mycobacterial
17
Journal Pre-proof 18 invasion. The results showed that the tested compound exhibit low cytotoxicity as it bear bacteriostatic effect. [20,16,47,49, ]. The antimicrobial activity of iron complex of sulfamethoxazole against different bacterial strains S. aureus, B. subtilis, P. aeruginosa, K. pneumonia and E.coli were studied. It showed remarkable activity against S. aureus with minimum inhibitory concentration 6.25ug/ml and least activity against K. pneumoniae. [Ni (SMX)2Cl].2H2O has also been observed to show highest activity
against
S.aureus
[12,46,35,44,56].
Fig.4. Antibacterial Analysis of metal compleces with SMX Cu (SMX)2 (H2O)4.3H2O and Cu(SMX)2.H2O were prepared and their antimicrobial activity against different bacterial strain were studied. The MIC values for the aforesaid complexes were found to be 4ug/ml for S. aureus and 32ug/ml for E. coli of the Cu (SMX)2 H2O complex and 16ug/mL for S. aureus and E.coli of the Cu(SMX)2.H2O complex. Although both the complexes were active against bacteria but the activity was different due to different stoichiometric ratio [18, 33, 45,51, 56].The antimicrobial activity of [Au 18
Journal Pre-proof 19 (SMX) Cl2] was investigated. Its cytotoxic activity was performed on human colon carcinoma cell line and human hepatocellular carcinoma cell line in the presence of standard drug Doxorubicin. From the results obtained it was found that the complex was more effective against hepatocellular carcinoma cell line [11]. Table.3 Antibacterial activity data for SMX metal complexes. Sr. No. 1
2
Complex
Bacterial strain
MIC
Reference
[Fe(SMX)2Cl2].2H2O
S. aureus
6.25(u g/ml)
Bouchoucha et al., 2013
Bacillus subtilis
12.5(u g/ml)
P. aeruginosa
100(u g/ml)
K. pneumonia
25(u g/ml )
E.coli
25(u g/ml)
S. aureus
4(u g/ml)
E.coli
32(u g/ml)
Cu(SMX)2(H2O)4.3H 2O
Borthagaray et al., 2016
3
Co(SMX)2.3H2O
M. tuberculosis
>25(u g/ml)
Mondelli et al.,2013: Blasco et al 1996.
4
Cu(SMX)2.H2O
S. Aureus E.coli
16(u g/ml) 16(u g/ml)
Borthagaray et al., 2016
5
Ag-SMX
S. aureus Salmonella P. aeruginosa
13.9(mmol/L) 13.9(mmol/L) 1.74(m mol/L)
Nunes et al., 2015
6
[Ni(SMX)2.Cl].2H2O
S. aureus
25(u g/ml)
Bouchoucha et al., 2013
E. coli
100(u g/ml) 19
Journal Pre-proof 20 P. aeruginosa
>200(u g/ml)
K. pneumoniae
25(ug/ml)
B. subtilis
12.5(ug/ml)
2. Anti-fungal activity: Metal complexes additionally exasperate the breath procedure of the cell and in this manner hinder the amalgamation of proteins, which limits further development of the organism. Finally, it is proposed that the explanation behind this higher antimicrobial viability could be identified with the hindrance of a few basic catalysts that assume a key job in fundamental metabolic pathways of the microorganisms[50]. In view of the huge natural and pharmacological properties that the sulfamethoxazole has, another class of such mixes was accounted for by consolidating the science of sulfonamides with first row transition metals and to investigate their organic exercises with the point of acquiring progressively powerful anti-fungal compounds.[40].SMX alone showed no activity against fungal strains but the complex of SMX-Fe showed a little activity against different fungal strains S. cerivisiae, A. fumigatus, A. niger while no activity against C. albicans and C. tropicalis. The complex of [Ni (SMX)2Cl].2H2O has not shown any activity against any type of fungal strains[12,28,37]. The complexes of Manganese, Lanthanum and Neodymium with SMX
having the formula [Mn (SMX)2Cl2].2H2O,
[La(SMX)2Cl3].3H2O & [Nd(SMX)2Cl3].2H2O were synthesized and their antifungal 20
Journal Pre-proof 21 activity was studied against the two fungal strains A. fumigatus and A. flavus. The complex of La with SMX showed the highest activity against the two aforesaid fungal strains [50, 30, 35,57-59]. Table 4. Antifungal activity data of SMX metal complexes: Sr. Complex No
Fungal strain
MIC
Zone of inhibition( mm)
[Fe(SMX)2Cl2].H2O
C. tropicalis
>200 -----
[Ni(SMX)2.Cl2.2H2O
Cndiada ----- -----albicans Saccharomyces ------ ------cervisiae
Reference
1
2
A. fumigatus,
-----
------
C. tropicalis
-----
------
A.fumigatus
-----
27
A.flavus
------ 35
Bouchoucha et al., 2013
Bouchoucha et al.,2013
3 [La(SMX)2Cl2].2H2O
[Nd(SMX)2Cl2].2H2 O
Yasmin et al.,2017
A.fumig ------ 26 atus A.flavus
------ 36
A.fumigatus
-----
22
[Mn(SMX)2Cl2].2H2O
21
Journal Pre-proof 22 A.flavus
-----
25
Conclusion The structural geometry of the synthesized transition metal complexes with sulfa drugs permits them to rupture the cell wall of bacteria and fungi which enhance their applications in pharmaceutical and synthetic chemistry. Literature justifies that sulfa drug based metal complexes of transition metals have been found excellent in field of research and development now a day, that is why sulfa drug metal complexes synthesis is getting more and more attention of modern researchers. So, it has been concluded from the review that transition metal complexes of sulfa drug derivatives have beneficial prospective against numerous syndromes so there is a dire need for the exploration of these types of complexes in the field of pharmaceutical and pharmacological processes. Future prospects. The pharmaceutical scope of sulfa drug metal complexes have enriched the attention of researchers so, in future the project can also be boosted up to homo bimetallic and hetero bimetallic transition metal complexes of sulfa drugs which may act as strong antibacterial and antifungal agents.
22
Journal Pre-proof 23
References: 1. L.L. Marques, O.D.G., Manzoni, E.S. Lang, C.D. Anraku, L.R.S Gris. New gold(I) and
silver(I)
characterization
complexes and
of
sulfamethoxazole:
microbiological
synthesis,
activities
of
X-ray
structural
triphenylphosphine
(sulfamethoxazole-N2) gold(I) and (sulfamethoxazolato)silver(I).Inorganic chemistry communications,10:10 (2007) 83-1087. 2. W. Byarugaba,, H.W. Rudiger, T. Koske-Westphal, W. Wöhler, E.Passarge..Toxicity of antibiotics on cultured human skin fibroblasts. Humangenetik, 28: (1975) 263–267. 3. M.F.Mahdi, R.F, Al-Smaism, Z.M.Al-Khaliq..2015.Synthesis ,Characterization and antibacterial activity of new series of sulfamethoxazole derivatives. World journal of pharmacy and pharmaceutical sciences,4 (10): (2015)284-293 4. R.Bentley. Different roads to discovery; Prontosil (hence sulfa drugs) and penicillin (hence beta-lactams).journal of Indian microbiological and biotechnology, 36 (6): (2009)775-786. 5. G.Kanagaraj, G.N. Rao, Synthesis and characterization of some first row transition metal complexes of 4-amino-N-(5-methyl-3-isoxazolyl)benzenesulfonamide. Synthesis and reactivity in inorganic and metal-organic chemistry,22 (1992) 559-574. 6. Z.Guo, P.J Sadler.Metals in medicine.Angewandte chemie international,38(11) (1999)1512-1531. 7. S.S.AShah, G.Rivera, Ashfaq. M. Recent advances in medicinal chemistry of sulfonamides. Rational design as anti-tumoural, antibacterial and anti-inflammatory agents. Mini Rev Med Chemistry,13(1): (2013)70-86.
23
Journal Pre-proof 24 8. M.F. Alias, M.M.Abdulhassan..Synthesis and Characterization of Some Metal Complexes with their Sulfamethoxazoleand 4,4'-dimethyl-2,2'-bipyridyl and study Cytotoxic Effect on Hep-2 Cell Line. Baghdad Science Journal ,12(4)( 2015) 740-752. 9. B.Kesimli, A. Topacli,A. Infrared studies on Co and Cd complexes of sulfamethoxazole. Spectrochimica Acta Part A ,Molecular biomolecular spectroscopy.57: (2001) 1031–1036. 10. B.Jain, S. Malik, N.Sharma,S. Sharma. Synthesis, physico-chemical and spectral studies of Hg(II) and Cu(II) complexes with sulfamethoxazole schiff base.
Der Chemica
Sinica, 4(5)( 2013) 40-45. 11. F.A.I. Al-Khodir. Ca(II), Zn(II) and Au(III) Sulfamethoxazole Sulfa-drug Complexes: Synthesis, Spectroscopic and Anticancer Evaluation studies.Oriental journal of chemistry,31(3)( 2015)1277-1285. 12.
A.Bouchoucha,
A.
Terbouche,
M.Zaouani,
F.
Derridj,
S.Djebbar.
Iron and Nickle complexes with heterocyclic ligands:stability,synthesis,spectral characterization,antimicrobial activity,acute and sub-acute toxicity.Journal of trace elements in medicine and biology 27 ( 3) (2013): 191-202. 13. J.H.N Bromio, R.F.E. Paiva,, A.Cuin, W.Lustri, P.P. Corbi. Silver complexes with sulfathiazole
and
sulfamethoxazole:synthesis,spectroscopic
characterization,crystal
structure and antibacterial assays,Polyhedron,85: (2015)437-444. 14. W. Baran,, E. Adamek, J. Ziemianska, Sobczak. Effects of the presence of sulfonamides in the environment and their influence on human health. Journal of Hazardous Materials,196 (2011)1–15.
24
Journal Pre-proof 25 15.
Bozkurt,
A.,
Basci,
N.E.,
Isimer,
A.,
Tuncer,
M.,
Erdal,
R.
and
Kayaalp,S.O.1990.Sulfamethoxazole acetylation in fast and slow acetylators. International journal of clinical pharmacology, therapy and toxicology, 28:164-166. 16.M.Mondelli, F.Pavan, P.C. Souza, C.Q.Leite, J. Ellena, O.R. Nascimento, G.,Facchin, M.H.Torre. Study of series of cobalt sulfonamide complexes; synthesis, spectroscopic characterization, microbiological evaluation against M.tuberculosis .crystal studies of [Co(SMX)22H2O].H2O.Journal of molecular structure,1036(2013)180-187.
17. A. Samuel, O. Oladpo, O. Olukemi, B.Oladayo. Spectroscopic Studies of Mixedligand Complexes of Cu(II), Co(II), Mn(II) and Zn(II) with Sulfa Drug and Heterocyclic Compound. Der Pharma Chemica , 9(10): (2017)55-58. 18. G. Borthagaray, M. Mondelli, M.H.Torre. Essential transition metal ion complexes as strategy to improve the antimicrobial activity of organic drugs.Journal of infectious diseases and epidemiology,2(2). 2014 10.23937/2474-3658/1510014 19..M.A.El-Nawawy. Synthesis,spectroscopic,
R.S.Farag, Thermal
studies
I..Sabbah, and
Biological
I.A.A.M.Abu-Yamin, activity
of
a
new
sulfamethoxazole Schiff base and its copper complexes.International journal of pharmaceutical sciences and research,2(12): (2011) 3143-3148. 20. Z.H. Chohan, K Mahmood-ul-Hassan, K.M. Khan.C.T. Supuran. Invitro antibacterial,sntifungal and cytotoxic properties of sulfonamidederived schiff’s basesand their metal complexes.Enzyme Inhib.Med.chem, 20(2)( 2005)183-188.
25
Journal Pre-proof 26 21. T. Arora, A. K. Mehta, V. Joshi, K. D. Mehta, N. Rathor, P. K. Mediratta, K. K. Sharma. Substitute of Animals in Drug Research: An Approach Towards Fulfillment of 4R’sIndian journal of pharmaceutical sciences, 73 (1): (2011)1-6. 22. M.H.Torre, S. Calvo, H. Pardo, A.W. Mombru. Synthesis, spectroscopic characterization and crystal structure of disulfamethoxazole and diaquo Ni(II) monohydrate.Journal of coordination chemistry,58(6):( 2005)513-520. 23. F.R.Pavan, D.N. Sato,C.Q.F. leite. An approach to the search for new drugs against Tuberculosis.doi:10.5772/31618 (2010). 24. A. Rani, M. Kumar, R. Khare, H.S.Tuli. Schiff bases as antimicrobial agent. A review. Journal of biological and chemical sciences, 2(1): ( 2015)62-91. 25. S. Eckhardt, P.S. Brunetto, J.Gagnon, P. Magdalene. B.Giese. Nanobio silver ;its interaction with peptides and bacteria and its uses in medicine.Chem.Review, 113(7): (2013)4708-4754. 26.
K.K.Nrang.
Sulfadrugs
complexes
of
Zinc(II),Cadmium(II)
and
Mercury(II).Transition metal chemistry,2(11): (1977)181-183. 27.
K.K.Nrang,
J.K.Gupta.
Cu(II)
Complexes
of
sulfanilamide,
sulfaguanidine,sulfathiazole,sulfamerazine,sulfadiazine and sulfapyridine.Indian.Journal of chemistry,13(1975)705. 28. Z.H.Chohan, S.H.Sumrra, M.H.Youssoufi, T.B.Hadda. Metal based biologically active compounds:design ,synthesis and antibacterial/antifungal/cytotoxic properties of triazolederived Schiff bases and their oxovanadium(IV) complexes.European journal of medicinal chemistry,45(2010)1189-1199.
26
Journal Pre-proof 27 29. S. Djebbar, O.B. Baitich, J.P. Deloume. Synthesis, characterization , electrochemical behavior and catalytic activity of manganese(II) complexes with linear and tripodal tetradentate ligands derived from Schiff bases.Transition metal chemistry,23(4)( 1998)443-447. 30 G..Karthikeyan, k.Mohanaraj, K.P.Elango, K.Girishkumar. Synthesis and spectral characterization of lanthanide complexes with sulfamethoxazole and their antibacterial activity. Russian journal of coordination chemistry,32(2006.)380-385.
31. G.M. Gehad, M.O.Mohammad, M.H. Ahmed. Metal complexes of Schiff bases: preparation characterization and their biological activity. Turkish journal of chemistry,30: (2006)361-382. 32. J. Joseph, B.G.Janaki, K. Nagashri. Novel metal based anti- tuberculosis agent: synthesis, characterization, catalytic and pharmacological activities of copper complexes. European journal of medicinal chemistry, 49 (2012)151-163. 33. C.T.Supuran, F.Minicione, A. Scozzafav, F. Briganti, G. Minicinone, M.A. Ilises. Metal complexes of heterocyclic sulfonamides:a new class of strong topical intraocular pressure-lowering agents in rabbits. European journal of medicinal chemistry, 33(1998.)247. 34. ,F.A .Saad. Elaborated molecular docking and DFT/B3LYP studies for novel sulfa drugs complexes, spectral and antitumor investigations. Journal of thermal analysis and calorimetry,129(1):( 2017) 425-440. 35.
B.A.A.Oluwatoosin,
M.S.
Wakil.
A.A.Osowole.
Synthesis,
Spectroscopic
Characterization and Antimicrobial Activities of Some Mixed Drug Metal (II) Complexes
27
Journal Pre-proof 28 of Sulfamethoxazole and Paracetamol. Journal of Research & Developments in Chemistry. (2014) DOI: 10.5171/2014.400324 36. M.E.Moustafa. Synthesis and structural and biological activity studies on some lanthanide chelates with O- and N-containing ligands. Spectroscopy letter,38(1): (2005)2334.
37. P.J.Sadler, Zijien. Metal complexes in medicine, Designed and Mechanism of Action. Journal of Pure and Applied Chemistry, 70( 4): (1998) 863-871. 38. M.F.Melina, P.Fernando, C. Paula, Q.L.Clarice, E.Avier, R.N. Otaciro, Gianella,F. H.T.Maria. Study of a series of cobalt(II) sulfonamide complexes: synthesis, spectroscopic characterization, and microbiological evaluation against M.Tuberculosis. Journal of molecular structure,1036: (2013)180-187. 39. B.C. Rudy, B.Z. Senkowski. Sulfamethoxazole.Profile of drug substances excipients and related methodology, doi:10.1061/S0099-5428(08)60051-9 1st edition (1973) 562. 40. P. Edder, A. Cominoli, C. Corvi. Analysis of residues of sulfonamides in foods of animal origin (liver, kidney, meat, fish, eggs, milk) by liquid chromatography with prederivatization and fluorimetric detection. Mitt. Geb. Lebensmittelunters. Hyg, 88(1997) 554–569. 41. J. Koch-Weser, V.W. Sidel, M. Dexter, C. Parish, D.C. Finer, P. Kanarek. .Adverse reactions to sulfisoxazole, sulfamethoxazole, and nitrofurantoin. Arch. intern. Med, 128 (1971) 399–404. 42. F. Blasco, L. Perello, J. Latorre, J. Borras, S. Garcia-Granda, J. Inorg. Cobalt(II), Nickel(II), and Copper(II) Complexes of Sulfanilamide Derivatives: Synthesis,
28
Journal Pre-proof 29 Spectroscopic
Studies,
and
Antibacterial
Activity.
Crystal
Structure
of
[Co(sulfacetamide)2(NCS)2]. Journal of Inorganic Biochemistry, 61(1996)143-154.
43. S. Ramesh, Y.Yamgar, N.Satish, M.Mustapha, R.G.Atram.S.S.Sudhir. Novel Zinc(II) Complexes of Heterocyclic Ligands as Antimicrobial Agents: Synthesis, Characterisation, and
Antimicrobial
Studies.Bioinorganic
Chemistry
and
Application,(2014)
doi.org/10.1155/2014/276598 44. M. Rizzotto.2013 Metal complexes as antimicrobial agents, InTechoPen (2013). 45. R.N.Patel, P.V. Sondhiya, k.K. Shukla, D.K.Patel, V.P.R. Singh. Design, synthesis, and characterization of a series of biologically active copper(II) Schiff-base coordination compounds. Journal of Indian Chem, 89(2012)1085-1092. 46.S.Ghosh, B. Jain, S, Malik, S.A.Iqbal. Synthesis, characterization, antimicrobial and diuretic study of Mg(II), Mn(II), Fe(II) and VO(II) complexes of chemotherapeutic importance.Journal of Saudi Chemical Society,16(2): (2012)137–143. 47. S. Ahmad, A. Anvarhusein. A. Isab, R.Abdul. Perspectives in bioinorganic chemistry of some metal based therapeutic agents Polyhedron ,25 (2006) 1633–1645. .48.S.S.A.Shah, M.Ashfaq, T. Najam, M.M.Ahmed, R.Tabassum, S.Abida. Synthesis of Sulfonamides, Metal Complexes and the Study of In vitro Biological Activities. Current bioactive compounds, 9(3): (2013): 211-220. 49. K. Palaniappan, R.A. Holley. Use of natural antimicrobials to increase antibiotic susceptibility of drug resistant bacteria. International journal of food microbiology, 140 (2010)164-168.
29
Journal Pre-proof 30 50.M.S.Yasmin, M.A.Al-Maqtari,M.K.Al-Qadasi. Ligational and spectroscopic on some sulfamethoxazole metal complexes as antimicrobial agents. European
journal of
pharmaceutical and medical research,4(7): (2017) 95-105. 51 M. Pervaiz, I. Ahmad, M.Yousaf, S. Kirn, A.Munawar, Z. Saeed, A. Adnan, T. Gulzar, T. Kamal, A. Ahmad, A.Rashid. Synthesis, spectral and antimicrobial studies of amino acid derivative Schiff base metal (Co, Mn, Cu, and Cd) complexesSpectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 206 (2019) 642–649. 52. R. Tabaraki , E. Heidarizadi.
Spectrophotometric determination of phenol and
chlorophenols by salting out assisted liquid-liquid extraction combined with dispersive liquid-liquid microextraction. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 25 (2019). 405-409. 53. M. Pervaiz, M. Yousaf, M. Sagir, M. Mushtaq, M.Y. Naz, S. Ullah, R. Mushtaq, Synthesis and characterization of bimetallic post transition complexes for antimicrobial activity, Synth. React. Inorg., Met.-Org., Nano-Met. Chem. 45 (2015) 546–552. 54. K. Meena, K. Muthu, V. Meenatchi, M. Rajasekar, G. Bhagavannarayana, S. Meenakshisundaram. "Spectrochimica acta part A: molecular and biomolecular spectroscopy." Spectrochim Acta Part A 124 (2014): 663-669. 55. L.H. Abdel-Rahman, R.M. El-Khatib, L.A.E. Nassr, A.M. Abu-Dief, F.E.-D. Lashin, Design, characterization, teratogenicity testing, antibacterial, antifungal and DNA interaction of few high spin Fe(II) Schiff base amino acid complexes, Spectrochim. Acta A. Mol. Biomol. Spectrosc. 111 (2013) 266–276. 56. M.Pervaiz. Muhammad Yousaf, Ameer Fawad Zahoor, Abdullah Ijaz Hussain, Muhammad Kaleem Khan Khosa, Sadia Ashraf, Muhammad Sagir, Ashar-uz-Zaman,
30
Journal Pre-proof 31 KhurramShehzad, Synthesis, characterization and biological studies of Bis-{μ-2,2¢[ethane-1,3-diyl-bis(nitrilomethylidyne)]diphenolato}dicopper(II) using triple component solvent system, Asian J. Chem. 25 (2013) 521–524. 57. A.-U. Zaman, I. Ahmad, M. Pervaiz, , S. Ahmad ,S. Kiran, M. A. Khan, T. Gulzar, T. Kamal. A novel synthetic approach for the synthesis of pyrano[3,2-c]quinolone3carbaldehydes by using modified Vilsmeier Haack reaction, as potent antimicrobial agents Journal of Molecular Structure 1180 (2019) 227e236 58. M. Pervaiz, M. Yousaf, A. Jabbar, A. F. Zahoor, T. H. Bokhari, A. Anjum, M. Sagir, M.A. Khan, K. G. Ali, S. Ahmad, M. Z. Rehman, S. Ashraf, K.S. Qeureshi, Synthesis, characterization
and
biological
studies
of
bis{m-2,2'-[N,N'-diylbis
(nitrilomethylidyne)]diphenolato}dicobalt(II) using triple component solvent system, Asian J. Chem. 25 (2013) 2161e2164. 59. M. Pervaiz, M. Yousaf, M. Sagir, A. Pervaiz , M. Y. Naz.. Novel preparation and spectral investigation of a series of schiff base derivatives monometallic transition metal complexes as bacteria and fungus inhibitors. Main Group Chemistry, 13 (2014)129-145. 60. Strianese M, Pellecchia C. Metal complexes as fluorescent probes for sensing biologically relevant gas molecules. Coordination Chemistry Reviews.1(318) (2016) 318:16-28. 61. Ma, Dik-Lung, Modi Wang, Chenfu Liu, Xiangmin Miao, Tian-Shu Kang, and ChungHang Leung. "Metal complexes for the detection of disease-related protein biomarkers." Coordination Chemistry Reviews 324 (2016): 90-105.
31
Journal Pre-proof 32 62. Kaushik, Rahul, Amrita Ghosh, and D. Amilan Jose. "Recent progress in hydrogen sulphide (H2S) sensors by metal displacement approach." Coordination Chemistry Reviews, 347 (2017): 141-157. 63. Galardon, Erwan, Alain Tomas, Mohamed Selkti, Pascal Roussel, and Isabelle Artaud. "Synthesis, characterization, and reactivity of alkyldisulfanido zinc complexes." Inorganic chemistry 48, no. 13 (2009): 5921-5927. 64. Strianese, Maria, Silvia Mirra, Valerio Bertolasi, Stefano Milione, and Claudio Pellecchia. "Organometallic sulfur complexes: Reactivity of the hydrogen sulfide anion with cobaloximes." New Journal of Chemistry 39, no. 5 (2015): 4093-4099. 65. Strianese, Maria, Marina Lamberti, and Claudio Pellecchia. "Chemically reversible binding of H 2 S to a zinc porphyrin complex: towards implementation of a reversible sensor via a “coordinative-based approach”." Dalton Transactions 46, no. 6 (2017): 18721877. 66. Cozzolino, Mariachiara, Vincenza Leo, Consiglia Tedesco, Mina Mazzeo, and Marina Lamberti. "Salen, salan and salalen iron (iii) complexes as catalysts for CO 2/epoxide reactions and ROP of cyclic esters." Dalton Transactions 47, no. 37 (2018): 13229-13238. 67. Borase, Pravin N., Pranila B. Thale, and Ganapati S. Shankarling. "Ru (Cl)‐Salen Complex: Solvent Selective Homogeneous Catalyst for One‐Pot Synthesis of Nitriles and Amides." ChemistrySelect 3, no. 20 (2018): 5660-5666. 68. Hida.S, Yoshida M, Nakabayashi I, Miura NN, Adachi Y, Ohno N.(2005) “Antifungal activity of sulfamethoxazole toward Aspergillus species” Biol Pharm Bull,28(5):773-778
32
Journal Pre-proof 33 69. Zhang.Y., Cao.Y., Leng. X., Chen.C & Huang.Z.(2014). Cationic Palladium(II) Complexes of Phosphine-sulfonamide Ligands: Synthesis, Characterization and catalytic ethylene oligomerization. Organomettalics. 33(14); 3738-3745.
33
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Highlights.
Being borne in mind the worth of sulfa drug based transition metal complexes, the review has recapitulated the synthesis, characterization and antimicrobial activities of sulfonamide metal complexes.
Due to broad spectrum range, sulfa drug derivatives have beneficial prospective against numerous syndromes so there is a dire need for the exploration of these complexes in the field of pharmaceutical and pharmacological processes.
In future, the project can also be boosted up to homo/hetro bimetallic metal complexes of sulfa drugs which may act as strong antimicrobial agents.