And Di-Organotin(IV) Carboxylates: Synthesis, Characterization and Biological Activities
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Germatranyl Substituted Mono- and Di-organotin(IV) Carboxylates: Synthesis, Characterization and Biological Activities U. Salma, M. Mazhar, Imtiaz-ud-Din* and S. Ali Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan *drimtiazuddin@yahoo. com ABSTRACT 2 1 Seven new germatranes having the general formula [R'GeCH(R )CH2COO]4.nSnR^ where R = 2 3 N(CH2CH20)3, R = CH3 ,C6Hs, P-CH3QH4, p-CH3OC6H9, p-FC6H4, , R = C6H5,CH2C6H5, η = lor 2, have been synthesized by the reaction of mono-, or di-organotin halide with germatranyl propionic acid in the presence of triethylamine and were characterized by elemental analysis, multinuclear ('H, L3C, ll9Sn) NMR , ll9mSn Mossbauer,IR and mass spectrometry. Anti-leishmanial and enzyme inhibition bioassay techniques were employed to evaluate their activity and found promising results. Keywords: Germatranyl, Monoorganotin, Spectroscopy, Antileishmanial activity, Enzyme inhibition. INTRODUCTION The wide range of academic /1,2/ and industrial applications /3/, favourable environmental and toxicological properties /4,5/ has resulted in the high level of world consumption of organotins. Some organogermanium compounds exhibit biocidal and fungicidal activities /6/, while organogermanium- transition metal complexes have been reported as catalysts or co-catalysts for various organic reactions 111. Toxicological and pharmacokinetic studies have revealed that organogermanium compounds exhibit low toxicity /8/, but with marked biological activities. The bioactive properties of organotin and organogermanium compounds have been actively studied recently and a link between them was established 191. Mono-organotin trichlorides with various functional groups are of interest in catalysis /10/, in organic synthesis applications and as key intermediates for the preparation of fiinctionalized mono-organotin trialkoxides /11-12/. Being the least toxic compounds, mono-organotins are often used as hydrophobic agents for building materials and cellulosic matter /13/. In continuation of our previous work /14,15/, we have now synthesized a new series of mono- and di- organotin derivatives of germatranyl substituted propionic acid with the general formula: 259 Vol.30, No. 5, 2007 Germatranyl Substituted Mono-and Di-organotin(IV) Carboxylates 3 2 K n Sn[OCOCH2CH(R )GeR']4.•,n where η = 1 (compounds 1-4) and η = 2 (compounds 5-7) R1 R2 R3 N(CH2CH20)3 C6H5 C6H5 (1) N(CH2CH20)3 p-CH3C6H4 C6H5 (2) N(CH2CH20)3 P-CH3OC6H4 C6H5 (3) N(CH2CH20)3 P-FC6H4 C6H5 (4) N(CH2CH20)3 C6H5 CH2C6H5 (5) N(CH2CH20)3 P-CH3C6H4 CHJC^HS (6) N(CH2CH20)3 CH3 CH2C6H5 (7) EXPERIMENTAL Material and Instruments Germanium dioxide, phenyltin trichloride, tribenzyltin and triethylamine were purchased from Aldrich, USA and used without further purification. All organic solvents were purchased from Ε-Merck, Germany and dried before use according to standard methods. Details of all apparatus and instruments used are given elsewhere /15/. Synthesis The ligands, germatranyl(substituted)propionic acids, were synthesized by the literature method /16/. The target compounds (1-7) were prepared by the following general procedure. The appropriate amount of germatranyl substituted propionic acid was suspended in dry acetone in a two- necked round-bottom flask fitted with a reflux condenser and magnetic stirring bar. The stoichiometric amount of triethylamine was added, followed by dropwise addition of mono- or diorganotin chloride at room temperature. The mixture was refluxed for 9-10 hours. After cooling, triethylamine hydrochloride was filtered off. Acetone was evaporated under reduced pressure and the resulting thick residue kept at low temperature (-9°C) for few days. The resulting mass was recrystallized from chloroform and acetone (3:1) mixture as a white solid, but we could not obtain crystals suitable for single crystal X-ray analysis. Biological Activities Enzyme Inhibition Bioassay Inhibitory activities of organotin carboxylates containing germanium against α-glucosidase type VI (Sigma G6136) were observed spectrophotometrically at pH 6-8 and at 37°C, using 0.7 mM p-nitrophenyl a- D-glucopyranoside (PNP-G) as a substrate and 0.017 units/mL enzyme, in 50 mM sodium phosphate buffer containing 100 mM NaCl,. 0.3 mM 1-deoxynojirmycin was used as a positive control /17/. 260 U. Salma et al. Main Group Metal Chemistry Anti-Leishmanial Bioassay The compounds (1-7) were screened for their leishmanicidal activity against promistigotes of L. donovani in vitro, using pentamidine as a standard drug. The whole operation was carried out aseptically in an UV chamber/18/. RESULTS AND DISCUSSION Germanium substituted mono- and di-organotin carboxylates were synthesized by the reaction of the respective germatranyl substituted propionic acid and organotin chloride in 1:2 mole ratio in the presence of a stoichiometric amount of triethylamine, as follows: Ο The compounds (1-7) are white solids and are quite stable in moist air. They were characterized by elemental analysis and using various spectroscopic techniques such as multinuclear ('H, l3C, ll9Sn) NMR and Snll9m Mössbauer, IR spectroscopy and mass spectrometry.. Physical data and various R-group descriptions of target compounds are reported in Table 1. The main IR spectroscopic data are presented in Table 2. The coordination of the carboxylate group to tin is decided on the basis of the magnitude of Av[v(COO)asy-v(COO)sym]. In these organotin derivatives the v(COO) frequencies are shifted far from free 1 1 1 acid (-1700 cm" ) and occur in the range 1576-1604 cm" as ν(000)ωγιη and 1370-1403 cm" as v(COO)sym. The Δν values of the compounds range between 198-215 cm"1 and suggest the bidentate nature of the carboxylate group /19/. The broad band at 3400-3500 cm"1 due to v(OH), present in spectrum of the ligand, is absent in the spectra of the corresponding organotin derivative, thus showing complex formation. The appearance of a new IR absorption band around 450 cm"1, assignable to Sn-O bond, thus indicates the presence of Sn-O-C unit in all the complexes /20/.The Ge-C and Sn-C absorption bands are in accordance with our earlier reports /14,15/. The 'H NMR data of compounds (1-7) are given in Table 3. The expected resonances are assigned by their intensity pattern, multiplicity, integration of the peaks and coupling constants. The CH2CHGe unit in the germatranyl propionate framework comprises an ABX system by presenting CHGe as a chiral centre and CH2 as a prochiral centre. The prochiral and chiral centres give two multiplets in region 2.9-3.1 ppm and 3.6- 4.1 ppm respectively; for details see elsewhere/15/. The cyclic skeleton of germatranes gives two triplets at ca. 3.6 ppm for OCH2 and ca. 2.7 ppm for NCH2 in solution (CDC13) and corresponds to AABB spin system. The relative values of the vicinal coupling constant (3JAB) are in the range 4-8 Hz. The aromatic protons absorb in their usually region i.e. 6.5-7.7 ppm. In the dibenzyltin series, the CH2 group of the benzyl moiety absorbs at 2.5 ppm as a singlet. Phenyl group of the benzyl moiety and phenyl attached to the germyl moiety as well as to tin overlap in the aromatic region and are difficult to differentiate for these compounds. 261 Vol.30, No. 5, 2007 Germatranyl Substituted Mono-and Di-organotin(IV) Carboxylates •Ο Α ο (Ν Ο tri (Ν U-1 >5 s?~ οο ΟΟ Γ- r- vo ν© ι <=> {Ν Μ οο Ο Ά £ VO t— ^ I- «ι ΓΟ ^ CόS a2 *—s m ο Ο (Ν ο — — ο Ο οο (Λ Ζ fN Ο fN) rn — <Ν r- vc I Ο VO "(Λ χ® vi VO Π"! ΓΟ rö ro CS CS rn (Ν a d «—ν Ο fN Ο <Λ> Ον Ο (Ν Ο σν οο An ο S CN (Ν ττ ΟΟ l ac (Ν Ο — ΟΟ I >/"> VO <Λ1 TT u-i u-i (Foun . χ Ό γ- ο ΙΛι Γ- I - * Ο Μ ο C Calc ο c-1 ιη «=» £ in ο οο Elementa υ I \D οο Γ-^ S _; ο Ο 1 Μ- s 5 s c —- s oCOb ί- Ο a C tt. C C C οο C C C ο CO COη-ι COfi άΓ COΜ coπ Ν e ) V α> <υ α> υ <υ ο Ο ^ α α Οc> Ο α Ο < •> (Ν <Ν ν -C Ζ ο Ζ <Ν Ο. Formul Ζ ^ Ζ s Ζ Ζ ίΝ Wt. Τ. οο r ^ Ο 'k- . — Ο ^V > ΕCO ο ON ι "> ο c i <υ N«ΛO qr » Β © ε ο " I•Λ I I3 I" ΟfN w (Mol 5C DC DC ν<ΟΝ Χ DC I 1 « ν» Vt i «Λ> DC * οτο mTT Η υ υ υ «Λ •t υ υ Ο Molecula υ Im U οιί (Λ «Λ >ο vi «ο v~> VI •π ΧνΟ DCνΟ Χ Ο Ό I DC DC χ Lpm οί Ο ο •Ο νΟ υ υ υ CO r-i ΓΊ fN > ο υ υ υ I Χ I -α υ υ υ c Λ τ 4-CO* •t χ CO I DC Ό -α «Λ νΟ Ο DC •Λ f» Ν Ι υ I U QÄ «ο L υ -Ο n DC U DC 8 UmI υ DC U υι £ Ο. Uι J>S> α. υ α. α. fl Ο π Χ : : ; es υ - - - «Ν Ι ζU . - Ν Tt «Λ νβ No Comp 262 U.Salma et al. Main Group Metal Chemistry Table-2 Characteristic IR absorption frequencies (cm"') of organotin carboxylates. Comp. V(COO)„vm V(COO),vm Δν v(Ge-O) v(Ge<-N) v(Sn-C) v(Sn-O) 1 1576 1375 201 903, 830 693 661,533 451 2 1585 1370 215 900, 819 695 620, 539 463 3 1595 1397 198 897, 825 694 617, 530 445 4 1595 1395 200 896, 832 694 615,535 460 5 1604 1403 201 900, 852 694 617, 523 450 6 1604 1402 202 895, 825 692 620, 541 417 7 1595 1388 207 900, 852 694 617, 523 464 Table-3 'H NMR data*3 of organotin carboxylates.