J. Nig. Soc. Phys. Sci. 1 (2019) 95–102 Journal of the Nigerian Society of Physical Sciences Original Research Synthesis, Characterization and Molecular Docking Studies of Mn (II) Complex of Sulfathiazole I. E. Otuokerea,∗, J. G. Ohwimua, K.C. Amadia, C. O. Alisab, F. C. Nwadirea, O. U. Igwea, A. A. Okoyeagua, C. M. Ngwua aDepartment of Chemistry, Michael Okpara University of Agriculture, Umudike, Nigeria bDepartment of Chemistry, Federal University of Technology Owerri, Nigeria Abstract 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 O2 N H 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 O2 N H 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 O2 N H. 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. Keywords: Sulfathiazole, Spectra Bacteria, Complex, Docking Article History : Received: 15 June 2019 Received in revised form: 01 September 2019 Accepted for publication: 02 September 2019 Published: 13 October 2019 c©2019 Journal of the Nigerian Society of Physical Sciences. All rights reserved. Communicated by: W. A. Yahya 1. Introduction Sulfathiazole (Figure 1) was the first therapeutic agents used systematically for the cure and prevention of bacterial infec- tions. Furthermore, sulfadrugs and their metal complexes, pos- ∗Corresponding author tel. no: +2348065297631 Email address: ifeanyiotuokere@gmail.com (I. E. Otuokere ) sess many applications as diuretic, antiglaucoma or antiepilep- tic drugs, among others. Sulpha drugs show important biologi- cal activity e.g mechanism of action is based on the competitive antagonism of PABA (p-aminobenzoic acid) and the sulfanil- amide [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 pharmaco- logical relevance because the metal chelates of sulfadrugs have 95 Otuokere et al. / J. Nig. Soc. Phys. Sci. 1 (2019) 95–102 96 been found to be more bacteriostatic than the drugs themselves [5, 6]. The role of metal ions in living systems has been well estab- lished 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]. Metal complexes containing the sulphonamide group has found importance because of their applications as biological, biochemical, analytical, antimicrobial, anticancer, antibacterial, antifungal and antitumor activity [10, 11, 12]. They also find application as antibiotics, anti-inflammatory agents and in the industry as anticorrosion agents [13-17]. 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 Sulfa- guanidine were assessed to be more potent than the free lig- and [19]. It is in view of this pharmacological importance of sulphonamide that we have reported the synthesis, characteri- zation and molecular docking studies of Mn-sulphathiazole. Figure 1: Structure of sulfathiazole 2. Material and Methods All chemicals and reagent used in this experimental work were of analytical grade. Pure sulfathiazole, and MnCl2 ·4H2O 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 fol- lowing a reported procedure [21]. Mn (II) salt solution was pre- pared by dissolving 3.96 g(0.02 mol) MnCl2 ·4H2O 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 maintain- ing the PH between 6.0 - 6.5 by adding dilute solution of KOH. The synthesis was carried out with stirring at room temper- ature. 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 com- pany) [20]. Infrared spectrum was collected on Perkin Elmer Paragon 1000 FT-IR spectrophotometer (spectrum BX) equipped with cesium iodide window (4000 − 350cm−1) in K Br 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 diffrac- tometer operating in transmission mode usin Germanium monoch- romated CuKα1 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 Es- cherichia 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 per- formed using PatchDock Server: an automatic server for molec- ular docking [22]. Refinement was done in FireDock Server: An automatic server for fast interaction refinement in molecular docking and processed with Molegro molecular viewer [23-26]. 3. Results and Discussion Crystallographic data and structure refinement parameters for [Mn(SFTZ)] is given in Table 1, whereas the powdered X- ray diffraction is shown in Figure 2 Figure 2: Powdered x-ray diffraction of [Mn(SFTZ)]. 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◦. Elemental and physical properties of sulfathiazole and its metal complex are shown in Table 2 The elemental analysis of sulfathiazole and its Mn(I I) com- plex 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 Otuokere et al. / J. Nig. Soc. Phys. Sci. 1 (2019) 95–102 97 Table 1: Crystal data and structure refinement for sulfathiazole and its (Mn(II) complex Parameters [Mn(SFTZ)] Temperature (K) 298 Wavelength (Å) 0.71073 Crystal system Monoclinic Space group P 1 a(Å) 4.519 b(Å) 8.704 c(Å) 12.608 α(◦) 90 β(◦) 95.69 γ(◦) 90 Volume (Å 3 ) 493.51 (1.0V) Table 2: Elemental and physical properties of SFTZ and [Mn(SFTZ)] Ligand/complex % Mn Colour Melting point Yield (%) Found ◦C (Calculated) SFTZ — White 202 – 202.5 — [Mn(S FT Z)] 17.50 Pink 141 - 142 86 (17.77) are coloured. The change in melting point also indicated the formation of new complex. The infrared spectra data of sul- fathiazole and its Mn(I I) complex are presented in Table 3 Figure 3: IR spectrum of sulfathiazole [21]. Figure 4: IR spectrum of [Mn(SFTZ)]. A comparison of IR spectrum of SFTZ and that of the com- plex 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(I I) complex, this vibration frequency remained unchanged. This suggested that N H2 was not involved in complexation. Vibration fre- quency 1323.00 cm−1 and 1140.00 cm−1 were assigned to be Vas(O=S=O) and Vs(O=S=O) in SFTZ. In the complex, these frequencies showed up at 1319.79 and 1138.39 cm−1 in [Mn(SFTZ)]. It is evident that sulfonyl group was not involved in coordina- tion to Mn. In SFTZ spectrum C − N stretching vibration was observed at 1497.00 cm−1. In the spectrum of the complex, these functional group was observed at 1494.05 cm−1 [Mn(SFTZ)]. This observation suggest that coordination did not occurred through C − N in [Mn(SFT)]. The N − H stretch of S O2 N H appeared at 3255.23 cm−1 in the free ligand. In the IR spectrum of the metal complex this band was absent. This suggested the depro- tonation of the N−H of S O2 N H during complexation reaction. The UV spectral data of sulfathiazole and its Mn(I I) com- plex are presented in Table 4, while the spectra are present in Figures 5 and 6. Figure 5: UV-Vis spectrum of sulfathiazole. The UV-Vis spectrum of SFTZ showed a band centered at 269 nm. It was assigned π − π∗ due to intra-ligand charge 97 Otuokere et al. / J. Nig. Soc. Phys. Sci. 1 (2019) 95–102 98 Table 3: Infrared spectral data of sulfathiazole and its Mn(I I) complex Ligand/complex Vas(O=S=O) Vs(O=S=O) V (N H) V (CN) (N − H) (cm−1) (cm−1) (cm−1) (cm−1) (cm−1) (primary amine) (S O2 N H) SFTZ 1323.00 1140.00 3354.00, 3321.00 1497.00 3255.23 [Mn(S FT Z)] 1319.79 1136.39 3350.32, 3320.10 1494.05 Absent Table 4: The UV spectral data of sulfathiazole and its complex. Ligand/Metal complex λmax(nm) Assignment SFT 269 π−π∗(ILCT) [Mn(S FT Z)] 270 π−π∗(ILCT) 230 LMCT Figure 6: UV-vis spectrum of [Mn(SFTZ)]. transfer (ILCT).The UV-Vis spectrum of [Mn(SFTZ)] showed a band centered at 270 nm which has been assigned ILCT due to π−π∗. The chromophores that may exhibit this transition are S=O and C=N. A sharp peak centered at 230 nm suggested lig- and to metal charge transfer (LMCT). The 1 H − N MR spectral data of sulfathiazole and its Mn(I I) complex are presented in Table 5. The spectra are shown in Figures 7 and 8. Figure 7: 1 HN MR spectrum of sulfathiazole [21]. In the 1 HN MR spectrum of SFTZ, the aromatic protons ap- peared at 6.51 and 7.43 ppm while the thiazole protons are ob- served between 6.71 and 7.18 ppm [21]. NH2 protons were ob- served 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 Figure 8: 1 HN MR spectrum of [Mn(SFTZ)]. the (O2S − N − H) group of SFTZ when coordination occurred through the nitrogen to the metal centre. Based on the UV, IR, 1 HN MR spectra and x-ray powder diffraction, the structure (Figure 9) has been proposed for [Mn(SFTZ)]. Figure 9: Proposed structure of [Mn(SFTZ)]. The solutions Tables of the molecular docking are shown in Tables 6 - 9. The crystal structure of the E. coli RNA degra- dosome component enolase and S. aureus nuclease are shown in Figures 10 and 11 respectively. The crystal structure of E. coli contains four protein chains (A, B, C and D) and 506 wa- ter molecules. The crystal structure of S. aureus nuclease is made up of one protein chain (A) and 83 water molecules. The molecular docking and molecular interactions of sulfathiazole with E. coli are presented in Figures 12a and 12b. The molecu- lar docking and molecular interactions of [Mn(SFTZ)] with E. coli are presented in Figures 13a and 13b. The molecular dock- ing and molecular interactions of sulfathiazole with S. aureus 98 Otuokere et al. / J. Nig. Soc. Phys. Sci. 1 (2019) 95–102 99 Table 5: 1 H − N MR spectral data of sulfathiazole and its complex. Ligand/ Thiazole protons O2S − N − H N H Aromatic complex (δ ppm) (δ ppm) (δ ppm) (δ ppm) SFT 6.71 - 7.18 12.4 5.80 6.51-7.43 [Mn(S FT Z)] 7.02 -7.45 Absent 5.80 6.51-7.43 nuclease are presented in Figures 14a and 14b. . The molecu- lar docking and molecular interactions of [Mn(SFTZ)] with S. aureus nuclease are presented in Figures 15a and 15b. Figure 10: Crystal structure of E. coli RNA degradosome component enolase. Figure 11: Crystal structure of S. aureus nuclease. Figure 12: (A) Crystal structure of E. coli RNA degradosome compo- nent enolase docked with sulfathiazole. (B) Molecular interactions of sulfathiazole with E. coli RNA degradosome component enolase. The best ranking in Table 6 is solution 2 with global en- ergy -46.74 Kcal/mol. This suggested that sulfathiazole has the Figure 13: (A) Crystal structure of E. coli RNA degradosome compo- nent enolase docked with [Mn(SFTZ)]. (B) Molecular interactions of [Mn(SFTZ)] with E. coli RNA degradosome component enolase. Figure 14: (A) Crystal structure of S. aureus nuclease docked with sul- fathiazole. (B) Molecular interactions of sulfathiazole with S. aureus nuclease. Figure 15: (A) Crystal structure of S. aureus nuclease docked with [Mn(SFTZ)]. (B) Molecular interactions of [Mn(SFTZ)] with S. au- reus nuclease. ability to inhibit E. coli. The attractive Vander waals and atomic contact energy (ACE) showed negative values. These suggested that sulfathiazole docked effectively with E. coli. The molecu- lar interactions (Figure 12b) show that E. coli formed hydrogen bonding with sulfathiazole using Ala 247(C) and Glu 250(C). Steric interaction between E. coli and sulfathiazole were ob- served with Gly 156(C), Glu 157(C), Asn 161(C), Ala 260(C), Asn 162(C), Val 163(C), and Asp 164(C). The best global energy in Table 7 is -40.08 Kcal/mol (so- 99 Otuokere et al. / J. Nig. Soc. Phys. Sci. 1 (2019) 95–102 100 Table 6: Solution Table of SFTZ docked with E. coli(VdW = Vanderwaals; ACE = Atomic Contact Energy). Rank Solution Global Attractive Repulsive ACE Number Energy VdW VdW (Kcal/mol) (Kcal/mol) (Kcal/mol) (Kcal/mol) 1 2 -46.74 -15.12 1.68 -16.11 2 5 -39.59 -14.83 1.49 -12.46 3 9 -34.11 -12.29 1.08 -10.99 4 10 -25.97 -13.63 0.99 -4.88 5 6 -21.88 -13.34 3.23 -3.65 6 1 -21.72 -12.16 0.20 -2.46 7 4 -17.18 -13.71 3.19 0.16 8 7 -11.34 -8.06 2.10 -2.04 9 3 -5.73 -12.05 18.51 -2.15 10 8 3.31 -12.71 29.59 -1.56 Table 7: Solution Table of [Mn(SFTZ)] docked with E. coli(VdW = Vanderwaals; ACE = Atomic Contact Energy). Rank Solution Global Attractive Repulsive ACE Number Energy VdW VdW (Kcal/mol) (Kcal/mol) (Kcal/mol) (Kcal/mol) 1 9 -40.08 -11.96 3.61 -15.77 2 4 -38.68 -14.27 2.68 -12.57 3 1 -35.93 -13.63 2.29 -11.48 4 6 -33.85 -11.60 1.10 -11.54 5 8 -29.70 -11.47 1.62 -9.17 6 10 -29.18 -9.28 0.71 -10.35 7 3 -20.15 -10.26 1.42 -5.76 8 5 -19.49 -10.86 3.63 -6.83 9 7 -18.03 -12.44 4.59 -2.38 10 2 -10.31 -13.92 8.90 1.35 Table 8: Solution Table of SFTZ docked with S. aureus (VdW = Vanderwaals; ACE = Atomic Contact Energy). Rank Solution Global Attractive Repulsive ACE Number Energy VdW VdW (Kcal/mol) (Kcal/mol) (Kcal/mol) (Kcal/mol) 1 1 -25.35 -11.53 3.66 -7.77 2 9 -24.36 -13.36 1.42 -5.00 3 2 -21.31 -9.73 2.95 -6.32 4 6 -19.93 -8.76 1.77 -7.08 5 3 -19.27 -6.79 0.61 -7.54 6 8 -18.63 -11.33 1.99 -3.87 7 7 -16.25 -9.00 2.49 -5.05 8 10 -10.07 -5.26 2.43 -3.60 9 5 -9.98 -8.36 5.39 -4.11 10 4 -9.65 -5.51 2.56 -4.53 100 Otuokere et al. / J. Nig. Soc. Phys. Sci. 1 (2019) 95–102 101 Table 9: Solution Table of [Mn(SFTZ)] docked with S. aureus (VdW = Vanderwaals; ACE = Atomic Contact Energy). Rank Solution Global Attractive Repulsive ACE Number Energy VdW VdW (Kcal/mol) (Kcal/mol) (Kcal/mol) (Kcal/mol) 1 4 -23.56 -9.86 4.80 -9.09 2 8 -23.48 -10.23 1.83 -7.94 3 1 -22.65 -11.19 4.93 -8.21 4 5 -16.39 -9.69 1.59 -3.65 5 9 -13.64 -6.72 4.14 -6.44 6 2 -13.17 -6.45 5.68 -5.97 7 6 -11.25 -7.38 2.10 -3.20 8 7 -7.27 -4.41 2.60 -4.43 9 10 -5.71 -4.97 2.29 -1.96 10 3 0.59 -11.04 38.87 -9.47 lution 9). This suggested that [Mn(SFTZ)] has the ability to inhibit E. coli. The attractive Vander waals and atomic con- tact energy (ACE) were also predicted. Their negative value predicted effective binding. The molecular interactions (Fig- ure 13b) showed that E. coli formed hydrogen bonding with [Mn(SFTZ)] through Gly 166(B) and HOH 208(B). Steric in- teractions between [Mn(SFTZ)] and E. coli occured with His 158(B), Ala 247(B), Ser 249(B), Gln 166(B) and Asp 316(B). The best ranking in Table 8 is solution 1 with global energy -25.35 Kcal/mol. This suggested that sulfathiazole has the abil- ity 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 molec- ular 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 sulfathi- azole were observed with Gln 80, Lys 116, Tyr 115 and Pro 117. The best ranking in Table 9 is solution 4 with global energy - 23.56 Kcal/mol. This suggested that [Mn(SFTZ)] has the abil- ity to inhibit S. aureus. The attractive Vander waals and atomic contact energy (ACE) showed negative values. These suggested that [Mn(SFTZ)] docked effectively with S. aureus. The molec- ular interactions (Figure 15b) show that S. aureus formed hy- drogen bonding with [Mn(SFTZ)] using HOH 295(A), HOH 242(A) and Glu 52. Steric interaction between S. aureus and [Mn(SFTZ)] were observed with Pro 42, Lys 110, Tyr 41, Glu 43 and Glu 52. 4. Conclusion Complex of manganese ion with sulfathiazole was success- fully synthesized. The colour, IR, UV 1 H NMR spectra and x- ray 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. Molec- ular docking study predicted the binding energies and interac- tions between the compounds and bacterial strains. It helped us to understand the mechanism of action of the proposed com- plex. 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