Synthesis, Characterization and In Vitro Antibacterial Studies of Organotin(IV) Complexes with 2-Hydroxyacetophenone-2-methylphenylthiosemicarbazone (H2dampt)

Five new organotin(IV) complexes of 2-hydroxyacetophenone-2-methylphenylthiosemicarbazone [H2dampt, (1)] with formula [RSnCln-1(dampt)] (where R = Me, n = 2 (2); R = Bu, n = 2 (3); R = Ph, n = 2 (4); R = Me2, n = 1 (5); R = Ph2, n = 1 (6)) have been synthesized by direct reaction of H2dampt (1) with organotin(IV) chloride(s) in absolute methanol. The ligand (1) and its organotin(IV) complexes (2–6) were characterized by CHN analyses, molar conductivity, UV-Vis, FT-IR, 1H, 13C, and 119Sn NMR spectral studies. H2dampt (1) is newly synthesized and has been structurally characterized by X-ray crystallography. Spectroscopic data suggested that H2dampt (1) is coordinated to the tin(IV) atom through the thiolate-S, azomethine-N, and phenoxide-O atoms; the coordination number of tin is five. The in vitro antibacterial activity has been evaluated against Staphylococcus aureus, Enterobacter aerogenes, Escherichia coli, and Salmonella typhi. The screening results have shown that the organotin(IV) complexes (2–6) have better antibacterial activities and have potential as drugs. Furthermore, it has been shown that diphenyltin(IV) derivative (6) exhibits significantly better activity than the other organotin(IV) derivatives (2–5).


Introduction
Thiosemicarbazones and their metal complexes have received considerable attention in chemistry and biology, primarily because of their marked and various biological properties [1][2][3]. The pharmacological profiles of 2-formyl, 2-acetyl, and 2-benzoylpyridine thiosemicarbazones have been investigated [4]. Seena and Kurup [5] have synthesized and characterized dioxomolybdenum(IV) complexes with 2-hydroxyacetophenone-N(4)-cyclohexyl and N(4)-phenyl thiosemicarbazone which suggested that the Mo(IV) complex is pentacoordinated [5]. For the past few years, studies of the coordination chemistry of thiosemicarbazone involved complexes with transition metal ions [6][7][8]. Organotin(IV) complexes have been the subject of interest for some time because of their biomedical and commercial applications including in vitro and in vivo antitumor activity [9,10]. Many organotin(IV) complexes have been found to be as effective as or even better than traditional anticancer drugs [11][12][13][14]. Organotin(IV) chelates with nitrogen, sulfur, and oxygen donor ligands have gained attention during the last few years [15]. The coordination chemistry of tin is extensive with various geometries and coordination numbers known for both inorganic and organometallic complexes [16,17]. In our previous work, we have reported some new organotin(IV) complexes with heterocyclic-N(4)-cyclohexylthiosemicarbazone ligands [18,19]. The results revealed that thiosemicarbazones derived from 2-benzoylpyridine and 2-acetylpyrazine and their tin (IV)/organotin(IV) complexes have been characterized by different spectroscopic techniques. From the literature survey, the studies on the organotin(IV) complexes derived from substituted thiosemicarbazone ligands con-taining ONS-donor atoms are still lacking.
To the best of our knowledge, there was no report on the organotin(IV) complexes of the 2-hydroxyacetophenone-2-methylphenylthiosemicarbazone. In this view, we have synthesized a series of organotin(IV) complexes with 2hydroxyacetophenone-2-methylphenylthiosemicarbazone. These complexes have been characterized by elemental analysis, 1 H, 13 C, and 119 Sn NMR spectroscopy. X-ray crystal structure of 2-hydroxyacetophenone-2-methylphenylthiosemicarbazone (1) is also described. Their biological activity data has also been reported.

Materials and Methods.
All reagents were purchased from Fluka, Aldrich, and JT Baker. All solvents were purified according to standard procedures [20]. UV-Vis spectra were recorded in CHCl 3 solution with a Perkin Elmer Lambda 25 UV-Visible spectrometer. Infrared spectra were recorded on KBr discs using a Perkin Elmer Spectrum GX Fourier-Transform spectrometer in the range 4000-370 cm −1 at room temperature. 1 H, 13 C, and 119 Sn NMR spectra were recorded on a JEOL 500 MHz-NMR spectrometer; chemical shifts were given in ppm relative to SiMe 4 and SnMe 4 in CDCl 3 solvent. CHN analyses were obtained with a Flash EA 1112 series CHN elemental analyzer. Molar conductivity measurements were carried out with Jenway 4510 conductivity meter using DMF solvent mode.

UV-Visible Spectra.
The UV-Vis spectra of ligand (1) and its organotin(IV) complexes (2-6) were carried out in CHCl 3 (1 × 10 −4 mol L −1 ) at room temperature. The free ligand (1) exhibited three absorption bands at 262, 318, and 359 nm assigned to the HOMO/LUMO transition of phenolic group, azomethine, and thiolate function, respectively [23]. After complexation, the UV-Vis spectra of the complexes (2-6) exhibited four absorption bands in the region at 262-268, 327-338, 367-382, and 384-414 nm, respectively. In the electronic spectra of the complexes (2-6), the intraligand transition is shifted to higher wavelength as a result of coordination. In the spectra of organotin(IV) complexes (2-6), one new absorption band appeared at 384-414 nm which is assigned to the ligand → metal charge transfer (LMCT) [24]. The shift of the λ max band from the ligand to the complex is supported by the coordination of ligand (1) to the tin(IV) ion.   [31]. In organotin(IV) compounds, the 1 J[ 119 Sn, 13 C] value is an important parameter to assess the coordination number of the Sn atom. The calculated coupling constants for dimethyltin(IV) (4) and diphenyltin(IV) (5) compounds were found to be 557 and 546 Hz, which described the penta-coordinate environment about the Sn atom in these compounds [32]. All these statements are also supported by the 1 H NMR spectra analyses.

IR
3.6. 119 Sn NMR Spectra. 119 Sn NMR spectra can be used as an indicator of the coordination number of the tin atom. 119 Sn NMR of all the complexes (2-6) shows only one resonance signals in the range of −149.60 to −185.32 ppm. 119 Sn NMR values are characteristic for the five-coordinated

X-Ray Crystallography Diffraction
Analysis. The molecular structure of the ligand (1) with atom numbering scheme is depicted in Figure 1. The main crystal parameters are reported in Table 1. Selected bond lengths and bond angles are given in Table 2. The compound crystallizes into monoclinic crystal system with a space group of P2 1 /c. In the title substituted thiosemicarbazone, C 16 H 17 N 3 OS, the hydroxy-and methyl-substituted benzene rings form dihedral angles of 9.62 (12) and 55.69 (6) • , respectively, with the central CN3S chromophore (r.m.s. deviation = 0.0117Å) in (C 16 H 17 N 3 OS) ( Figure 1) and the OH-and Mebenzene rings are twisted as seen in the respective dihedral angles of 9.62 (12) and 55.69 (6) • . The almost coplanarity of the central atoms is ascribed to the formation of an intramolecular hydroxyl-O-H· · ·N-imine hydrogen bond ( Table 3). The N1-N2 bond length (1.375Å) is closer to single bond length (1.45Å) than to double bond length (1.25Å) [37]. The C9-S1 bond distance (1.694Å) is close to that expected of a C=S double bond (1.60Å) [37] and the C7-N1 bond length (1.295Å) is nearly the same as that of the    (1) showing the atom-labelling scheme and displacement ellipsoids at the 50% probability level.
C=N double bond (1.28Å) [38]. These bond distances are in strong support of the existence of 2-hydroxyacetophenone-2-methylphenylthiosemicarbazo in the thione form in the solid state. The H atoms of the NH groups are syn, and the conformation about the N1=C7 double bond [1.295 (4)Å] is E. The syn arrangement in (C 16 H 17 N 3 OS)) contrast the antiarrangement often seen in such derivatives but is readily explained in terms of the intramolecular O-H· · ·N-imine hydrogen bond in (C 16 H 17 N 3 OS)) by contrast to the normally observed intramolecular N-H· · ·N-imine hydrogen bond [39,40]. Helical supramolecular chains along the b axis dominate the crystal packing ( Figure 2 and Table 3). These arise as a result of the thione-S interacting with both N-H atoms of a neighboring molecule thereby forming sixmembered hydrogen-bond-mediated rings.
3.8. Antibacterial Activity. The synthesized ligand (1) and its organotin(IV) complexes (2-6) were tested against Escherichia coli, Staphylococcus aureus, Enterobacter aerogenes, and Salmonella typhi bacterial strains for their antibacterial activity using agar-well diffusion method and data are shown in Table 4 and Figure 3. The doxycycline was used as a reference drug. The results showed that the substituted thiosemicarbazone ligand (1) possessed moderate antibacterial activity. The antibacterial studies of the compounds (2-6) showed relatively better activity against Table 4: Antibacterial activity a,b of the free ligand (1) and its organotin(IV) complexes 2-6 (inhibition zone in mm).

Bacterium
Clinical implication Zone of Inhibition (mm) (1) (   the selected bacteria than the free ligand (1), but low activities as compared to the reference drug. Among all the organotin(IV) derivatives, the bactericidal activities of 5 and 6 are fairly good. Complex 2 is the least active among all the organotin(IV) complexes, while complex 4 was found to be active against all the studied strains except Staphylococcus aureus. The most probable reason for this difference might be due to chelation which reduces the polarity of the central Sn atom because of the partial sharing of its positive charge with donor groups and possible π-electron delocalization within the whole chelating ring. As a result, the lipophilic nature of the central Sn atom increases, which favours the permeation of the complexes through the lipid layer of the cell membrane [41]. In addition, among the organotin(IV) complexes (2-6), complex (6) is found to be more active and it can be attributed to the presence of bulky phenyl groups which facilate binding to biological molecules π-π interactions.

Conclusion
The ligand (1) and its organotin(IV) complexes (2-6) have been synthesized and fully characterized by different spectroscopic techniques. The ligand (H 2 dampt) exists in thione form in a solid state but it takes on a thiol form when it is in solution. All organotin(IV) complexes (2-6) of H 2 dampt were proposed to be five coordinated and the ligand binds to the central tin(IV) atom in dinegative tridentate form.
Single crystal X-ray analysis of newly synthesized ligand (1) has been reported. The in vitro antibacterial activities of the synthesized complexes against the selected bacterial strains have been established. All compounds have been found biologically active, while the studies have confirmed that compounds 5 and 6 are more active and have the potency to be used as antibacterial agents. Trials to obtain single crystals suitable for structure determination by X-ray crystallography were in vain due to the amorphous nature of the complexes.