Antioxidant, antimicrobial, and theoretical studies of the thiosemicarbazone derivative Schiff base 2-(2-imino-1-methylimidazolidin-4-ylidene)hydrazinecarbothioamide (IMHC)
© Al-Amiery et al; licensee Springer. 2012
Received: 14 September 2011
Accepted: 2 February 2012
Published: 2 February 2012
Adverse antimicrobial activities of thiosemicarbazone (TSC) and Schiff base derivatives have widely been studied by using different kinds of microbes, in addition different methods were used to assay the antioxidant activities using DPPH, peroxids, or ntrosyl methods. However, there are no studies describing the synthesis of TSC derived from creatinine.
In this study, 2-(2-imino-1-methylimidazolidin-4-ylidene)hydrazinecarbothioamide (IMHC) was synthesized by the reaction of creatinine with thiosemicarbazide. The novel molecule was characterized by FT-IR, UV-VIS, and NMR spectra in addition of the elemental analysis. The free radical scavenging ability of the IMHC was determined by it interaction with the stable-free radical 2,2"-diphenyl-1-picrylhydrazyl (or nitric oxide or hydrogen peroxide) and showed encouraging antioxidant activities. Density functional theory calculations of the IMHC performed using molecular structures with optimized geometries. Molecular orbital calculations provide a detailed description of the orbitals, including spatial characteristics, nodal patterns, and the contributions of individual atoms. Highest occupied molecular orbital-lowest unoccupied molecular orbital energies and structures are shown.
IMHC shows considerable antibacterial and antifungal activities. The free radical scavenging activity of synthesized compound was screened for in vitro antioxidant activity.
Keywordsantibacterial antioxidant antifungal creatinine Schiff base thiosemicarbazone
Schiff-base compounds have been used as fine chemicals and medical substrates . Azomethine group (-C = N-)-containing compounds, typically known as Schiff's bases, have been synthesized via condensation of primary amines with active carbonyls. It is well established that the biological activity of hydrazone compounds is associated with the presence of the active (-CO-NHN = C-) pharmacophore and these compounds form a significant category of compounds in medicinal and pharmaceutical chemistry with several biological applications that include antitumoral [2, 3], antifungal [4–9], antibacterial [10, 11], antimicrobial , and anthelmintic uses . Schiff's base complexes play an important role in designing metal complexes related to synthetic and natural oxygen carriers [14, 15]. Schiff bases (SBs) are important intermediates for the synthesis of some bioactive compounds such as ß-lactams [16–18], and employed as ligands for the complexation of metal ions . SBs and their complexes are largely studied because they interested and important properties such as their ability to bind reversibly oxygen  redox systems in biological systems and oxidation of DNA .
Antioxidants are extensively studied for their capacity for protect organism and cell from damage that is induced by oxidative stress. Scientists in many different disciplines become more interested in new compounds, either synthesized or obtained from natural sources that could provide active components to prevent or reduce the impact of oxidative stress on cell [22, 23].
The preparation of a 2-(2-imino-1-methylimidazolidin-4-ylidene)hydrazinecarbothioamide (IMHC) from thiosemicarbazide and creatinine is presented in this study. The structure established based on the extensive NMR spectroscopic studies. The microbial activities of IMHC and their in vitro antioxidant activities were also investigated. It was envisaged that these two active pharmacological molecules (thiosemicbazide and creatinine) if linked together would generate novel molecular templates, which are likely to exhibit interesting biological properties.
Results and discussion
The UV-VIS of IMHC was recorded. The solution of IMHC in DMF exhibited two peaks at 255 and 322 nm (39215 and 31055 cm-1) which are attributed to π → π* or n → π*.
The FT-IR spectra provide valuable information regarding the nature of functional group of IMHC. The appearance of a broad strong band in the IR spectra of IMHC in 3421 cm-1 is assigned to N-H stretching vibrations of the primary amine group. The spectrum of IMHC shows two different -C = N bands at 1631 and 1618 cm-1.
Density functional theory (DFT) studies
HOMO and LUMO energy
According to Overtone's concept of cell permeability, the lipid membrane that surrounds the cell favors the passage of only lipid-soluble materials, so lipophilicity is an important factor controlling the antifungal activity. Delocalization of π-electrons over the IMHC increased lipophilicity facilitates the penetration of the IMHC into lipid membranes, further restricting proliferation of the microorganisms. Although the exact biochemical mechanism is not completely understood, the mode of action of antimicrobials may involve various targets in the microorganisms.
Interference with the synthesis of cellular walls, causing damage that can lead to altered cell permeability characteristics or disorganized lipoprotein arrangements, ultimately resulting in cell death.
Deactivation of various cellular enzymes that play a vital role in the metabolic pathways of these microorganisms.
Denaturation of one or more cellular proteins, causing the normal cellular processes to be impaired.
Formation of a hydrogen bond through the azomethine group with the active centers of various cellular constituents, resulting in interference with normal cellular processes .
All chemical used were of reagent grade (supplied by either Merck or Fluka) and used as-received. The FTIR spectra were recorded as KBr disc on FTIR 8300 Shimadzu Spectrophotometer. The UV-Visible spectra were measured using Shimadzu UV-Vis. 160 A spectrophotometer. Proton NMR spectra were recorded on Bruker - DPX 300 MHz spectrometer with TMS as internal standard. Elemental microanalysis was carried out using C.H.N elemental analyzer model 5500-Carlo Erba instrument.
Synthesis of IMHC
The biological activity of the new IMHC was studied against selected types of bacteria which included positive bacteria (Staphylococcus aureus), and gram negative bacteria (Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Pseudomonas aeruginosa), in brain hart broth agar media, which is used DMF as a solvent and as a control for the disc sensitivity test . This method involves the exposure of the zone of inhibition toward the diffusion of microorganism on agar plate. The plates were incubated for 24 h, at 37°C. The antimicrobial activity was recorded as any area of microbial growth inhibition that occurred in the diffusion area.
IMHC was screened for it antifungal activity against A. niger and C. albicans in DMSO by serial plate dilution method using sabourand agar media. Normal saline was used to make a suspension of corresponding species. Twenty milliliters of agar media was poured in each Petri dish. Excess suspension was decanted and the plates were dried by placing in an incubator at 37°C for 1 h . The fungal zone of inhibition values is given in Figure 3. The nutrient broth was inoculated with approximately 1 × 105 cfu/mL. The cultures were incubated for 48 h at 35°C and the growth was monitored.
Hint: Sabourand agar media were prepared by dissolving peptone (1 g), D-glucose (4 g), and agar (2 g) in distilled water (100 mL) and adjusting pH to 5.7.
(2,2-diphenyl-1-picrylhydrazyl) radical scavenging activity
where A 0 is the absorbance of the control reaction and A 1 is the absorbance in the presence of the samples or standards.
Nitric oxide scavenging activity
Sodium nitroprusside in aqueous solution at physiological pH generates nitric oxide spontaneously; it interacts with oxygen to produce nitrite ions, which can be estimated by the use of GriessIllosvoy reaction [27, 28]. In this investigation, GriessIllosvoy reagent was modified using naphthylethylenediaminedihydrochloride (0.1% w/v) instead of 1-naphthylamine (5%). The reaction mixture (3 mL) containing sodium nitroprusside (10 mM, 2 mL), phosphate buffer saline (0.5 mL), and IMHC (250, 500, 750, and 1000 μg/mL) or standard solution (0.5 mL) was incubated at 25°C for 150 min. After the incubation, 0.5 mL of the reaction mixture containing nitrite was pipetted and mixed with 1 mL of sulfanilic acid reagent (0.33% in 20% glacial acetic acid) and allowed to stand for 5 min for completing diazotization. Then, 1 mL of naphthylethylenediaminedihydrochloride (1%) was added, mixed, and allowed to stand for 30 min. A pink-colored chromophore was formed in diffused light. The absorbance of these solutions was measured at 540 nm against the corresponding blank. Ascorbic acid was used as standard. Nitric oxide percentage scavenging activity was then calculated using Equation 1.
Hydrogen peroxide scavenging activity
A solution of hydrogen peroxide (40 mM) was prepared in phosphate buffer (pH 7.4). Different concentrations (250, 500, 750, and 1000 μg/mL) of IMHC (or ascorbic acid) were added to a hydrogen peroxide solution (0.6 mL, 40 mM). Absorbance of hydrogen peroxide at 230 nm was determined after 10 min against a blank solution containing phosphate buffer without hydrogen peroxide . Hydrogen peroxide percentage scavenging activity was then calculated using Equation 1.
All quantum chemical calculations were performed using the DFT in the methodology. DMol3 model was employed to obtain quantum chemical parameters and optimization of the molecule geometry.
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