Synthesis, characterization and antimicrobial activity of diorganotin(IV) derivatives of some bioactive bifunctional tridentate Schiff base ligands

Syntheses of organotin(IV) derivatives

Ligands have been synthesized by the condensation reaction of β-diketones and selected amino alcohols in unimolar ratio. These ligands may exist in various forms (Scheme 1). The structure (C) seems to be more likely in view of the spectroscopic studies and the single crystal X-ray diffraction analysis of organotin compounds of similar ligands reported in the literature (Dey et al., 2009).

Scheme 1:

Syntheses of bifunctional tridentate Schiff bases (1a–1d) and diorganotin derivatives (2a–2l) and schematic drawings of the different forms of ligands (A–D).

The reactions of R₂SnCl₂ with the sodium salt of Schiff base ligands (synthesized by the reaction of Schiff bases and freshly prepared sodium methoxide) in 1:1 molar ratio in refluxing tetrahydrofuran (THF) yield organotin complexes.

Spectroscopic studies

¹³C NMR spectra

¹³C NMR spectral data of these derivatives have been summarized in Table 2. The spectra of all these derivatives (2a–2l) exhibit signal for >C-O- enolic group carbon in the range δ 187.5–195.8 in these organotin compounds as well as their corresponding ligands. A small downfield shift is observed in the position of this signal as compared to their corresponding free ligands. Signal for >C=N imine group carbon has been observed in the range δ 162.9–165.9. A downfield shift of ~2–5 ppm has been observed as compared to its position in corresponding free Schiff base ligands. The shifts in the positions of carbon atom adjacent to the imine group nitrogen suggest that nitrogen is involved with tin in these complexes. The signal for CH₂O- group carbon (deprotonated amino alcohol group) appeared in the range of δ 60.7–68.3 having a slight downfield shift (~2 ppm) as compared to their position in free Schiff base moieties. Signals for CH₃-Sn group carbon appeared in the range δ 19.4–20.3 in 2a–2d derivatives. The ¹J(¹¹⁹Sn-¹³C) coupling constant values were found in the range 553–596 Hz for 2a–2d derivatives, which is consistent with pentacoordination range (470–610 Hz) (Lockhart et al., 1985).

Table 2

¹³C NMR spectroscopic data (δ) of some new diorganotin(IV) Schiff base derivatives.

Compound			Phenyl carbon				Alkylene carbon
			C1 C1′	C2 C2′	C3 C3′	C4 C4′
1a			–	–	–	–	93.6(=CH-), 62.1(CH2O), 57.6(CH2N), 33.3(CH3CO), 25.8(CH3CN)
	191.1	162.6	–	–	–	–
1b			–	–	–	–	94.1(=CH-), 61.3(CH2O), 57.7(CH2N), 40.5(CH2), 32.5(CH3CO), 26.2(CH3CN)
	193.5	163.4	–	–	–	–
1c			–	–	–	–	94.3(=CH-), 61.7(CH2O), 58.2(CH2N), 26.6(CH3CN)
	188.2	161.7	140.9	135.1	130.5	126.1
1d			–	–	–	–	95.8(=CH-), 62.4(CH2O), 58.5(CH2N), 41.2(CH2), 26.3(CH3CN)
	187.1	163.8	140.5	135.4	129.4	126.9
2a			–	–	–	–	94.9(=CH-), 62.2(CH2O), 58.1(CH2N), 33.9(CH3CO), 26.4(CH3CN), 19.4(CH3Sn), 1J(119Sn-13C)=553 Hz
	194.2	164.2	–	–	–	–
2b			–	–	–	–	96.6(=CH-), 68.3(CH2O), 51.2(CH2N), 41.2(CH2), 31.2(CH3CO), 24.3(CH3CN) 20.3(CH3Sn), 1J(119Sn-13C)=561 Hz
	195.8	165.0	–	–	–	–
2c	189.7	164.3	–140.2	–135.7	–130.1	–126.5	94.7(=CH-), 67.2(CH2O), 57.7(CH2N), 28.0(CH3CN) 19.9(CH3Sn), 1J(119Sn-13C)=578 Hz
2d			–	–	–	–	92.2(=CH-), 70.1(CH2O), 59.5(CH2N), 39.9(CH2), 26.4(CH3CN) 19.4(CH3Sn), 1J(119Sn-13C)=596 Hz
	187.6	165.4	140.4	136.0	129.9	126.8
2e			–	–	–	–	95.7(=CH-), 67.6(CH2O), 52.4(CH2N), 33.2(CH3CO), 27.4,(CH3CN), 23.1–19.2(C4H10)
	194.8	164.2	–	–	–	–
2f			–	–	–	–	94.6(=CH-), 62.7(CH2O), 56.2(CH2N), 38.9(CH2), 31.6(CH3CO), 28.3(CH3CN), 26.0–17.8(C4H10)
	194.1	162.9	–	–	–	–
2g			–	–	–	–	94.9(=CH-), 62.0(CH2O), 51.9(CH2N), 27.4(CH3CN), 25.4–19.6(C4H10)
	187.9	165.8	140.3	135.7	129.8	126.7
2h			–	–	–	–	95.2(=CH-), 60.9(CH2O), 53.6(CH2N), 39.8(CH2), 28.5(CH3CN) 21.8–15.7(C4H10)
	194.5	163.8	140.4	136.2	130.1	126.1
2i			139.4	136.6	129.1	125.8	94.2(=CH-), 65.2(CH2O), 57.2(CH2N), 35.2(CH3CO), 27.6(CH3CN)
	194.2	163.6	–	–	–	–
2j			139.4	135.9	129.5	126.5	92.2(=CH-), 66.3(CH2O), 59.3(CH2N), 40.1(CH2), 32.1(CH3CO), 27.1(CH3CN)
	187.5	165.7	–	–	–	–
2k			138.1	135.0	129.1	125.8	95.7(=CH-), 60.7(CH2O), 53.6(CH2N), 39.9(CH2), 24.8(CH3CN)
	192.9	164.9	139.3	136.8	130.4	126.3
2l			139.2	135.9	128.9	126.2	94.6(=CH-), 64.6(CH2O), 60.2(CH2N), 44.5(CH2), 26.2(CH3CN)
	193.7	162.9	140.9	137.1	130.3	127.0

C₁, C₂, C₃ and C₄ denote the phenyl carbons of group R. C_1′, C_2′, C_3′ and C_4′ denote the phenyl carbons of group R_′.

Structural elucidation

In view of the above mentioned spectroscopic data, the following structures having bifunctional tridentate Schiff bases with pentacoordinated tin may be proposed in solution for these diorganotin(IV) derivatives 2a–2l (see drawing in Scheme 1). According to the Bent’s rule, both the R- groups will occupy equatorial positions. Pentacoordination around tin atom (bond angle of 124°–131°) is confirmed by ¹H, ¹³C and ¹¹⁹ Sn NMR spectroscopic data, and the opening of the bond may be explained by the solvent effect.

Antimicrobial activity

Diorganotin derivatives (2a–2l) with their corresponding free Schiff bases (1a–1d) and metal precursors were screened against bacteria (Table 3: Figures S1, S2, S3 and S4) and fungi (Table 4: Figures S5 and S6) to examine their growth inhibitory potential towards the test organisms. Apparently, the complexes are more toxic towards Gram-positive strains (Staphylococcus aureus and Bacillus subtilis) than Gram-negative strains (Escherichia coli and Pseudomonas aeruginosa). The reason probably lies in the difference between the structures of the cell walls. The relatively more complex walls of Gram-negative cells may prevent the diffusion of chemicals into the cytoplasm of the organisms, which may not be the case of Gram-positive cells. The results indicate that the metal chelates have higher activity than the free ligands as well as metal precursors. This increased activity of the metal chelates can be explained by Tweedy’s chelation theory (Tweedy, 1964) and Overtone’s concept. According to Overtone’s concept of cell permeability, the lipid membrane that surrounds the cell favors passage of only lipid-soluble material due to liposolubility, which is an important factor that controls antimicrobial activity. On chelation, the polarity of the metal ions is reduced to a greater extent due to the overlap of the ligand orbital and partial sharing of the positive charge of the metal ion with a donor group. Enhanced activity may be due to the coordination of ligand to tin leading to electron delocalization and therefore increasing the lipophilic character and efficient diffusion of the metal complexes into bacterial cells. It has been observed that a small structural change, such as change of alkyl group present, increases the activity of compounds in the order R=CH₃<C₄H₁₀<C₆H₅ (Sonika and Malhotra, 2011).

The concentration of a compound is another important factor on which the inhibition growth is affected. At lower concentration (2 mg/mL) growth will be slowed down, while at higher concentration more enzymes will become inhibited, leading to a quicker death of organism.

Materials and methods

Solvents were purified and dried by standard procedures. Schiff bases (1a–1d) were prepared by the condensation reactions of β-diketones with appropriate amino alcohols. Dialkyltin dichloride (Aldrich, USA) was distilled prior to use. Tin was estimated (Vogel, 1989) as tin dioxide in these derivatives. Carbon, hydrogen and nitrogen were analyzed on elemental analyzer Elementar Vario EL III.

¹H, ¹³C and ¹¹⁹Sn NMR spectra were recorded in CDCl₃ solution on Bruker FT 400 MHz NMR spectrometer (Brucker coorporation, Billerica, MA, USA). TMS was used as internal reference for ¹H and ¹³C NMR spectra. IR spectra were recorded on 8400 s SHIMADZU FT IR Spectrophotometer (Kyoto, Japan) as nujol mull in KBr disk in the range 4000–400 cm^-1. The FAB mass spectra of three representative compounds were recorded on Jeol-SX 102/Da-600 mass spectrometer (Jeol coorporation, Akishima, Tokyo, Japan).

As the synthetic procedure for all these compounds is the same, for the sake of brevity details of only one compound are given, and the analytical as well as preparative details of the rest of compounds are summarized in Table 5.

Syntheses of

The sodium salt of Schiff base has been synthesized by the reaction of sodium methoxide [prepared by the reaction of sodium (0.316 g, 6.84 mmol) in dry methanol (~10 mL)] and THF solution (~15 mL) of Schiff base (0.98 g, 6.84 mmol). The mixture was heated at reflux for half an hour.

To this solution, a THF solution (~40 mL) of dimethyltindichloride (1.505 g, 6.84 mmol) was mixed, and the reaction mixture was refluxed for ~6 h. NaCl thus precipitated was filtered off, and the excess of solvent was removed under reduced pressure to yield a creamish white solid (m.p. 155°C). The compound was recrystallized from THF/n-hexane mixture. Percent analyses for C₉H₁₇O₂NSn; found (calculated) Sn, 40.72 (40.79) C, 54.96 (55.07) H, 5.65 (5.88) N, 4.73% (4.81) FAB mass spectral data; fragments, m/z (relative intensity) [C₉H₁₇O₂NSn]⁺ • 291 (37.83%), [C₈H₁₆O₂NSn]⁺ • 279 (100%), [C₆H₁₃O₂NSn]⁺ • 251 (30.01%), [C₄H₁₀ONSn]⁺ • 208 (6.17%), [C₃H₈SnO]⁺ • 180 (8.54%), [C₂H₆SnO]⁺ • 166 (4.62%), [CH₃Sn]⁺ • 135 (50.80%).

Mass spectral data of compound

FAB mass spectral data; fragments, m/z (relative intensity) [C₁₅H₂₉O₂NSn]⁺ • 374 (29.11%), [C₁₄H₂₈O₂NSn]⁺ • 361 (100%), [C₁₂H₂₅O₂NSn]⁺ • 334 (18.81%), [C₁₀H₂₂ONSn]⁺ • 291 (7.19%), [C₉H₂₀SnO]⁺ • 263 (3.54%), [C₈H₁₈SnO]⁺ • 249 (9.21%), [C₄H₉Sn]⁺ • 176 (48.07%).

Mass spectral data of compound

FAB mass spectral data; fragments, m/z (relative intensity) [C₁₉H₂₁O₂NSn]⁺ • 414 (30.25%), [C₁₈H₂₀O₂NSn]⁺ • 401 (100%), [C₁₆H₁₇O₂NSn]⁺ • 374 (16.47%), [C₁₄H₁₄ONSn]⁺ • 331 (5.11%), [C₁₃H₁₂SnO]⁺ • 287 (3.89%), [C₁₂H₁₀SnO]⁺ • 273 (8.52%), [C₆H₅Sn]⁺ • 180 (46.45%).

Antimicrobial activity

The ligands (1a–1d) and their corresponding diorganotin derivatives have been screened for the growth inhibitory activity in vitro against bacteria (i.e. S. aureus, B. subtilis, E. coli and P. aeruginosa) and fungi (i.e. Fusarium oxysporum, Trichoderma reesei, Penicillium funiculosum and Aspergillus niger). For both bactericidal and fungicidal assays, in vitro disc diffusion method was adopted because of reproducibility and precision. In this method, the different test organisms were processed separately using a sterile swab over previously sterilized culture medium plates, and the zones of inhibition were measured around sterilized dried discs of Whatman paper no.1 (6 mm in diameter) in two different (2 mg/mL, 4 mg/mL) concentrations of the test solution. Dimethyl sulfoxide was used as solvent, and discs were air dried at room temperature to remove any residual solvent. After this, they were sterilized and inoculated. The plates were initially placed at low temperature for 1 h, so as to allow maximum diffusion of the compounds from the test discs into the plate, and later incubated for 24 h at 34°C in the case of bacteria and 48 h at 27°C for fungi, after which the zones of inhibition could be easily observed. The inhibition zone diameters in each case were recorded and shown in Tables 3 and 4. In account of antimicrobial activity, some images are given in the online supplementary material as Figures S1–S6.