Schiff base complexes of some drug substances (Review)

Schiff base complexes of some drug substances (Review)

Lekaa K.Abdul Karem , Fawzi Y.Waddai*Nisreen H. Karam

Department of Chemistry, College of Education for Pure Sciences, Ibn/al Haitham, University of Baghdad, Adhamiyah, Baghdad,10001, Iraq

*Department of Chemistry, Faculty of Science, Kufa University, Al-Najaf -31001-Iraq.

Abstract Schiff bases (SBs) represent multipurpose ligands that can be prepared from the concentration of prime amines with carbonyl clusters. Creation of SB transition metal compounds via as ligands has opportunity of attaining coordination complexes of abnormal arrangement and stability. These transition metal compounds have extraordinary attention as a consequence of their dynamic portion in metalloenzymes and as biomimetic prototypical complexes as a result of their proximity to usual enzymes and proteins. These complexes are imperative in medicinal disciplines owing to their widespread range of biological actions. They mostly exhibit organic actions involving antifungal, antibacterial, antitumor, antidiabetic, herbicidal, antiproliferative, anticancer, and anti-inflammatory actions. The organic action of transition metal compounds resulting from the Schiff base ligands was extensively investigated. This paper reviews the scope, significance, and antimicrobial actions of Schiff base metal compounds.

INTRODUCTION Synthesis of metallic compounds attained increasing interest owing to their multipurpose organization behaviour and accepting of molecular practices [1, 2]. These compounds have noteworthy consideration in its operational and organization chemistry. They have varied natural, photosensitive and magnetic features by modifying with dissimilar ligands. In specific, the investigation of metallic compounds of Schiff base (SB) ligands looks to be attractive in terms of unusual structure and stability. SB compounds are taken into account to be amid the imperative stereochemical prototypes in transition metallic organization chemistry as a result of their approachability and physical diversity [3, 4]. Structurally, a SB or imine or azomethine stands for a nitrogen equivalent of an aldehyde or ketone in which the carbonyl cluster (>C = O) is substituted by an imine or azomethine cluster, (Aromatic aldehydes particularly with an effectual conjugation scheme) [5]. Transition metallic compounds that typically comprise nitrogen, sulphur or oxygen as ligand atoms have been progressively significant for the reason that these SB can combine with diverse metallic centers including numerous organization sites and permit efficacious mixture of metallic compounds [6]. The extraordinary similarity for the chelation of the SB in the direction of the transition metallic ions can be exploited in formulating their solid compounds [7]. The interface of metal ions and these donor ligands provides compounds of diverse structures and the related reported studies shows that these compounds are organically effective compounds recently [8,

9]. These compounds have likewise received unique attention for the reason that their effective portion in metalloenzymes and as biomimetic prototypical complexes owing to their nearness to regular enzymes and proteins [10]. All studies that deal with metallic compounds are wide-ranging and have numerous areas like catalysis, bioinorganic chemistry, magneto and chemistry photochemistry [11]. The progresses in mineral chemistry have better prospects to employ metallic compounds as remedial drugs to recover numerous humanoid illnesses. The use of SB transition metallic compounds as remedial complexes has been increasingly noticeable. Synthetic of SB metal compounds are an emergent type of complexes with variable chemistry, dissimilar molecular designs as well as collections of donor atoms. It is a well-known that N atom has an important part in the organization of metals as the dynamic position of frequent metallobiomolecules [12-13] . These compounds have an unlimited assortment in their action; as antiseptic [14-15], antifungal [16-17], anticancer [18-19] and anti-inflammatory mediators [20-21]. As a result of the requirement of newfangled metal-based antiseptic complexes, metal organic

chemistry is being an evolving research scope [22]. Significant properties possibly interrelated with worthy antimicrobial actions are the lipophilicity and diffusion of compounds throughout the lipid skin. Microorganism has existence on earth greater than 3.8 milliard years and has highest genomic and metabolic variety. For the maintenance and sustainability of the ecosystem these microorganisms have an important role and thus they are considered as an important constituent of the biosphere [23]. At present, antimicrobial resisting amongst parasites, viruses, bacteria, and others is a dangerous threat to communicable infection managing [24]. The actions of antimicrobial agents are studied by understanding its mechanism of resistance. Antimicrobial agents show a minimal effect or inactivity on host performance when it's acted upon vital microbial performance. Diverse antimicrobial mediators work in dissimilar techniques. The appliance of antimicrobial mediators are categorised on the basis of the structure of microorganisms or the purpose that is influenced by the agents like inhibition of ribosome function, cell wall synthesis, folate metabolism, cell membrane function and nucleic acid synthesis. Resistance can be explained in dual methods: a) intrinsic or biological resistance whereby bacteria inherentlyhave not objective sites for the medications and consequently themedication don't influence them or they obviously have lowpenetrability to those mediators owing to the changes in thebiological drug quality and the bacterial membrane arrangementsparticularly for those which necessitate access into the bacterialcell to affect their performance.b) Attained resistance whereby an obviously vulnerable bacteriahas behaviors of not being influenced by the medicine. Generally,the actions of all obtained compounds have been sensible eventhough advanced applied concentrations. With the intention ofsurvive, microbes have progressively being resilient incontradiction of the arsenal antimicrobial agents to which theywere being targeted [25-26].Chaudhary,(2013)][27] A new-fangled SB ligand AMXPC hasbeen organized by condensation in weak acidic medium ofAmoxicillin trihydrate(Amox) with Pyrrole-2-carbaldehyde inmethanol solution. The metal complexes have been prepared byusing (Cu, Co and Zn) chloride salts. The new ligand and theircompounds have been partitioned for their in vitro antibacterialaction in contradiction of 3 pathogenic microorganisms E. coli,B. subtilis and S. aureus, through gauging zone span of inhibitingin millimeter units. (Amox)has been used as control medicine.The outcome of these research indicate resilient antibacterialaction of metal(II) compounds than ligand and drug controller.

Lekaa K.Abdul Karem et al /J. Pharm. Sci. & Res. Vol. 10(8), 2018, 1912-1917

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Scheme 1: scheme of Ligand synthesis

Figure 1: Structure of the organized SB ligands

Figure 2: Chemical arrangement of the organized complexes

Mouayed et al., (2014)[28], were reported 3 newfangled SB ligands resulting from piperonal and diamine complexes (ethane-1,2-diamine, propane-1,3- diamine, butane-1,4- diamine) were created. These ligands have been dealt with Co(II) chloride with a metal: ligand ratio of (1:1) to give 3 innovative compounds [CoL2(H2O)2]Cl2 , [CoL2(H2O)2]Cl2 and [CoL2(H2O)2]Cl2.The ligands and metallic compounds have been partitioned for their antimicrobial actions in contradiction of positive and negative gram bacteria. They were discovered to be organically dynamic. Taghreed et al.,(2014),[29] New-fangled SB ligand (E)-6-(2-(4 (dimethyl amino) benzylidene amino)-2-phenylacetamido) -3,3-dimethyl-7-oxo-4-thia-1 azabicyclo [3.2.0] heptane -2- carboxylic acid (HL) has been organized by concentration of Ampicillin and 4(dimethylamino) benzaldehyde in methanol. Polydentate diversified ligand compounds have been acquired from 1:1:2 molar ratio reacting with metallic ions and HL, 2NA by reacting with MCb .nH2O salt yields compounds analogous to the formulations [M(L)(NA)2Cl] ,where M = Fe(II),Co(II),Ni(II),Cu(II), in addition to Zn(II) and NA=nicotinamide. SB ligands task as tridentates and the deprotonated enolic arrangement is favored for organization. With the intention of assessing the consequence of the bactericidal

action, these created compoundsas compared with uncompounded SB was partitioned in contradiction of bacteriological sorts, Staphylococcus aureus,Escherichia and coli consequences have been described.

Scheme 2: Schematic depiction of (HL)ligand synthesis


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Abaas et al.,(2014),[30] were reported new-fangled SB of (4-chlorophenyl) (phenyl methanimine (6R,7R)-3-methyl-8-oxo-7-(2-phenylpropanamido)-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylate=HL) created from β-lactam antibiotic ;cephalexin mono hydrate and 4- chlorobenzophenone. The ligand and their metallic compounds have been partitioned for their antimicrobial action compared to 4 microorganisms (gram +ve) and (gram -ve) [Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus]. The suggested arrangement of compounds by means of Chem office simulator and broad-spectrum formulation were assumed for the organized assorted ligand compounds [M(Sac)3(L)].

Scheme 3: The synthesis route of ligand (HL)

Aurora et al., (2015) [31], were reported metallic compounds of SB obtained from dissimilar antibiotics that are extensively used as organic effective constituents, particularly as sterile mediators. The broad-spectrum formulation proven from tentative data has been [Co L2(H2O)2] and [Ni L2(H2O)2] . This arrangement has been additionally verified by thermal investigation and their thermal stability in nitrogen atmosphere has been studied. Antibacterial investigation revealed that the effectiveness of metallic compounds is greater than the initiated one of free Schiff base ligand.

Figure 3: Arrangement of the Schiff base ligand (HL).

May M. (2016), [32] , was reported six different Schiff bases were synthesized from ampicillin and amoxicillin with isatin, 5-bromoisatin, and 5-nitroisatin. Ampicillin and Amoxicillin are linked directly through their α-amino groups to the acyl side chain with isatin and isatin derivatives by nucleophilic addition using glacial acetic acid as a catalyst.The antiseptic behavior has assessed by determining smallest inhibitory concentration (MIC) values and showed various degrees of antibacterial activities when compared with parent drugs. Compounds 1a and 2b, which are the Schiff bases of ampicillin and amoxicillin with isatin, showed very noteworthy behavior in contradiction of methicillin-resistant Staphylococcus aureus (MRSA). Moreover, Schiff bases with 5-bromoisatin (1b and 2b) displayed significant activity against MRSA and less activity against Staphylococcus aureus (S. aureus).

Scheme 4: Synthesis of Ampicillin Schiff bases

Batool et al.,(2016),[33] synthesized a new-fangled Schiff base ligand throughout the concentration of amino penicillinic acid with o-nitrobenzyldehyde liquefied in absolute ethanol in alkaline. Metallic compounds of SB was produced from chloride salt of Co(II), Ni(II), Cu(II) and Zn(II) in ethanolic standard. The efficiency of prepared inhibitory compounds has been in contradiction of four investigated bacteria categories ( pseudomonas aeruginosa, Staphylococcus aureus, Proteus mirabilis and Streptococcus facials), that have been separated from diverse types of ulcerative contagions.

Scheme 5: Fragmentation pattern of ligand


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Figure 4: Proposed structure of Schiff base metal complexes.

Amins et al.,(2016),[34] , reported new usage in contradiction of safe life form, the change of current medicine by mixture to a metal concentration was given a late attention. As a consequence, metal-based medicine has capable replacements for for several existing medications. Consequently, SB metal compounds in this respect were synthesized. A sequences of transition metal (II) compounds of novel SB have created by concentration of sulphadizine and 2-carboxybenzaldehyde in ethanol. The formed ligand and metal compounds have been exposed to antiseptic investigations. These investigations presented the improved performance of metallic investigations in contradiction of one or more classes than uncompounded ligand.The results presented that transition metallic compounds have important enhanced

antiseptic performance as compared with parental medicine. Aun et al., (2017) , [35] were described methicillin resilient Staphylococcus aureus (MRSA) that is resilient to identified antibiotics and has been an excessive encounter for healthcare experts. Consequently, novel molecules are required to accomplish this condition. In this research, novel lead fragments of 4-Amino-5-(2-Hydroxy phenyl)-1,2,4-Triazol-3-Thione(U1)and4-(2-hydroxybenzalidine) amine-5-(2-hydroxy) phenyl-1,2,4-triazole-3-thiol(U1A SB) were synthesized by fusion technique that showed promising antibacterial activity (U1A: 26mm and U1: 14mm) against MRSA. New-fangled latent medicine targets of this bacterium were also identified by proportional and deduction genomics methods. In particular, octanoyl-[GcvH]: protein N-octanoyl transferase and phosphor mevalonate kinase were used as potential targets in AutoDock Vina studies. They can offer an outline to discover probable medicine targets for different pathogenic bacteria that can efficaciously be cut with U1 and U1A compound. Deepak et al.,(2017)[36] were reported a novel monobasic tridentate Schiff base salicylidene-trimethoprim, Sal-TMP, created from trimethoprim and salicylaldehyde, form stable compounds with aryltellurium(IV) trichlorides and diaryltellurium(IV) dichlorides of Sal-TMP.ArTeCl 2 and Sal-TMP.Ar 2 TeCl (where Ar = p-methoxyphenyl, p-ethoxyphenyl, p-hydroxyphenyl and 3-methyl-4-hydroxyphenyl). The complexes were also partitioned for their antimicrobial performances in contradiction of various fungi and bacteria organisms.

Scheme 6: 4-Amino-5-(2-Hydroxyphenyl)-1, 2, 4-Triazol-3-Thione Synthesis

Sheme 7: reaction of trimethoprim drug and salicylaldehyde

Scheme 8: Synthesis of sulfadiazine Schiff bases


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Scheme 9: Synthetic scheme for the ligand (HL) and its metallic compounds.

Narendra et al. (2017)[38] ,were reported The four complexes of a novel SB ligand has been organized by reacting amoxicillin trihydrate and nicotinaldehyde. The in vitro antiseptic action of all complexes, at their two different concentrations, was screened against four bacterial pathogens, namely, E. coli, P. vulgaris, K. pneumoniae, and S. aureus, and showed better activity compared to parent drug and control drug. Martin et al.(2017)[37] were created a sequences of SBs resulting from the sulfa prescription sulfadiazine and numerous salicylaldehydes. The subsequent 4-[(2-hydroxybenzylidene)amino]-N-(pyrimidin-2-yl)benzene-sulfonamides have been categorized and assessed in contradiction of Gram-positive and Gram-negative bacteria, mushrooms, moulds, Mycobacterium tuberculosis, nontuberculous mycobacteria (M. kansasii, M. avium) and their cytotoxicity has evaluated. Amongst microorganisms, the genus Staphylococcus, containing methicillin-resistant S. aureus, presented the maximum vulnerability, with smallest inhibitory concentration magnitudes from 7.81 µM. The growing of Candida sp. and Trichophyton interdigitale has reserved starting from 1.95 µM concentrations. 4-[(2,5-Dihydroxybenzylidene)amino]-N-(pyrimidin-2-yl)-benzenesulfonamide was identified as highly discriminating SB for these strains with no specious cytotoxicity and a selectivity index higher than 16. With regard to M. tuberculosis and M. kansasii that have been reserved within 8 to 250 µM v, unsubstituted 4-[(2-hydroxy-benzylidene)amino]-N-(pyrimidin-2-yl)benzenesulfonamide has the selectivity constraint. On the whole, dihalogenation of the salicylic moiety enhanced antiseptic and antifungal performance, however, they augmented the cytotoxicity, particularly with increased atomic mass. Several results have further useful features than parental sulfadiazine, therefore creating capable hits for additional antimicrobial medicine expansion.

ACKNOWLEDGEMENT The authors state their truthful appreciations to the University Department of Chemistry, Ibn -Al-Haitham, University of Baghdad for fiscal funding for this study.

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Schiff base complexes of some drug substances (Review)