SYNTHESIS, SPECTRAL ANALYSIS AND BIOLOGICAL EVALUATION OF SOME NOVEL FLUROBENZOTHIAZOLE INCORPORATED 1, 3, 4 – THIADIAZOLE

SYNTHESIS, SPECTRAL ANALYSIS AND BIOLOGICAL EVALUATION OF SOME NOVEL FLUROBENZOTHIAZOLE INCORPORATED 1, 3, 4 - THIADIAZOLE

M. Sugumaran* and R. Hemachander

Department of Pharmaceutical Chemistry, Adhiparasakthi College of Pharmacy, Melmaruvathur- 603 319, Tamil Nadu, India

ABSTRACT

A new series of flurobenzothiazole incorporated 1, 3, 4 - thiadiazole compounds have been synthesized. The structure of the synthesized compounds was confirmed by UV,  IR, ¹H NMR, Mass spectral analysis and evaluated for their antimicrobial activity against Proteus vulgaris NCTC 4635, Micrococcus leutus NL98, Aspergillus flavus ATCC 46646by disc diffusion method. The compounds SH₈ and SH₁₁ were also evaluated for the anti-inflammatory activity by carrageenan-induced paw oedema method. The synthesized compounds (SH₆ to SH₁₁) showed good antimicrobial activity. However the antimicrobial activity of the synthesized compounds against the tested organisms was found to be less than that of respective standard drugs used at tested dose level. The anti-inflammatory activity confirmed that the test compound SH₁₁ showed superior activity in the inhibition of oedema than SH_8. However, both the test compounds were found to be less active than the standard drug used.

Anti-Inflammatory

INTRODUCTION:Research for the development of new therapeutic agents is becoming the major interest in many academic and industrial research laboratories all over the world with the aim to discover newer, more potent molecules, with higher specificity and reduced toxicity than the existing ones. In addition, the various types of resistant microorganisms that are discovered now-a-days are becoming a great challenge for the scientists. The existing drugs that are available are either very expensive or are prone to microbial resistance. Most of the drugs that are marketed today are modified derivatives of existing pharmacophores. No new pharmacophore having a novel mechanism of action has been identified in the recent past. To overcome these problems, it becomes necessary for further investigating newer molecules to treat infections at affordable costs.

Fluorine incorporated benzothiazole and 1,3,4 - thiadiazole derivatives individually known  to possess a variety of biological properties like anti-microbial ¹, anti-inflammatory ², anti-tumor ³, anti-viral ⁴, anti-tubercular ⁵, anti-convulsant ⁶, anthelmintic ⁷, antioxidants ⁸, anti-diabetic ⁹, diuretic ¹⁰, analgesic ¹¹ anti-depressants ¹², etc., It was felt interesting to bring these two biologically active moieties within a molecular frame work with a view to study their additive effect on biological properties.

With the dual aim of developing potential therapeutic agents and studying their chemistry, we undertook the synthesis and biological evaluation of flurobenzothiazole incorporated with 1, 3, 4 - thiadiazole compounds for antimicrobial and anti-inflammatory activity.

MATERIALS AND METHODS: Melting point was determined in open capillary tubes on melting point apparatus (Sunbim, Guna enterprises) and are uncorrected. The ¹H NMR spectra were recorded on Bruker-NMR 400 mHZ using DMSO – d₆ as solvent. The Mass spectra were recorded on JEOL GC mate mass spectrometer. The IR spectra recorded on Perkin-Elmer FT-IR spectrophotometer using KBr pellets. The UV spectra were recorded by using Double beam SHIMADZU 1700 UV spectrometer. The purity of the compounds was checked by TLC on pre-coated silica gel G plates by using ethyl acetate and chloroform (2:1) as a mobile phase and visualized in iodine vapour. Analytical grade solvents and reagents were used for throughout the experiment. Carrageenan was obtained from Sigma Chemical Co., USA. Plethysmometer (Inco Co., Ambala, India) was used for anti-inflammatory activity.

Experimental Animals: The animals (Wistar albino rats of either gender) were obtained from the Kings Institute of Preventive Medicine, Guindy, Chennai. Animals were housed in animal house in Adhiparasakthi College of Pharmacy in standard environmental conditions of temperature (25±20º C), humidity (55±10%) and light (12:12 hour light: dark cycle). The animals were fasted prior to dosing but water was given ad-libitum. The anti-inflammatory activity was carried out as per CPCSEA (Committee for the Purpose of Control and Supervision of Experiments on Animals) guidelines after obtaining the approval from the Institutional Animal Ethical Committee.

Synthesis of 2-Amino-6-Fluoro-7-Chloro-(1,3)-Benzothiazole ¹³: To the glacial acetic acid (20 ml) which was cooled below room temperature, added 8 gm (0.08 mole) of potassium thiocyanate and 1.44 gm (0.01 mole) of 4-flouro-3-chloro aniline. The mixture was placed in cold mixture of ice and salt and mechanically stirred. 1.6 ml of bromine in 6 ml of glacial acetic acid was added from a dropping funnel at such a rate that temperature never rose beyond 0º C. After all the bromine was added (105 minutes) the solution was stirred for 2 hours in ice cold condition and at room temperature for 10 hours. It was then allowed to stand overnight, during the period orange precipitate settled at the bottom, water (6 ml) was added quickly in it and slurry was heated to 85º C on a steam bath and filtered while hot.

The orange residue was placed in a reaction flask and treated with 10 ml of glacial acetic acid heated again to 85º C on a steam bath and filtered hot. The combined filtrate was cooled and neutralized with concentrated ammonia solution up to pH-6. The precipitate was collected and recrystallized from benzene and ethanol (1:1) after treatment with charcoal gave yellow crystal of 2-amino-6-fluoro-7-chloro benzothiazole.

Synthesis of 6-Fluoro-7-Chloro-(1,3)-Benzothiazole-2-Thiosemicarbazide ¹⁴: 20.1 gm (0.1 mole) of 2-amino-6-fluoro-7-chloro benzothiazole was dissolved in 50 ml of ethanol (95%) and 8 ml of ammonia solution was added to it. The reaction mixture was cooled below 30º C and 8 ml of carbon disulphide was added slowly within 15 minutes with continuous shaking. After complete addition of disulphide the solution was cooled to stand for 1 hour. Then 9.4 gm of sodium chloro acetate (0.1 mole) was added to it. The reaction was exothermic. To it 20 ml of 50% hydrazine hydrate was added. The mixture was warmed gently, filtered and boiled to half of its volume and kept overnight. Next day, the product thiosemicarbazide was filtered and recrystalised from ethanol.

Synthesis of 7-Chloro-6-Fluoro-N- (5-Aryl -1, 3, 4-Thiadizol-2-yl) 1-3-Benzothiazol-2-Amine ¹⁵: A mixture of 6- fluro- 7- chloro-(1, 3)- benzothiazole- 2- thiosemi carbazide (0.01 mole), an aromatic acid (0.1 mole) and phosphrous oxychloride (25 ml) was refluxed for 18 – 24 hours. After cooling to the room temperature the reaction mixture was slowly poured to crushed ice and kept overnight. The solid separates out was filtered, dried and recrystallized from methanol.

Synthesis of 7-Aryl-6–Fluoro-N- (5- Aryl -1, 3, 4 -Thiadizol-2-yl) 1-3-Benzothiazol-2-Amine ¹⁶: 0.0025 mole of 7-chloro-6-fluoro-N-(5-aryl-1, 3, 4-thiadizol-2-yl)1-3-benzothiazol-2amine was treated with equimolar quantity (0.0025 mole) of various substituted aromatic amines and refluxed for 2 hours in the presence of DMF. The mixture was then cooled and poured in the crushed ice. The solid separated was filtered, dried and recrystallized from benzene and absolute alcohol (1:1).

SYNTHETIC SCHEME

  TABLE 1:DIFFERENT SUBSTITUTIONS IN COMPOUNDS SH₆ – SH₁₁

After solidification, petriplates was inoculated with bacterial organisms in sterile nutrient agar medium at 45^oC, and fungal organism in sterile Sabouraud’s dextrose agar medium at 45^oC in aseptic condition. Sterile Whatmann filter paper discs (previously sterilized in U.V. lamp) were impregnated with synthesized compounds at a concentration of 25 and 100 mg/disc was in the organism-impregnated petri plates under sterile condition.Evaluation of Antimicrobial Activity ¹⁷: The antimicrobial screening of the synthesized compounds (SH₆ - SH₁₁) was carried out by determining the zone of inhibition using disc diffusion method. The synthesized compounds was dissolved in DMSO and sterilized by filtering through 0.45 μm millipore filter. Final inoculums of 100 µl suspension containing 10⁸ CFU/ ml of each bacterium and fungus used.  Nutrient agar (anti-bacterial activity) and sabouraud’s dextrose agar medium (anti-fungal activity) was prepared and sterilized by an autoclave (121^oC and 15 lbs for 20 min) and transferred to previously sterilized petridishes (9 cm in diameter).

The plates were left for 30 minutes to allow the diffusion of compounds at room temperature. Antibiotic discs of ciprofloxacin (100 µg/disc) and ketaconazole (100 µg/disc) was used as positive control, while DMSO used as negative control. Then the plates were incubated for 24 hours at 37±1^oC for antibacterial activity and 48 hours at 37±1^oC for anti-fungal activity.

The zone of inhibition was calculated by measuring the minimum dimension of the zone of no microbial growth around the disc.

Evaluation of Anti-inflammatory activity ¹⁸: The anti-inflammatory activity of the synthesized derivative SH₈ and SH₁₁ was evaluated by carrageenan-induced paw oedema method. Wistar albino rats of either sex (150-200 g) were randomly selected and the animals were divided into control, standard and test groups, each consisting of three animals.

The first group was treated with 1% polyethylene glycol (1%) suspension which served as control, second group was administered with a dose of 20 mg/kg suspension of diclofenac sodium intra-peritoneally which served as standard and other groups was treated with 50 mg/kg of suspension of test compounds in polyethylene glycol. After 30 minutes, the rats were injected with 0.1 ml of carrageenan (1% w/v) to the sub plantar region of left paw of the rats.

The volume of paw was measured using mercury displacement technique with the help of plethysmograph in control and animals treated with standard and test compounds at 0, 1, 2 and 3 hours after injection of carrageenan.

The percentage inhibition of oedema was calculated by using formula,

12Percentage Reduction=Vo-VtVoX 100" wrapcoords="13874 514 -83 6171 -83 11829 10135 16971 15535 16971 16034 19029 16117 19029 16782 19029 16782 16971 18194 16971 21600 11314 21600 7200 21102 5657 17945 514 13874 514" o:allowoverlap="f">

Where, V_t = mean paw volume of the test drug, Vo = mean paw volume of the control.

 TABLE 2: IN-VITRO ANTI-MICROBIAL ACTIVITY OF SYNTHESIZED COMPOUNDS BY DISC DIFFUSION METHOD

TABLE 3:  ANTI-INFLAMMATORY ACTIVITY OF COMPOUNDS SH₈ and SH₁₁ BY CARRAGEENAN INDUCED PAW OEDEMA METHOD

SEM = Standard Error Mean, n = 3 in each group.*p< 0.05, **p < 0.01 and ***p<0.001 when compared to control (One-way ANOVA followed by Bonferroni test); Figures in the parenthesis indicate % inhibition of paw oedema

RESULTS AND DISCUSSION: The structure of the synthesized compounds was established by spectral (UV, IR, ¹H NMR and Mass) analysis data and were as follows:

Compound SH₁: Yield = 47.5%, mp = 212º C, R_f = 0.57, λ_max (MeOH) 232.50, IR (KBr)   cm^-1 3228 (N-H stretching), 3288 (Ar C-H stretching), 1637(C=N stretching), 1543 (Ar C=C ring stretching), 1346 (Ar C=N stretching), 1193 (C-F stretching), 617 (C-S stretching). ¹H NMR (DMSO – d₆) δ: 8.09 (1H, d, Ar-H of benzothiazole), 7.20 (1H, d, Ar-H of benzothiazole), 4.0 (2H, s, NH₂).  EI-MS m/z 202.63 (Calculated for C₇H₄ClFN₂S: 202.63).

Compound SH₂: Yield = 51.63%, mp = 241º C, R_f = 0.69, λ_max (MeOH) 247.28, IR (KBr) cm^-1 3473 (N-H stretching ), 3077 (Ar C-H stretching ), 1645 (C=N stretching ), 1452 (Ar C=C ring stretching), 1337 (Ar C-N stretching), 1216 (Ali C-F stretching), 715 (C-Cl stretching), 686 (C-S stretching). ¹H NMR (DMSO – d₆) δ: 8.09 (1H, d, Ar-H of benzothiazole), 7.20 (1H, d, Ar-H of benzothiazole), 4.0 (1H, s, NH), 2.0 (3H, s, NH & NH₂). EI-MS m/z 352.79 (Calculated for C₈H₆ClFN₄S₂: 276.74).

 Compound SH₃: Yield = 36.5%, mp = 224º C, Rf  = 0.62, λ_max (MeOH) 280.50,  IR (KBr) cm^-1 3392 (N-H stretching), 3032 (Ar C-H stretching), 1653 (C=N stretching), 1477 (Ar C=C ring stretching), 1337 (Ar C=N stretching), 1029 (C-F stretching), 844 (C-Cl stretching), 714 (Ar C-H stretching), 642 (C-S stretching). ¹H NMR (DMSO – d₆) δ: 8.09 (1H, d, Ar-H of benzothiazole), 7.4 (1H, d, CH of furan), 7.20 (1H, d, Ar-H of benzothiazole), 6.3 (2H, d, CH of furan), 4.0 (1H, s, NH). EI-MS m/z 352.79 (Calculated for C₁₃H₆ClFN₄OS₂: 352.79).

Compound SH₄: Yield = 42.19%, mp = 192º C, R_f = 0.57, λ_max (MeOH) 282.45, IR (KBr) cm^-1 3292 (N-H stretching), 3090 (Ar C-H stretching), 3022 (Ar CH stretching), 1632 (C=N stretching), 1543 (C=C, C=N ring stretching), 1454 (Ar C=C stretching), 1341 (Ar C-Nsec vibrations), 1032 (C-F stretching), 844 (C-Cl stretching), 716 (Ar C-H bending), 645 (C-S stretching). ¹H NMR (DMSO – d₆) δ: 8.85 (1H, d, CH of pyridine), 8.81 (1H, s, CH of pyridine), 8.09 (1H, d, Ar-H of benzothiazole), 7.97 (1H, d, CH of pyridine), 7.44 (1H, d, Ar-H of benzothiazole), 7.20 (1H, d, Ar-H of benzothiazole), 4.0 (2H, s, NH). EI-MS m/z 377.84 (Calculated for C₁₄H₇ClFN₅S₂: 377.84).

Compound SH₅: Yield = 39.42%, mp = 227º C, R_f = 0.53, λ_max (MeOH) 284.60, IR (KBr) cm^-1 3388 (N-H stretching), 3078 (Ar C-H stretching), 1634 (C=N stretching), 1546 (N-H bending), 1458 (Ar C=C stretching), 1116 (C-F stretching), 809 (C-Cl stretching), 685 (C-S stretching). ¹H NMR (DMSO – d₆) δ: 8.09 (1H, d, Ar-H of benzothiazole), 7.23 (1H, d, CH of aromatic ring), 7.20 (1H, d, Ar-H of benzothiazole), 6.97 (1H, t, CH of aromatic ring), 6.68 (1H, t, CH of aromatic ring), 6.52 (1H, d, Ar-H), 4.0 (3H, s, NH₂). EI-MS m/z 377.84 (Calculated for C₁₅H₉ClFN₅S₂: 377.84).

Compound SH₆: Yield = 54.79%, mp = 210º C, R_f = 0.81, λ_max (MeOH) 297.50, IR (KBr) cm^-1. 3477 (N-H asymmetrical stretching), 2925(Aromatic C-H stretching), 1741 (C-H out of plane bending), 1569 (C=N stretching), 1507 (NO₂ asymmetrical stretching), 1345 (C-N stretching).  ¹H NMR (DMSO – d₆) δ: 8.20 (1H, d, Ar – H of aniline group), 7.87 (1H, d, CH of furan),  7.68 (1H, t, Ar – H of aniline group), 7.60 (1H, t, Ar – H of aniline group), 7.54 (1H, d, Ar – H of benzothiazole), 7.31 (1H, d, Ar – H  of benzothiazole), 7.17 (1H, d, Ar – H of aniline group), 6.86 (1H, d, CH of furan) 6.68 (1H, t, CH of Furan), 4.39 (2H, s, NH). EI-MS m/z 454.45 (Calculated for C₁₉H₁₁FN₆O₃S₂: 454.45).

Compound SH₇: Yield = 43.53%, mp = 212º C, R_f = 0.69, λ_max (MeOH) 302.50, IR (KBr) cm^-1 3361 (N-H stretching), 2923 (Ar C-H stretching), 1505 (C=N stretching), 1109 (C-F stretching), 753 (C-S Stretching). ¹H NMR (DMSO – d₆) δ: 8.03 2H, d, Ar – H of aniline group, 7.87 (1H, d, CH of furan), 7.52 (1H, d, Ar – H of benzothiazole), 7.30 (1H, d,  Ar – H  of benzothiazole), 7.26 (2H, m, Ar – H  of aniline group), 6.86 (1H, d, CH of furan), 6.68 (1H, t, CH of furan), 4.39 (2H, s, NH). EI-MS m/z 454.45 (Calculated for C₁₉H₁₁FN₆O₃S₂: 454.45).

Compound SH₈: Yield = 54.49%, mp = 216º C, R_f = 0.84, λ_max (MeOH) 307.00, IR (KBr) cm^-1 3348 (N-H stretching), 2841 (Ar C-H stretching), 1628 (Ar C-H stretching), 1507 (C=N stretching), 1283 (Ar C-N stretching), 1101 (C-F stretching), 742 (C-S stretching). ¹H NMR (DMSO – d₆) δ: 9.09 (1H, s, CH of pyridine), 8.70 (1H, d, CH of pyridine), 8.20 (1H, d, Ar – H  of aniline group), 8.04 (1H, d, CH of pyridine), 7.68 (1H, t, Ar – H  of aniline group), 7.60 (1H, t, Ar – H  of aniline group) 7.55 (1H, d, Ar – H of benzothiazole), 7.47 (1H, t, CH of pyridine), 7.32 (1H, d, Ar – H  of benzothiazole), 7.16 (1H, d, Ar – H  of aniline group), 6.33 (2H, s, NH). EI-MS m/z 465.48 (Calculated for C₂₀H₁₂FN₇O₂S₂: 465.48).

Compound SH₉: Yield = 47.06%, mp = 217º C, R_f = 0.81, λ_max (MeOH) 301.75, IR (KBr) cm^-1 3345 (N-H stretching), 2857 (Ar C-H stretching), 1515 (C=N stretching), 1330 (Ar C-H stretching), 1273 (Ar C-N stretching), 1108 (C-F stretching), 970 (N-N stretching), 881 (C-H stretching), 742 (C-S stretching). ¹H NMR (DMSO – d₆) δ: 9.09 (1H, s, Ar – CH  of pyridine),  8.70 (1H, d, Ar – CH  of pyridine),  8.05 (1H, d, Ar – H  of pyridine),  8.04 (2H, m, Ar – H  of aniline group),  7.47  (1H, t, Ar – CH  of pyridine),  7.38 (1H, d, Ar – H of benzothiazole), 7.34 (2H, d, Ar – H of aniline group), 7.23 (1H, d, Ar – CH  of benzothiazole), 6.62 (1H, s, NH) EI-MS m/z 465.48 (Calculated for C₂₀H₁₂FN₇O₂S₂: 465.48).

Compound SH₁₀: Yield = 49.54%, mp = 220º C, R_f = 0.58, λ_max (MeOH) 298.45, IR (KBr) cm^-1 3351(N-H stretching), 2925 (Ar C-H stretching), 1506 (C=N stretching), 1346 (Ar C-N ring stretching), 1101 (Ar C-F stretching), 1016 (N-N stretching), 743 (C-S stretching), 694 (C-H out of bending). ¹H NMR (DMSO – d₆) δ: 8.20 (1H, d,  of aniline group), 7.68 (1H, t, Ar – H  of aniline group), 7.60 (1H, t, Ar – H  of aniline group) 7.46 (1H, d, Ar – H  of aniline group), 7.43 (1H, d,  Ar – H), 7.29 (1H, d, Ar – H  of benzothiazole), 7.23 (1H, t,   Ar – H), 7.12 (1H, d, Ar – H  of benzothiazole), 6.96 (1H, t,   Ar – H), 6.77 (1H, d,   Ar – H), 6.35 (2H, s, NH₂), 4.47 (2H, s, NH). EI-MS m/z 479.51 (Calculated for C₂₁H₁₄FN₇O₂S₂: 479.51).

Compound SH₁₁: Yield = 44.04%, mp = 217º C, R_f = 0.78, λ_max (MeOH) 301.40, IR (KBr) cm^-1 3482 (N-H stretching), 2919 (Ar C-H stretching), 1504 (C=N stretching), 1285 (Ar C-N stretching), 1103 (C-F stretching), 1015 (Ar N-N stretching), 842 (C-H out of plane bending), 751 (C-S stretching). ¹H NMR (DMSO – d₆) δ: 8.03 (2H, d, Ar – H of aniline group), 7.51 (1H, d, Ar – H of benzothiazole), 7.41 (1H, d, Ar – H), 7.29 (1H, d, Ar – H  of benzothiazole),  7.27 (2H, m, Ar – H of aniline group),  7.23 (1H, t, Ar – H), 6.96 (1H, t, Ar – H), 6.74 (1H, d, Ar – H), 4.55 (2H, s, NH₂)_, 4.44 (2H, s, NH). EI-MS m/z 479.51 (Calculated for C₂₁H₁₄FN₇O₂S₂: 479.51).

In SH₁, the NH band at 3463-3114 cm^-1 and NH proton signal δ 4.0 of 2-amino benzothiazole in IR and ¹H NMR spectrum respectively confirmed the formation of benzothiazole nucleus. In SH₂, three protons singlet at δ 2.0 and one proton singlet at δ 4.0 confirmed the formation of thiosemicarbazide group.

In the compounds SH₃, SH₄, SH₅ C = N band (1700 – 1430 cm^-1) and C – S band (800 - 600 cm^-1) of IR spectrum conforms the formation of 1,3,4 thiadiazole nucleus. In SH₃, two doublets at δ 6.3 and one doublet proton at δ 7.4 indicates the formation of furan ring. In SH₄, three doublet protons at δ 8.85, δ 7.97, δ 7.44 and one singlet proton at δ 8.81 confirmed the formation of an aromatic nucleus. In the case of SH_5, two triplets at δ 6.97, δ 6.68 and two doublets at δ 7.23, δ 6.52 indicates the formation of an aromatic nucleus.

The presence of nitro group in SH₆-SH₁₁ was ascertained from stretching on bands at (1584 -1510 cm^-1) and (1365-1335 cm^-1) corresponding to asymmetric and symmetric O=N=O stretching respectively. The C – Cl stretching band which appeared at SH₁-SH₅ at (809 – 683cm^-1) was disappeared in SH₆-SH₁₁. Instead, C – N stretching band appeared at (1346.02-1255.90cm^-1) in SH₆-SH₁₁ indicated the attachment of ortho nitro aniline (or) and para nitro aniline group.

In compounds SH₆, SH₈, SH₁₀, two doublet for 2 protons (δ 8.20, δ 7.17- δ7.46) and two triplet protons at  (δ 7.68, δ 7.60) confirmed the presence of nitro group at ortho position in the aromatic ring. In compounds  SH₇, SH₉ & SH_11, two doublet protons at (δ 7.26- δ 7.34, δ 8.03 - δ 8.04) confirmed the presence of nitro group at para position in aromatic ring.

In the mass spectrum of the synthesized compounds produced (M⁺) Molecularion peaks at  202.63, 276.74, 351.12, 362.21, 376.16, 454.45, 454.45, 463.48, 463.48, 479.51 and 479.51 values for SH₁, SH₂,SH₃, SH₄, SH₅,SH₆, SH₇, SH₈, SH₉, SH₁₀, and SH₁₁ respectively corresponds to their molecular formulas.

All the compounds showed very good anti-bacterial and anti-fungal activity even at less concentration. From the data, it is evident that the compound SH₆ and SH₈ was the most potent candidate against Micrococcus leutus and Proteus vulgaris in the anti-bacterial studies and compound SH₁₁ was the much potent candidate against Aspergillus flavus in the anti-fungal studies. Since only fewer species had been used in this study, it was warranted to screen these compounds with various species of resistant strains.

The anti-inflammatory activity confirmed that the test compound SH₁₁ showed superior activity in the inhibition of oedema than SH_8. However, both the test compounds were found to have less activity than the standard drug diclofenac sodium.

ACKNOWLEDGEMENT

The authors wish to express their sincere gratitude to our principal Prof. Dr. T. Vetrichelvan, Adhiparasakthi College of Pharmacy, Melmaruvathur, for providing necessary facilities to carry out this research work. They also thankful to Dr. R. Murugesan, Scientific Officer, SAIF,  IIT, Chennai for spectral analysis.

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