The Mn2+, Fe2+, Cu2+, Co2+, Zn2+, Cd2+ complexes of mixed  of Trimethoprim- Isoniazid were synthesized. The complexes were characterized using solubility, melting point, conductivity measurement and infrared spectroscopy.Trimethoprim complexes of coordination of the metal to the ligands is through the nitrogen of the pyrimidine group and coordination through the nitrogen of the amine group. The antimicrobial activity of the complexes were carried out against Staphylococcus aureus, Pseudomonas aureginosa, Klebsiella pneumonia, Escherichia coli. The results show that the complexes were more active  than their ligands. Keywords: Trimethoprim, Isoniazid, synthesis, complexes, characterized, antimicrobial ligands metal

J.A, Obaleye

M, Lawal

M.O, Bamigboye

O.M, Aluko

English

International Institute for Science, Technology and Education (IISTE): E-Journals

Chemistry and Materials Research                                                                www.iiste.org ISSN 2224- 3224 (Print) ISSN 2225- 0956 (Online) Vol 2, No.3, 2012  1 Synthesis, Characterization and Antimicrobial Study Of Mixed Isoniazid-Trimethoprim Metal Drug Complexes Bamigboye M.O*1,  Obaleye J.A1 Lawal M2. and Aluko O.M1. 1. Department of Chemistry, University of Ilorin, Ilorin, Kwara State, Nigeria. 2. Kebbi State, University of Science and Technology. Aliereo  Kebbi State. Department of Pure and Applied Chemistry. Email: seymercyx@yahoo.com  ABSTRACT The Mn2+, Fe2+, Cu2+, Co2+, Zn2+, Cd2+ complexes of mixed  of Trimethoprim- Isoniazid were synthesized. The complexes were characterized using solubility, melting point, conductivity measurement and infrared spectroscopy.Trimethoprim complexes of coordination of the metal to the ligands is through the nitrogen of the pyrimidine group and coordination through the nitrogen of the amine group. The antimicrobial activity of the complexes were carried out against Staphylococcus aureus, Pseudomonas aureginosa, Klebsiella pneumonia, Escherichia coli. The results show that the complexes were more active  than their ligands. Keywords: Trimethoprim, Isoniazid, synthesis, complexes, characterized, antimicrobial ligands metal.  1. INTRODUCTION        Antibiotic is a compounds or substance which inhibit the growth of bacteria(1).  Tuberculosis is a disease caused by Mycobacterium tuberculae, a bacteria that is passed from people to people through the air. Combinations of the drugs are used to treat tuberculosis (TB) which are normal  for effective treatment(2,3).  Antituberculosis drugs are drugs which are used to treat tuberculosis that are available only in tablets, capsules, liquid and injectable forms(4). This work is aimed as:   1. To synthesize more new alternative effective drugs.   2. To carry out some analysis on the metal drug complexes such as solubility, melting point, conductivity measurements and infrared spectrometry .   3. To carry out anti-microbial analysis on the synthesized metal complexes  against the organisms. 2. MATERIALS AND METHODS        Trimethoprim was obtained from Jostade pharmaceuticals Ilesa, Osun State, while Isoniazid was obtained from SIGMA-ALDRICH. Physico-chemical analysis such as Solubility, Melting point and Conductivity measurement were carried out in Chemistry Department, University of Ilorin with the use of HANNA instrument conductivity meter at cell constant 1.34. The infrared spectra were also carried out in REDEEMERS University in Lagos, Lagos state using FT-IR spectrophotometry. Antimicrobial activity of the synthesized complexes were done by screening the complexes against the tested organisms. Escherichia coli, Staphylococcus aureus, Klebsiella pneumonia, and Pseudonoma aureginosa which were obtained from Microbiology Department, University of Ilorin Teaching Hospital.  2.1 METHODOLOGY SYNTHESIS OF THE COMPLEXES. 2.1.1 SYNTHESIS OF [Co (TMP)(ISO)Cl2] [Zn (TMP)(ISO)SO4] and [Fe (TMP)(ISO)Cl2] COMPLEXES.  Procedure described by Obaleye et al 1993(5) was used to synthesized  this complexes. 5mmol of  the solution of  the metal salts used were dissolved in a beaker containing 20ml of  their suitable solvents and solution of 5mmol of the ligands were also dissolved in a beaker containing 20ml of their suitable solvents. The solutions were Chemistry and Materials Research                                                                www.iiste.org ISSN 2224- 3224 (Print) ISSN 2225- 0956 (Online) Vol 2, No.3, 2012  2 mixed together. Immediately there was formation of precipitate. The results obtained were washed and dried. They were kept in a sample bottle for analysis.  2.1.2 SYNTHESIS OF [Mn(TMP)(ISO)Cl2] [Cd(TMP)(ISO)SO4] [Co(Py)(Iso)Cl2] COMPLEXES. Procedure described by Tella et al 1993(6)5mmol of  the metal salts used were dissolved in a beaker containing 20ml of  their suitable solvents and 5mmol of the ligands were also dissolved in a beaker containing 20ml of their suitable solvents. The solutions were mixed together and refluxed for 5 hours but no precipitate were formed. The refluxed solution were and left for 5 weeks. A dried precipitate obtained were washed and dried. They were kept in a sample bottle for analysis.  3. ANTIMICROBIAL SCREENING PROCEDURE Method used by Matangi S. et al (7) was adopted in studying the antimicrobial activity.7 gram of nutrient agar was weighed in to a 250ml  conical flask,250ml distilled water(sterilized for 24hrs) was mixed with the agar and it was cover properly with cotton wool and foil paper so as to avoid contamination. The solution was then heated for 15mins so as to dissolve the nutrient agar. it was sterilized foe 24hours in an autoclave.   The nutrient agar was then introduce into the Petri dish and was allowed to set properly to solidified. 1cm hole was bored at the center of the plate with the aid of a hole borer and was allowed to remove the cracked hole so as to view the bottom of the Petri dish. The antibacterial activity of the ligands and complexes were determined at various concentrations: 20ppm, 40ppm, 50ppm and 100ppm. This various concentrations of complexes and ligands solutions were poured gently into the hole bored in the Petri dish and left covered.This was left in the incubator for 24hrs to allow the out growth of the micro organism. The zone inhibitory of the complexes and ligands were determined. 4.RESULTS AND DISCUSSIONS The complexes were synthesized by the reaction of Isoniazid and Trimethoprim with metals in the ratio 1:1:1. The melting point obtained for each of the complexes is higher than the melting point of the ligands ranging from 180-260oC. This shows that there is co-ordination between the ligands and their metal salts, thereby resulting to complexation(8).  The IR spectra of the ligands and the complexes are shown in table 2. In Isoniazid, the band at 1725cm-1  was assigned to √(C=O). The bands at 3325cm-1 was assigned to  √(N-H) which is shifted to higher frequency (3300-3400cm-1). This indicates that coordination of the Isoniazid occurs through the nitrogen of the amine group(10). Isoniazid acts as a tetradentate ligand.      In the infrared spectra of Trimethoprim, the band at 1083cm-1 was assigned to √ (C-O).  The reaction of Isoniazid and Trimethoprim with the metal salts was evidenced by the shifting of the band 3300 cm-1 which is assigned to √ (O-H) to lower frequency in the complexes. From the results obtained in conductivity measurements, it was observed that the complexes are non-electrolyte(9). The molar conductance values were measured in DMSO solution. The antimicrobial activities of the ligands and their complexes were screened on Staphylococcus aures, Pseudomonas aureginosa, Klebsiella pneumonia, Esherichia coli. The results shows that the micro organisms are active over the synthesized metal complexes.   Chemistry and Materials Research                                                                www.iiste.org ISSN 2224- 3224 (Print) ISSN 2225- 0956 (Online) Vol 2, No.3, 2012  3 Proposed structure for metal complexes of TMP and ISO            NNH2NNH2OOONONHH2NM                                             WHERE M is Cd, Fe, Zn, Cu, Mn or Co   5.CONCLUSION The transition metal of Co2+, Cu2+, Zn2+, Cd2+, Fe2+ and Mn2+ complexes of mixed ligands have been synthesized . The complexes undergo various characterization using solubility, electric conductivity, melting point, Thin Layer Chromatography and infrared Spectroscopy. The ligands form a chelating complex. The new alternative drugs obtained, confirmed that they are more effective than their parent ligands. From the results obtained in infrared spectra, it was revealed that the complexes are tetrahedral in nature.  Also, the complexes were subjected into antimicrobial activity against Staphylococcus aures, Pseudomonas aureginosa, Klebsiella pneumonia,  and Esherichia coli .The result of this shows that the complexes were active on the micro organism than the original corresponding ligands. The combined result of the physical and spectroscopic studies confirmed formation of complexes. REFERENCES 1. Von Nussbaum F. (2006). "Medicinal Chemistry of Antibacterial Natural Products – Exodus or Revival?". Angew. Chem. Int. Ed. 45 (31): 5072–5129. 2. Menzies, D; Al Jahdali, H, Al Otaibi, B (2011 Mar). "Recent developments in treatment of latent tuberculosis infection." The Indian journal of medical research 133: 257–66. PMC 3103149. PMID 21441678. 3. Cornwall, J. "Tuberculosis: A Clinical Problem of International Importance." The Lancet (August 30, 1997): 660 Chemistry and Materials Research                                                                www.iiste.org ISSN 2224- 3224 (Print) ISSN 2225- 0956 (Online) Vol 2, No.3, 2012  4 4. Harries A.D; Hargreaves N.J, Kumwenda J., Kwanjana1 J.H, Salaniponi1 F.M (2000). "Trials of anti-tuberculosis treatment in areas of high human immunodeficiency virus prevalence in sub-Saharan Africa". Int J Tuberc Lung Dis 4 (11): 998–1001. 5. Obaleye, J.A, Orjiekwe, C.L.(1993). Synthesis and characterization of Cu(II) and Zn(II) complexes of ascorbic acid. Int. Chem., Vol 4, pg 37-51. 6. Tella A. C (2008) Synthesis, Characterization and Biological studies of Quinoline- Methanol, Sulphone, Pyridine and Sulpha metal Complexes Ph.D Thesis, Unilorin, Nigeria 7. . Matangi S., Pragathi J., Bathini U., and Gyana K. (2012) Synthesis, Characterization and Antimicrobial Activity of Transition Metal Complexes of Schiff Base Ligand Derived from 3-Ethoxy Salicylaldehyde and 2-(2-Aminophenyl) 1-H-benzimidazole E-Journal of Chemistry Volume 9 (2012), Issue 4, Pages 2516-2523. 8. Anthony P., Robert L. and LeNeal E. (1969)Determination of Melting Sequences in DNA and DNA-Protein Complexes by Difference Spectra biophysical journal Vol 9(4) pp473-488. 9.  Lee, P.V. (1982)Wright Morphology and ionic conductivity of complexes of  sodium iodide and sodium thiocyanate with poly(ethylene oxide) ScienceDirect Volume (23)5, Pages 681–689. 10. Anacona, J.R and  Carman C.G (2005). Synthesis and antibacterial activity of cefoxitin metal complexes. Trans .Met. Chem., 30:605-609. Table 1:  ANALYTICAL DATA OF MIXED ISONIAZID-TRIMETHOPRIM METAL DRUG COMPLEXES.  Complexes/ ligand Melting point (oC) Conductivity Ω-1cm2 mol-1 TLC (Rf) Mn[TMP][ISO]Cl2 195-197 5.67 4.90 Fe[TMP][ISO]Cl2 215-218 5.05 3.20 Cu[TMP][ISO]SO4 190-192 5.25 3.80 Co[TMP][ISO]Cl2 260-262 5.06 5.70 Cd[TMP][ISO]SO4 224-226 5.21 4.65 Zn[TMP][ISO]SO4 180-182 5.66 5.97 TRIMETHOPRIM 140-143 - 6.10 ISONIAZID 168-170 - 6.00   Chemistry and Materials Research                                                                www.iiste.org ISSN 2224- 3224 (Print) ISSN 2225- 0956 (Online) Vol 2, No.3, 2012  5 Table 2: INFRARED SPECTRAL OF MIXED ISONIAZID-TRIMETHOPRIM METAL DRUG COMPLEXES.  Complexes/ Ligand √N-H √C=C √C- √C-N √C=O √C-H √M-L Mn[TMP][ISO]Cl2 3466 1640 1279 1233 1738 3075 748 Fe[TMP][ISO]Cl2 3325 1669 1086 1228 1743 3060 737 Cu[TMP][ISO]SO4  3270 33733323533325347345332534663T3433333326.17 1658 1279 1329 1750 3055 751 Co[TMP][ISO]Cl2 3232 33255673187.80 1660 1149 1190 1748 3040 763 Cd[TMP][ISO]SO4 3299 1657 1084 1200 1735 3064 781 776.37 Zn[TMP][ISO]SO4 3346 1669 1085 1186 1745 3060 778 TRIMETHOPRIM 3300 1647 1083 1293 - 3038 - ISONIAZID 3304  1635 -  1062  1725 3032 -          Chemistry and Materials Research                                                                www.iiste.org ISSN 2224- 3224 (Print) ISSN 2225- 0956 (Online) Vol 2, No.3, 2012  6 Table 3: Antimicrobial study of some mixed isoniazid-trimethoprim metal drug complexes: Fe(Iso)(Tm) Cl2    Cd(Iso)(Tm) (SO4 )            Zn(Iso)(Tm) (SO4 )          Cu(Iso)(Tm)(SO4 )    Co(Iso)(Tm)Cl2   Mn(Iso)(Tm)Cl2  Trimethoprim Isoniazid Concentration (ppm) Complexes/ Ligands 60 35 43 0 50 0 0 0 20 Escherichia Coli (mm) (+ve) 15 55 25 24 25 3 1 0 40 22 12 12 38 0 51 4 0 50 25 10 18 0 34 45 0 0 100 18 14 44 43 42 60 0 0 20 Staphylococcus aureus (mm)     (-ve) 23 45 15 9 27 22 5 0 40 35 0 20 10 0 0 3 10 50 16 45 6 65 0 30 3 0 100 33 0 17 8 0 23 0 5 20 Klebsiella      pneumonia (mm)   (-ve) Chemistry and Materials Research                                                                www.iiste.org ISSN 2224- 3224 (Print) ISSN 2225- 0956 (Online) Vol 2, No.3, 2012  7 0 0 5 36 2 20 0 0 40 0 19 8 45 8 45 1 2 50 47 43 30 9 8 60 0 0 100 24 12 6 12 1 24 0 0 20 Pseudomonas aureginosa(mm) (-ve) 10 24 31 18 1 54 0 0 40 53 27 36 46 0 0 0 0 50 18 12 42 39 0 0 0 0 100   This academic article was published by The International Institute for Science, Technology and Education (IISTE).  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Synthesis, Characterization and Antimicrobial Study Of Mixed Isoniazid-Trimethoprim Metal Drug Complexes

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Synthesis, Characterization and Antimicrobial Study Of Mixed Isoniazid-Trimethoprim Metal Drug Complexes

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