Synthesis, Characterization and Molecular Docking Studies of Mn (II) Complex of Sulfathiazole

Sulfathiazole (SFTZ) is an antibacterial drug that contains organosulfur compound. It is used as a short-acting sulfa drug. The metal complexes of sulfa-drug have gained considerable importance due to their pronounced biological activity. The sulfa-drugs have received great attentions because of their therapeutic applications against bacterial infections. Mn(II) complex of sulfathiazole was synthesized by reaction of sulfathiazole with MnCl2 ·4H2O. The Mn (II) complex was characterized based on UV, IR, 1H NMR Spectroscopy and x-ray powder diffraction. The electronic spectrum of the ligand showed intra charge transfer which were assigned to the chromophores present in the ligand, while that of the complex suggested intra ligand charge transfer (ILCT) and ligand to metal charge transfer (LMCT). In the IR spectrum of sulfathiazole the N −H stretch of S O2NH appeared at 3255.23cm−1. In the IR spectrum of the metal complex this band was absent. This suggested the deprotonation of the N − H of S O2NH during complexation reaction. This showed that sulfathiazole acted as a monodentade ligand. 1H NMR spectrum of [Mn(SFTZ)] complex showed the involvement of nitrogen atom of S O2NH. The crystal structure of [Mn(SFTZ)] complex belongs to monoclinic system, space group P1, with cell parameters of a = 4.519 Å, b = 8.704 Å, c = 12.608 Å, V = 493.5 Å 3 , β = 95.69◦. Molecular docking suggested that the ligand/complex binded effectively with the E.coli and S.aureus because their global binding energies were negative. The binding interactions of ligand/complex with E. coli and S. aureus were predicted. Molecular docking predicted the feasibility of the biochemical reactions before experimental investigation. It was concluded that sulfathiazole behaved as a monodentate ligand towards Mn (II) ion. The binding energy and interaction of [Mn(SFTZ)] with E.coli and S. aureus have also shown that inhibition of the bacterial species are feasible. The mechanism of action of [Mn(SFTZ)] with E. coli and S. aureus is now well understood.


Introduction
Sulfathiazole (Figure 1) was the first therapeutic agents used systematically for the cure and prevention of bacterial infections. Furthermore, sulfadrugs and their metal complexes, pos-sess many applications as diuretic, antiglaucoma or antiepileptic drugs, among others. Sulpha drugs show important biological activity e.g mechanism of action is based on the competitive antagonism of PABA (p-aminobenzoic acid) and the sulfanilamide [1,2]. It has been reported that the activity of the metal complex is much better than the ligand alone [3,4]. Studies on their metal chelates have much physiological and pharmacological relevance because the metal chelates of sulfadrugs have 95 been found to be more bacteriostatic than the drugs themselves [5,6].
The role of metal ions in living systems has been well established in recent years. The use of transition metal complexes as medicinal compounds has become more and more prominent. These complexes offer a great diversity in their action; they do not only have anti-cancer properties but have also been used as anti-inflammatory, anti-infective and anti-diabetic compounds [7].
Metal ions play pivotal roles in many biological processes, and the study of the roles of these metal ions in biological systems falls into the rapidly developing interdisciplinary field known as bioinorganic chemistry. When compared to other branches of natural sciences, bioinorganic chemistry seems to be a young discipline. However, there is a copious amount of information on the effects of metals on biological systems. For instance, the toxicities of metal ions such as mercury, lead and chromium on the environment have been well publicized [8,9].
Molecular complexes of sulfonamides have been reported [18]. Syntheses, Characterization, thermal and antimicrobial studies of binuclear metal complexes of Sulfa-guanidine Schiff bases have been reported [19]. The metal complexes of Sulfaguanidine were assessed to be more potent than the free ligand [19]. It is in view of this pharmacological importance of sulphonamide that we have reported the synthesis, characterization and molecular docking studies of Mn-sulphathiazole.

Material and Methods
All chemicals and reagent used in this experimental work were of analytical grade. Pure sulfathiazole, and MnCl 2 · 4H 2 O salt were all imported from Sigma-Aldrich Laboratories. The solvents are ethanol, methanol, acetone, chloroform, sodium hydroxide, benzene and dimethyl sulfoxide.
Synthesis of [Mn(SFTZ)]: The complex was prepared following a reported procedure [21]. Mn (II) salt solution was prepared by dissolving 3.96 g(0.02 mol) MnCl 2 · 4H 2 O in 25 ml of distilled water. The solution of the metal salt was added slowly with stirring in a separate 20 ml of distilled water containing 5.1 g of sulfathiazole (0.02 mol) at room temperature maintaining the PH between 6.0 -6.5 by adding dilute solution of KOH.
The synthesis was carried out with stirring at room temperature. After 1 hour, the complex separated out. The complexes were washed well with distilled water, recrystallized, filtered and finally dried in vacuum and weighed and melting point recorded.
Melting points of the complex was determined using MPA160 melting point apparatus. Atomic absorption spectroscopy was carried out on Duck-2010 spectrometer (Duck instrumental company) [20]. Infrared spectrum was collected on Perkin Elmer Paragon 1000 FT-IR spectrophotometer (spectrum BX) equipped with cesium iodide window (4000 − 350cm −1 ) in KBr pellets. The UV-Visible spectrum was obtained on a Perkin Elmer (lambda 25) spectrometer (200−800 nm) using distilled water as solvent.
The 1 H Nuclear Magnetic Resonance (NMR) spectra were obtained using Varian 400 MHz Unity INOVA, using DMSO as solvent. In the Crystallographic studies, appropriate amounts of the crystal was collected and deposited on Bruker D8 diffractometer operating in transmission mode usin Germanium monochromated CuK α1 radiation, λ = 1.5406 Å, linear position-sensitive detector covering 12 • in 2θ, 2θ mode range 3.5 • -70 • , step size 0.017 • and 17 h data collection time. FOX software was used for structure determination and refinement.
Molecular docking: The three-dimensional structure of Escherichia coli and Staphylococcus aureus and were obtained from the Protein Data Bank, PDB 1E91 and 1STN respectively. The protein structures were subjected to a refinement protocol using Molegro Molecular Viewer. Molecular docking was performed using PatchDock Server: an automatic server for molecular docking [22]. Refinement was done in FireDock Server: An automatic server for fast interaction refinement in molecular docking and processed with Molegro molecular viewer [23][24][25][26].

Results and Discussion
Crystallographic data and structure refinement parameters for [Mn(SFTZ)] is given in Table 1, whereas the powdered Xray diffraction is shown in Figure 2  Elemental and physical properties of sulfathiazole and its metal complex are shown in Table 2 The elemental analysis of sulfathiazole and its Mn(II) complex showed that the experimental values are in agreement with the calculated values The colour of the new product suggested the formation of complex because transition metal complexes 96   .77) are coloured. The change in melting point also indicated the formation of new complex. The infrared spectra data of sulfathiazole and its Mn(II) complex are presented in Table 3 Figure 3: IR spectrum of sulfathiazole [21]. A comparison of IR spectrum of SFTZ and that of the complex was made (Figures 3 and 4). The infrared spectrum of SFTZ showed a broad band at 3354.00 and 3321.00 cm −1 [21]. This band was assigned N − H stretch of the primary amine due to asymmetric and symmetric stretching vibrations of the two N − H bonds. In the IR spectra of the Mn(II) complex, this vibration frequency remained unchanged. This suggested that NH 2 was not involved in complexation. Vibration frequency 1323.00 cm −1 and 1140.00 cm −1 were assigned to be The UV spectral data of sulfathiazole and its Mn(II) complex are presented in Table 4, while the spectra are present in Figures 5 and 6. The UV-Vis spectrum of SFTZ showed a band centered at 269 nm. It was assigned π − π * due to intra-ligand charge 270 π − π * (ILCT) 230 LMCT  In the 1 HN MR spectrum of SFTZ, the aromatic protons appeared at 6.51 and 7.43 ppm while the thiazole protons are observed between 6.71 and 7.18 ppm [21]. NH2 protons were observed at 5.80 ppm. In the spectrum of the metal complex, these chemical shifts remained relatively unchanged. In the HNMR spectrum of SFTZ, the hydrogen that appeared as a singlet at 12.4 ppm is no longer observed in the spectra of the metal complex. This is attributed to the loss of hydrogen atom of   Figures 13a and 13b. The molecular docking and molecular interactions of sulfathiazole with S. aureus 98    The best ranking in Table 6 is solution 2 with global energy -46.74 Kcal/mol. This suggested that sulfathiazole has the   The best global energy in Table 7 is -40.08 Kcal/mol (so-     Table 8 is solution 1 with global energy -25.35 Kcal/mol. This suggested that sulfathiazole has the ability to inhibit S. aureus. The attractive Vander waals and atomic contact energy (ACE) showed negative values. These suggested that sulfathiazole docked effectively with S. aureus. The molecular interactions (Figure 14b) showed that S. aureus formed hydrogen bonding with sulfathiazole using HOH 225(A) and HOH 291(A). Steric interaction between S. aureus and sulfathiazole were observed with Gln 80, Lys 116, Tyr 115 and Pro 117. The best ranking in Table 9

Conclusion
Complex of manganese ion with sulfathiazole was successfully synthesized. The colour, IR, UV 1 H NMR spectra and xray powder diffraction suggested that new products were formed. This also shows that sulfathiazole can be used to remove toxic metals from the environment or from the biological system. This is because they can be complexed with sulfathiazole. Molecular docking study predicted the binding energies and interactions between the compounds and bacterial strains. It helped us to understand the mechanism of action of the proposed complex. A thorough investigation should be carried out to find out whether the synthesized drugs can be safely used as a metal based anti-bacterial drug for the treatment of bacterial infections. We also recommend toxicology test for the complexes.