New antimicrobial polyurea: Synthesis, characterization, and antibacterial activities of polyurea-containing thiosemicarbazide-metal complexes

A novel class of polymer–metal complexes was prepared by the condensation of a polymeric ligand with transition-metal ions. The polymeric ligand was prepared by the addition polymerization of thiosemicarbazides with toluene 2,4-diisocyanate in a 1 :
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  New Antimicrobial Polyurea: Synthesis, Characterization,and Antibacterial Activities of Polyurea-ContainingThiosemicarbazide–Metal Complexes Nahid Nishat, 1 Tansir Ahamad, 1 M. Zulfequar, 2 Sumaiya Hasnain 1 1  Materials Research Lab, Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India 2  Materials Research Lab, Department of Physics, Jamia Millia Islamia, New Delhi 110025, India Received 7 September 2007; accepted 3 January 2008DOI 10.1002/app.28752Published online 10 September 2008 in Wiley InterScience ( ABSTRACT:  A novel class of polymer–metal complexeswas prepared by the condensation of a polymeric ligandwith transition-metal ions. The polymeric ligand was pre-pared by the addition polymerization of thiosemicarba-zides with toluene 2,4-diisocyanate in a 1 : 1 molar ratio.The polymeric ligand and its polymer–metal complexeswere characterized by elemental analysis, thermogravimet-ric analysis, Fourier transform infrared spectroscopy, and 13 C-NMR and  1 H-NMR spectroscopy. The geometries of the central metal ions were determined by electronic spec-tra (UV–visible) and magnetic moment measurement. Theantibacterial activities of all of the synthesized polymerswere investigated against  Bacillus subtilis  and  Staphylococ-cus aureus  (Gram positive) and  Escherichia coli  and  Salmo-nella typhi  (Gram negative). These compounds showedexcellent antibacterial activities against these bacteria withthe spread plate method on agar plates, and the numberof viable bacteria were counted after 24 h of incubationperiod at 37 8 C. The antibacterial activity results revealedthat the Cu(II) chelated polyurea showed a higher anti- bacterial activity than the other metal-chelated polyureas. V V C  2008 Wiley Periodicals, Inc. J Appl Polym Sci 110: 3305–3312,2008 Key words:  metal–polymer complexes; NMR; thermalproperties INTRODUCTION Since the discovery of manmade polymers, continu-ous efforts have been made to make polymers morestable, increase their mechanical and chemicalstrengths, and make them durable in the environ-ment. Now, it is time to meet the challenges for thesynthesis of biomedical materials. The use of antimi-crobial polymers offers promise for enhancing the ef-ficacy of some existing antimicrobial agents andminimizing the environmental problems accompany-ing conventional antimicrobial agents by reducingthe residual toxicity of the agents, increasing their ef-ficiency and selectivity, and prolonging the lifetimeof the antimicrobial agents. Also, polymeric antimi-crobial agents have the advantage that they are non-volatile and chemically stable and do not permeatethrough skin. Therefore, they can reduce losses asso-ciated with volatilization, photolytic decomposition,and transportation. In the field of biomedical poly-mers, infections associated with biomaterials repre-sent a significant challenge to the more widespreadapplication of medical implants. Polymers containingmetal ions have found widespread applications inthe biomedical field and as catalysts in organic syn-thesis, nuclear chemistry, the preconcentration andrecovery of trace metal ions, pollution control, hydro-metallurgy, polymer drug grafts, and wastewatertreatments. 1–4 Thiosemicarbazides are of considerableinterest because of their chemistry and ability to formstable chelates with essential metal ions and theirpotentially beneficial biological activities, such asantitumor, antibacterial, antiviral, and antimalarialactivities. 5–13 The potential biological activity of com-pounds containing sulfur and nitrogen may be re-sponsible for this increased interest. Toluene 2, 4-diisocyanate (TDI) is an extremely reactive chemicalwith amino and hydroxyl groups that form polyureaand polyurethane, respectively. 14 TDI also interactswith the amino group of proteins, DNA, and RNA( in vitro ) and, results from a combination with theprimary amide and the amino group to form poly-urea. A series of polymer–metal complexes have beensynthesized in our laboratory that are used as antimi-crobial materials in biomedical fields such as antimi-crobial coating materials. 15–17 To continue our efforts,in this study, we synthesized a novel polymeric  JournalofAppliedPolymerScience,Vol.110,3305–3312(2008) V V C  2008 Wiley Periodicals, Inc. Correspondence to:  N. Nishat ( grant sponsor: The Third World Academy of Sciences Italy (for the PerkinElmer EZ-201 UV–visiblespectrophotometer); contract grant number: 00-047 RG/CHE/AS.  ligand (polyurea) and its polymer–metal complexeswith transition-metal ions. All the of the synthesizedpolymers were characterized by various techniques,such as elemental analysis, thermogravimetric analy-sis (TGA), Fourier transform infrared (FTIR) spectros-copy, and  13 C-NMR and  1 H-NMR spectroscopy. Theantibacterial activities of these compounds weretested against  Bacillus subtilis  and  Staphylococcus aur-eus  (Gram positive) and  Escherichia coli  and  Salmonellatyphi  (Gram negative) with the shaking flask method,where 25-mg/mL concentrations of each compoundwere tested against 10 5 cfu/mL bacterial solutions. EXPERIMENTALMaterials and bacterial strains Thiosemicarbazide, TDI, and all of the solvents werepurchased from S. D. Fine Chemical, Ltd. (Mumbai,India), and the solvents were recrystallized frommethanol before use. All of the other chemicals wereused as received. Tryptic soy agar was purchasedfrom Difco Laboratories (Lawrence, KS). It contained15.0 g of a pancreatic digest of casein, 5.0 g of an enzy-matic digest of soybean meal, 5.0 g of sodium chlo-ride, and 15.0 g of agar. Tryptic soy broth (TSB) wasalso purchased from Difco Laboratories. It contained17.0 g of a pancreatic digest of casein, 3.0 g of an enzy-matic digest of soybean meal, 2.5 g of dextrose, 5.0 gof sodium chloride, and 2.5 g of dipotassium phos-phate. The bacterial strains used for the antimicrobialactivity tests included  S. aureus  (IFO 2340),  B. subtilis (IFO 24370),  S. typhi  (IFO 3807), and  E. coli  (IFO 3628).The strains were kept at  80 8 C in a freezer. Measurements The elemental analysis of the polymers was carriedout on a PerkinElmer model 2400 elemental analyzer(Waltham, MA) (CDRI, Lucknow). The metal contentwas determined by complexometric titration againstethylene diamine tetraacetic acid after decompositionwith concentrated nitric acid (HNO 3 ). The FTIR spec-tra were recorded over the range 4000–500 cm  1 on aPerkinElmer infrared spectrophotometer model 621with KBr pallets. The UV–visible spectra wereobtained on a PerkinElmer Lembda EZ-201 spectro-photometer with dimethyl sulfoxide (DMSO) as a sol-vent, and the magnetic susceptibility measurementsof these resins were carried out on a Gouy balance(Malvern, PA) with Hg[Co(SCN) 4 ] as a celebrant.  1 H-NMR and  13 C-NMR spectra were recorded on a JeolSX 300-MHz FX-1000 Fourier transform NMR spec-trometer (Oxford, UK) with DMSO as a solvent andtetramethylsilane as an internal standard. The ther-mal behaviors of the polyurea were determined on aTGA analyzer 2000 (New Castle, DE) in a nitrogenatmosphere at a heating rate of 20 8 C/min. Synthesis Synthesis of the polymeric ligandThiosemicarbazide (9.14 g, 0.1 mol) and TDI (12.5 g,0.1 mol) were mixed in 60 mL of   N,N  -dimethylfor-mamide (DMF) in a 100-mL, round-bottom flask.The flask was closed with a rubber septum, and themixture was stirred at 40 8 C for 24 h. The reactionmixture was evaporated by a rotary evaporator, andthe final mixture was cooled and precipitated intodeionized water. A solid, light yellow product wasobtained; it was dried in a vacuum oven to removetrapped solvents to give the polymeric ligand (poly-urea (PU); 14.16 g) at a 73% yield. The polymericligand was insoluble in water, methanol, ethanol,and nonpolar solvent but was soluble in tetrahydro-furan, DMF, and DMSO at room temperature.Synthesis of the polymer–metal complexesThe polymer–metal complexes were synthesized bythe mixture of a hot solution of polymeric ligand(0.02 mol) with metal acetate (0.01 mol) in a 100-mL,round-bottom flask at 40 8 C for 24 h. The reactionmixture was cooled and precipitated into a 75/50 v/v water/acetone mixture. The solid colored productwas filtered and then reprecipitated from DMF intoethanol. The solid product was filtered and washedwith water and ethanol, respectively. Finally, theproduct was dried in a vacuum oven to removetrapped solvents; this gave a colored powder of polymer–metal complexes at a 70–75% yield. Antibacterial assessment The antibacterial activity tests were performed withthe shaking flask method, 18 and the number of via- ble cells was counted with the spread platemethod. 19 S. aureus, B subtilis, S. typhi,  and  E. coli were streaked out on tryptic soy agar plates andincubated at 37 8 C for 24 h. A representative colonywas lifted off with a wire loop and placed in 5 mLof TSB, which was then incubated with shaking at37 8 C for 24 h. The antibacterial activities of the newpolymeric ligand and its polymer–metal complexeswere determined by the testing of a 25-mg/mL con-centration of the compounds against these two typesof bacteria with the aforementioned methods. Onlyone concentration of these polymers was tested, asthese polymers were not soluble in TSB. The poly-meric ligand and its polymer–metal complexes werein powder form and were not soluble in water; theyformed suspensions when they were mixed withTSB. Each suspension containing antimicrobial agentwas mixed with 10 5 cfu of the test organism in a 10-mL culture tube (Falcon). The tubes were incubatedat 37 8 C for 24 h. The test was repeated at least three 3306 NISHAT ET AL.  Journal of Applied Polymer Science  DOI 10.1002/app  times for each antimicrobial agent. Samples weretaken from each tube and diluted with TSB. Thediluted solutions were spread on agar plates, andthe plates were incubated at 37 8 C for 24 h. The num- ber of bacterial cells was calculated by multiplicationof the number of colonies by the dilution factors. RESULTS AND DISCUSSIONChemistry of the polymer and itspolymer–metal complex The polymeric ligand was prepared according to thesynthetic route shown in Scheme 1. The nitrogen of thiosemicarbazides has an excess of electrons, so itwill react with species that are electron-deficient.The carbon atom in the isocyanate group is sand-wiched between two electronegative elements, oxy-gen and nitrogen. This carbon is also electron-deficient, so nitrogen donates a pair of electrons tothe carbon, and overall, a urea dimer is obtained.These dimers (urea) have amino or amide groups onone the hand and an isocyanate group on the other,so it can react with either a amine or amide or a dii-socyanate to form a trimer or a polymer. The poly-mer–metal complexes were coordinated withpolyurea and gave colored polymer–metal com-plexes, which were insoluble in common organic sol-vents but soluble in DMSO and DMF. The elementalanalysis results of the synthesized compounds werealso in a very good agreement with the calculatedvalues and are given in Table I. Scheme 1  Synthetic route of the polymeric ligand and its metal complexes. TABLE IElemental Analysis of the Polymeric Ligand and Its Polymer–Metal Complexes Compound abbreviation Empirical formulaElemental analysisCarbon Hydrogen Nitrogen Sulfur MetalPU (C 10 H 11 N 5 O 2 S) x  45.27 4.18 26.40 12.09 —(45.28) (4.19) (26.42) (12.10) —PU–Mn(II) (C 20 H 20 N 10 O 4 S 2 A Mn) x  41.17 3.45 24.00 10.99 9.42(41.20) (3.50) (24.09) (10.97) (9.43)PU–Co(II) (C 20 H 20 N 10 O 4 S 2 A Co) x  40.89 3.43 23.84 10.92 10.03(40.90) (3.44) (23.85) (10.90) (10.01)PU–Ni(II) (C 20 H 20 N 10 O 4 S 2 A Ni) x  40.90 3.43 23.85 10.92 9.90(40.92) (3.45) (23.89) (10.91) (9.92)PU–Cu(II) (C 20 H 20 N 10 O 4 S 2 A Cu) x  40.57 3.40 23.66 10.83 10.73(40.58) (3.42) (23.67) (10.84) (10.75)PU–Zn(II) (C 20 H 20 N 10 O 4 S 2 A Zn) x  40.44 3.39 23.58 10.80 11.01(40.44) (3.41) (23.65) (10.82) (10.09) x  ¼  number of repeating units of polymeric chain. The calculated values of metal-to-ligand stoichiometry are listed out-side parentheses, and the observed values are listed inside parentheses.NEW ANTIMICROBIAL POLYUREA 3307  Journal of Applied Polymer Science  DOI 10.1002/app  Characterization FTIR spectraFTIR spectroscopy was used for the analysis of thepolymeric ligand and its polymer–metal complexesand is illustrated in Table II; it indicated the forma-tion of the expected compounds. The IR spectrum of the polymeric ligand showed bands at 3060, 3175,and 3240 cm  1 due to N A H groups, but the band at3240 cm  1 was absent in the polymer–metal com-plexes, which indicated a loss of protons via thioe-nolisation. 20 Two strong and sharp bands appearedin all of the synthesized polymers at 2970–2940 and2850–2840 cm  1  because of the asymmetrical andsymmetrical stretching vibrations of the  A CH 3 groups. The peaks at 1680 and 1670 cm  1 wereassigned to  m  C ¼¼ O groups. In the polymer–metalcomplexes, the peaks at 1680 showed a negative shiftof 20–30 cm  1 , which indicated bonding throughthis oxygen of polyurea. The band at 1560 cm  1 wasobserved due to the  m  C ¼¼ S group and was absent inthe polymer–metal complexes, but the presence of anew band at 1575 cm  1 due to  m  C ¼¼ N indicated theremoval of a hydrazinic proton through thioenolisa-tion and the subsequent participation of thioenolicsulfur in bonding The bands at 3050, 1230, 1480, and840 cm  1 remained unchanged in the polymer–metalcomplexes. In all of the polymer–metal complexes,the coordination of metal ion to the polymeric ligandwas further supported by the appearance of   m   M-O, m   M-N, and  m   M-S stretching vibrations at the620–590, 440–420, and 380–375 cm  1 regions,respectively. 21,2213 C-NMR and  1 H-NMR spectraThe synthesized polymers were followed by  13 C-NMR and  1 H-NMR spectroscopy. Figure 1(a,b)shows  1 H-NMR spectra of the polymeric ligand andits Zn(II) polychelates. The  1 H-NMR spectra of PUshowed signals at 2.15 and 6.3–7.4 ppm due to themethyl group and aromatic protons, respectively. 23 The signals at 3.52, 5.42, 5.63, and 6.12 ppm wereassigned to the NH group; the signal at 3.52 disap-peared in the case of Zn(II) complexes because of the deprotonation of NH of a hydrazinic protonthrough thioenolisation. The aromatic signals became broad and less intense because of the drift-ing of a ring electron toward the metal ions. The 13 C-NMR spectra of the polymeric ligand and itsZn(II) polychelate are given in Figure 2(a,b). The 13 C-NMR chemical shifts for the methyl CH 3 appeared at 16.23 ppm, respectively. 24 The thionyl TABLE IIFTIR Spectral Bands with Their Assignments Assignment PU PU–Mn(II) PU–Co(II) PU–Ni(II) PU–Cu(II) PU–Zn(II)NH 3240, 3175, 3060(s) 3170, 3060(s) 3170, 3065(s) 3180, 3065(s) 3170, 3065(s) 3170, 3060(s)CH 2  2970–2855(s) 2942–2840(s) 2960–2850(s) 2950–2845(s) 2940–2850(s) 2945–2850(s)C ¼¼ O 1680, 1670 1671, 1655(s) 1671, 1655(s) 1670, 1660(w) 1672, 1650(s) 1672, 1657(s)C ¼¼ S 1560(s) — — — — —C ¼¼ N — 1575(s) 1572(s) 1575(w) 1572(s) 1575(s) d (CH) 1480(s) 1470(m) 1465(s) 1465(w) 1475(s) 1470(s) d (C A N) 1435(s) 1435(m) 1440(s) 1425(s) 1425(m) 1430(s) m  M-O — 620(s) 621(s) 590(s) 600(s) 620(b) m  M-N — 440(w) 435(s) 430(s) 420(m) 438(s) m  M-S — 380(s) 370(s) 375(s) 380(s) 375(b) s  ¼  strong; vs — very strong; m  ¼  medium; b  ¼  broad; w  ¼  weak. Figure 1  1 H-NMR spectra of (a) the polymeric ligand(PU) and (b) Zn(II) polychelate [PU–Zn(II)].3308 NISHAT ET AL.  Journal of Applied Polymer Science  DOI 10.1002/app  and carbonyl peaks of the polymeric ligand showedresonance signals at 188.1 and 153.2 ppm. In thepolymer–metal complexes, the thionyl peaks shiftedfrom 188 to 156.2, which indicated the formation of the S A C ¼¼ N group 25 and bonding with metal ions.Six signals at 111.2, 115.3, 125.2, 131.4, and 134.6ppm were due to the presence of aromatic carbons.The  1 H-NMR and  13 C-NMR spectra of the PU andPU–Zn(II) showed that the metal ions were attachedthrough the carbonyl group, thionyl group, andhydrazinic nitrogen of the polymeric ligand.Electronic spectra and magnetic momentThe electronic spectra of all of the synthesized poly-mers were recorded in DMSO solution. The variouscrystal field parameters,  Dq, B,  b , and  b 0 , were calcu-lated with a known equation, and the values aregiven in Table III. The magnetic moment of PU–Mn(II) was 5.80  l B , which suggested the presence of five unpaired electrons. The electronic spectrum of this complex exhibited three absorption bands at18,520, 22,760, and 24,540 cm  1 , which were Figure 2  13 C-NMR spectra of (a) the polymeric ligand (PU) and (b) Zn(II) polychelate [PU–Zn(II)]. TABLE IIIMagnetic Susceptibility and Electronic Spectra and Their Parameters*** Abbreviation Magnetic moment ( l B )Electronic spectral data10 Dq B  b b  (%)Electronic transition (cm  1 ) Assignment24,540  4 A 1g (G) / 6 A 1g (F)PU–Mn(II) 5.80 22,760  4 T 2g (G) / 6 A 1g (F) 7685 645 .839 17%18,520  4 T 1g (G) / 6 A 1g (F)19,570  4 T 1g (P) / 4 T 1g (F)PU–Co(II) 4.74 16,340  4 A 2g (F) / 4 T 1g (F) 9615 810 .842 16%8,580  4 T 2g (F) / 4 T 1g (F)24,360  3 T 1g (P) / 3 A 2g (F)PU–Ni(II) 3.12 13,980  3 T 1g (F) / 3 A 2g (F) 8840 742 .839 16%9,020  3 T 2g (F) / 3 A 2g (F)PU–Cu(II) 1.81 27,580 Charge transfer15,360  2 A 1g / 2 B 1g NEW ANTIMICROBIAL POLYUREA 3309  Journal of Applied Polymer Science  DOI 10.1002/app
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