Synthesis, characterization and anti-inflammatory activity some 1-(4-substituted)-2-(-4-(piperazine-1-yl) bis-thiazole-5-yl) 2-methyl-4-nitro-1h-imidazole-1-yl) ethanone

 

Aejaz Ahmed¹*, Khurshid I. Molvi², Gulam Javed Khan³

¹Department of Pharmaceutical Chemistry, Ali-Allana College of Pharmacy, Akkalkuwa, 425451, Nandurbar, Maharashtra, India

²Department of Clinical Pharmacy, Ibne-Sina National Medical College Jeddah, Saudi Arabia

³Department of Pharmacology, Ali-Allana College of Pharmacy, Akkalkuwa, 425451, Nandurbar,Maharashtra, India

*Corresponding Author E-mail: aejazboraji@gmail.com

Novel set of 1-(4-substituted)-2-(-4-(piperazine-1-yl) bis-thiazole-5-yl) 2-Methyl-4-Nitro-1H-imidazole-1-yl) ethanon compounds were synthesized. The adduct of piperazine were synthesized by nucleophilic addition of benzoyl isothiocyanate / substituted benzoyl isothiocyanate in bi-molar quantity at reflux temperature. The target compounds (AR-15a to AR-55a) were synthesized as 1-chloro-3-(2-methyl-4-nitro1H-imidazole-1-yl) propane-2-on (a) was added in bi-imolar quantity to a solution of adduct (substituted-bis-piperazinyl-4-thioyl) benzamide/ chlorobenzamide in acetonitrile. The synthesized compounds were characterized by physicochemical parameters and IR, ¹H NMR, Mass and elemental spectral analysis. The synthesized compounds were evaluated for their in-vitro anti-inflammatory activity using HRBC membrane stabilization method and in-vivo anti-inflammatory activity by carrageenin-induced rat paw oedema model at 20 mg/kg body weight using diclofenac and ibuprofen as standard drugs. Compounds AR-45a and AR-55a showed maximum in-vitro anti-inflammatory activity membrane stabilization at 65% and 68% protection at 200 m/mL. However moderate to poor protection was observed by in-vivo anti-inflammatory study in carragenane induced rat hind paw edema.

 

 

 

1. INTRODUCTION:

The piperazine is a wide-ranging class of chemical compounds, many with important pharmacological property, which contain a center piperazine functional group. Most of these agents can be classified as phenyl piperazine or benzyl piperazine, diphenylmethyl piperazine (benzhydryl piperazine), pyridinyl piperazine, pyrimidinyl piperazine or tricyclics, (With the piperazine ring attached to the heterocyclic moiety via a side chain. The developments of piperazine as an anthelmintic agent for the treatment of nematode infection have been well documented. A wide variety of piperazine derivatives and salts as original discovery of anthelmintic agent was reported. Microbial infection is associated with pain and inflammation. In general, chemotherapeutic, analgesic and anti-inflammatory agents are prescribed simultaneously for such condition. However, very few of drugs possess these activities in a single molecule. Multi-drug treatment of inflammatory conditions associated with microbial infections poses a inimitable problem especially for patients with impaired hepatic or renal functions. Thus from the pharmacoeconomic and patient compliance points of view, the monotherapy with a drug having both anti-inflammatory and antimicrobial activities is needed. Thiazoles have recent conventional attention of their diverse pharmacological properties; these include anti-inflammatory, anti-ulcer, anthelmintics, virucidal, anesthetics, antibacterial, hypoglycemic, and anticonvulsant activities. Imidazole is one of the important heterocyclic compounds in the world of medicinal chemistry and essential component of several natural products including purine, histidine and nuclic acid. However substitution of nitro group in the imidazole or the nitroimidazole enhances the solubility and bioavailability parameter of proposed poorly soluble lead molecule. The approach of synthesis have been directed towards the construction of thiazole by the reaction of aryl isothiocyanate with active reagent followed by cyclization through reaction with nitroimidazole as α-halocarbonyl compounds while using benzoyl isothiocyanate as a starting material to afford originators for heterocyclic and fused heterocyclic ring system are significant,[1- 8].

 

2. MATERIAL AND METHODS:

All reagents and solvents were used as obtained from the supplier or recrystallized / redistilled as necessary. Drug sample of diclofenac sodium (purity > 98%), Ibuprofen (purity > 99%) were obtained as a gift from Glenmark pvt. Ltd. Mumbai, India. Carrageenan (λ) (purity > 97%) was procured from Sigma Aldrich, USA. Benzoyl chloride/ substituted benzoyl chlorides with higher purity were obtained as gift sample form Cambay Organics pvt Ltd Khambat Gujrat, India. Piperazine (purity > 96%), ammonium thiocyanate (purity > 95%), Alsevior reagent and other chemical with high grade purity were purchased from Sahyadri scientific suppliers Mumbai, India. Thin layer chromatography was performed on microscopic slides coated with silica gel G and toluene: acetonitrile as a mobile phase. The spots were visualized by normal TLC and exposure to iodine vapour. Melting points were recorded on open capillary melting point apparatus and were uncorrected. IR spectra were recorded in KBr on Shimadzu Fourier Transform Infrared 8400S spectrometer, Kyoto Japan. Mass spectra were recorded on Electron impact (EI) on a Jeol JMS-D-300 spectrometer with the ionization potential of 70eV. Nuclear Magnetic Resonance spectra (1H NMR) were recorded in DMSO-d6 on Bruker advance at 400 MHz using Tetramethyl silane (TMS) as internal standard and the chemical shift (δ) were reported in parts per million (ppm). Elemental analysis data were determined using a Carlo-Erba 1108 instrument or Elementar’s Vario EL III micro-analyzer.

 

2.1 General method for Synthesis of target compounds (AR-15a to AR-55a)

As shown in Scheme-I, isothiocyanate were obtained by stirring ammonium thiocyanate (0.1379 mol) in 100 mL acetone at room temperature with benzoyl chloride / substituted benzoyl chloride (0.1263 mol) for 15-25 minutes followed by refluxing the reaction mixture for 15 min. Substituted bis-(piperazinyl-4-thioyl) benzamide / chlorobenzamide (AR-15 to AR 55) were synthesized by nucleophilic addition of benzoyl isothiocyanate /substituted benzoyl isothiocyanate and in bi-molar quantity at reflux temperature as discussed above. The target compounds (AR-15a to AR-55a) were synthesized as per procedure reported by Reji et al [4] and Giri et al [5]. In brief the 1-chloro-3-(2-methyl-4-nitro1H-imidazole-1-yl) propane-2-on (a) was added in equimolar quantity to a solution of adduct (substituted-bis-piperazinyl-4-thioyl) benzamide/ chlorobenzamide in 12 mL acetonitrile. The reaction mixture was heated on a water bath at 100 ⁰C for 4-5 hr. The reaction mixture was cool and filtered. To the filtrate small amount of sodium bicarbonate was added, [9-12].  White to yellow precipitates thus obtained were filtered, wash with water, air dried and purified by recrystallization corresponding to the (AR-15a to AR-55) and was characterized as per the analytical data.

 

 

Scheme-I: 1-(4-substituted)-Bis-2-piperazine-1-yl) thiazole-5-yl) 2-methyl-4-nitro-1H-imidazole-1-yl) ethanone. Reagents and conditions: a) NH₄SCN, acetone, reflux 15-25 min; b) reflux for 20 min, pour reaction mixture to crushed ice; c) acetonitrile, stir at 100°C for 4-5 h, pour to crush.

 

Table 1: Physicochemical properties of synthesized derivatives (AR-15a-AR-55a)

 

 

* Melting point were determined on melting point apparatus using open glass capillary tube and represent the uncorrected values. ** All the reaction were monitored using thin layer chromatography (TLC) using glass plate coated with silica gel G. TLC Plates were developed in iodine and Toluene : Acetonitrile (7:3) were taken as mobile phase , unless mention otherwise.

AR-15a: Bis-1-(4-(phenyl)-2-(piperazin-1-yl) thiazol-5-yl)-2-(2-methyl-4-nitro-1H-imidazol-1-yl) ethanone

IR (KBr Cm¹): 3150 (aromatic stretching), 2852 (-CH3 stretching), 2950 (-C-H stretching) 1635 (C=O stretching), 1576-1553 (C=C stretching, aromatic), 1491-1433 (NO₂ ‑ stretching), 1329-1294 (N-C of aromatic), 830 (-C=C out of plane for mono substituted benzene), 1175-1138 (C-N-C stretching of amine)

¹H NMR: (400 MHz, DMSO) δ (ppm): 2.16 (s, 3H proton at 2^nd position of nitroimidazole –CH₃) 3.33 (m, 2H, piperazine N-CH₂) 4.78 (s, 2H, –CH₂-C=O) 7.41-7.64 (m, 4H, aromatic proton at 4^th position), 8.0 (s, 1H, aromatic proton at 5^th position of nitroimidazole) MASS:  m/z., 738, 739 (M+1) Elemental Analysis for C₃₄H₃₀N₁₀O₆S₂: Calculated: C, 55.27; H, 4.09; N, 18.96; Found:  C, 56.27; H, 4.09; N, 17.36;            

 

AR-25a: Bis-1-(4-(4-cholro-phenyl)-2-(piperazin-1-yl) thiazol-5-yl)-2-(2-methyl-4-nitro-1H-imidazol-1-yl) ethanone IR (KBr Cm¹): 3138 (aromatic stretching), 2852 (-CH3 stretching), 2926 (-C-H stretching) 1734 (C=O stretching), 1545-1448 (C=C stretching, aromatic), 1390 (NO₂ ‑stretching), 1332-1253 (N-C of aromatic), 896-840 (-C=C out of plane for mono substituted benzene), 1159-1012 (C-N stretching of amine), 752 (-C-Cl Bending)

¹H NMR: (400 MHz, DMSO) δ (ppm): 2.33 (s, 3H proton at 2^nd position of nitroimidazole –CH₃) 3.34-3.65 (m, 2H, piperazine N-CH₂) 4.89 (s, 2H, –CH₂-C=O) 7.084 (m, 4H, aromatic proton at 4^th position), 8.20 (s, 1H, aromatic proton at 5^th position of nitroimidazole) MASS:  m/z., 806, 807 (M+1) Elemental Analysis for C₃₄H₂₈C_l2N₁₀O₆S₂: Calculated:  C, 50.56; H, 3.49; N, 17.34; Found: C, 50.61; H, 3.49; N, 16.41

 

AR-35a: Bis-1-(4-(2-cholro-phenyl)-2-(piperazin-1-yl) thiazol-5-yl)-2-(2-methyl-4-nitro-1H-imidazol-1-yl) ethanone. IR (KBr Cm¹): 3192 (aromatic amine stretching), 2850 (-CH3 stretching), 2950 (-C-H stretching) 1669 (C=O stretching), 1528 (C=C stretching, aromatic), 1446-1464 (NO₂ ‑ stretching), 1352-1280 (N-C of aromatic), 798 (-C=C out of plane for mono substituted benzene), 1145-1017 (C-N stretching of amine), 739-694 (-C-Cl Bending ¹H NMR: (400 MHz, DMSO) δ (ppm): 2.25 (s, 3H proton at 2^nd position of nitroimidazole –CH₃) 3.34-3.63 (m, 2H, piperazine N-CH₂) 4.87 (s, 2H, –CH₂-C=O) 6.99 (m, 4H, aromatic proton at 4^th position), 7.94 (s, 1H, aromatic proton at 5^th position of nitroimidazole) MASS:  m/z., 806, 807 (M+1) Elemental Analysis for C₃₄H₂₈C_l2N₁₀O₆S₂: Calculated: C, 50.56; H, 3.49; N, 17.34; Found: C, 50.26; H, 3.29; N, 17.34;  UV Visible l Max: 281 nm

 

AR-45a: Bis-1-(4-(3-cholro-phenyl)-2-(piperazin-1-yl) thiazol-5-yl)-2-(2-methyl-4-nitro-1H-imidazol-1-yl) ethanone IR (KBr Cm¹): 3182 (aromatic stretching), 2850 (-CH3 stretching), 2950 (-C-H stretching) 1667 (C=O stretching), 1527 (C=C stretching, aromatic), 1476-1456 (NO₂ ‑ stretching), 1352 (N-C of aromatic), 780 (-C=C out of plane for mono substituted benzene), 1145-1105 (C-N stretching of amine), 750 (-C-Cl Bending) ¹H NMR: (400 MHz, DMSO) δ (ppm): 2.10 (s, 3H proton at 2^nd position of nitroimidazole –CH₃) 3.33 (m, 2H, piperazine N-CH₂) 4.78 (s, 2H, –CH₂-C=O) 7.40-7.62 (m, 4H, aromatic proton at 4^th position), 8.0 (s, 1H, aromatic proton at 5^th position of nitroimidazole) MASS:  m/z., 806, 807 (M+1) Elemental Analysis for C₃₄H₂₈C_l2N₁₀O₆S₂: Calculated: C, 50.56; H, 3.49; N, 17.34; Found: C, 50.56; H, 3.49; N, 17.34;UV Visible l Max: 306

 

AR-55a: Bis-1-(4-furon 2-yl)-2-(piperazin-1-yl) thiazol-5-yl)-2-(2-methyl-4-nitro-1H-imidazol-1-yl) ethanone IR (KBr Cm¹): 3138 (aromatic stretching), 2877 (-CH₃ stretching), 2982-2935 (-C-H stretching) 1737 (C=O stretching), 1545-1508 (C=C stretching, aromatic), 1427 (NO₂‑ stretching), 1392-1294 (N-C of aromatic), 995-839 (-C=C out of plane for furan), 1184-1128 (C-N-C stretching of amine), 1246 (C-O-C stretching of furoyl) ¹H NMR: (400 MHz, DMSO) δ (ppm): 1.24-2.0 (s, 3H proton at 2^nd position of nitroimidazole –CH₃) 3.41-3.77 (m, 2H, piperazine N-CH₂) 4.78 (s, 2H, –CH₂-C=O) 7.50-7.84 (m, 4H, aromatic proton of furoyl at 4^th position), 8.07 (s, 1H, aromatic proton at 5^th position of nitroimidazole) MASS:  m/z., 718, 719 (M+1) Elemental Analysis for C₃₀H₂₆N₁₀O₈S₂: Calculated: C, 50.13; H, 3.65; N, 19.49; Found: C, 50.13; H, 3.52; N, 18.79; UV Visible l Max: 278.40

 

3. BIOLOGICAL EVALUATION:.

3.1: In-vitro anti-inflammatory evaluation of 1-(4-substituted)-2-(-4-piperazine-1-yl) thiazole-5-yl) 2-methyl-4-nitro-1H-imidazole-1-yl) ethanone by HRBC membrane stabilization Method.

The Human red blood cells (HRBC) membrane stabilization has been used as method to study the anti-inflammatory activity. HRBC membrane analogous to lysosomal membrane apparatus, the prevention of hypotonicity induced HRBC membrane lysis was taken as a measure of anti-inflammatory activity of drugs.  Blood was collected from healthy human volunteer. The collected blood was mixed with equal volume of sterilized Alsever solution (2% dextrose, 0.8% sodium citrate, 0.5% citric acid and 0.42% sodium chloride in water). The blood sample was centrifuged at 3000 rpm and packed cell were washed with isosaline (0.85%, pH 7.2) and a 10% (v/v) suspension was made with isosaline. The assay mixture contained the drug 1 ml of phosphate buffer (0.15M, pH 7.4), 2ml of hyposaline (0.36%) and 0.5 ml of HRBC suspension. Diclofenac sodium was used as reference drug. Instead of hyposaline 2 ml of distilled water was used in the control. All the assay mixture were incubated at 37 ⁰C for 30 min and centrifuged. The hemoglobin content in the supernatant solution was estimated using spectrophotometer at 560 nm. The percentage hemolysis was calculated by assuming the hemolysis produced in presence of distilled water of as 100%. The percentage of HRBC membrane stabilization or protection was calculated using the following formula [13-19]

                               Optical density of Test

 % Protection =    100 -------------------------  X 100

                                    Optical density of Control

 

 

Table 2: In-vitro anti-inflammatory study of (AR-15a-AR-55a) synthesized compound by HRBC membrane stabilization Method

 

Fig-I: In-vitro anti-inflammatory study of (AR-15a-AR-55a) synthesized compound

 

 

3.2 In vivo antiinflammatory activity of 1-(4-substituted)-2-(-4-piperazine-1-yl) thiazole-5-yl) 2-methyl-4-nitro-1H-imidazole-1-yl) ethanone by carrageenan induced rat hind paw edema.

The experimental protocol was approved by the institutional ethics committee constituted by the Ministry of Social Justice and Empowerment, Government of India. The method adopted resembles essentially that described by Winter et al. [20], Albino rats weighing between 180-250 gm of either sex were starved for 18 hour prior to the experiment. The animals were studied for the toxicity of DMSO (up to 10% in saline) then up to 5 % DMSO was taken as vehicle to suspend the std. drug and test compounds. The animals were weighed and marked for identification and they are alienated in to group containing six each. The dose of standard drug was Diclofenac (10 mg / kg body weight) and all the test compounds were tested of 20 mg/kg body weight. Carrageenan solution (1% w/v) was prepared by dissolving 100 mg of carrageenan (Ranchem Mumbai) in 10 mL of sterile saline solution. The standard and test compounds were administered orally as a suspension using DMSO solution (up to 5%). One hour before carrageenan challenge. Foot paw edema was induced by injecting 0.10 mL of the carrageenan solution subcutaneously into the planter portion of the right hind paw of each rat. Initial foot paw volume was measured immediately by mercury Plethysmograph. Edema was measured three hour after carrageenan administration. The swelling in test group animals was used to calculate the percent inhibition + SEM of edema achieved by the compound at the test dose compared with the vehicle control group, [21, 22]. The percentage protection of edema was calculated according to the following formula.       

% Anti-inflammatory activity = 100 (1-Vt / Vt)

 

Where, Vt and Vc are the volume of edema in test compounds and control groups, respectively. The data of anti-inflammatory activity of the novel synthesized compounds are given below in the Table.

 

 

Table 3: In-vivo anti-inflammatory of 1-(4-substituted)-2-(-4-piperazine-1-yl) thiazole-5-yl) 2-methyl-4-nitro-1H-imidazole-1-yl) ethanone by carrageenan induce rat paw oedema % Protection

**Oral administration for all test compounds, P < 0.05, Student’s t-test versus controls, the standard drugs, i(dose and % protection) were:  ibuprofen (20 mg/kg, 75%) and Diclofenac Sodium(10 mg/kg, 77%).

n=6, ANOVA followed by Dunnet’s multiple comparison test

***p<0.001, **p<0.01 and *p<0.5 compared with control

Values are expressed in Mean ± SEM

 

Fig-II: In-vivo anti-inflammatory study of (AR-15a-AR-55a) synthesized compound   

 

4. RESULT AND DISCUSSIONS:

Novel series of trisubstituted thiazole analogues (AR-15a-AR-55a) were designed and synthesized. The synthesized compounds (AR-15a-AR-55a) were evaluated for their in-vitro and in-vivo anti-inflammatory activity. The in-vitro anti-inflammatory activity was carried out by membrane stabilization of Human Red Blood cells which was causing heat induced hemolysis of RBC as one of the mode of inflammation. Further in-vivo anti-inflammatory activity was performed in carrageenin-induced rat paw edema model at dose employed at 20 mg/kg body weight using diclofenac sodium as reference standard.

The compounds (AR-15a-AR-55a) were designed and synthesized by keeping (1-chloro-3-(2-methyl-4-nitro1H-imidazole-1-yl) propane-2-on at fifth position and 4-pipereazin at second position of thiazole ring. The fourth position of thiazole was substituted by introducing electron withdrawing group (–Cl), at different position in phenyl moiety.  The compounds (AR-15a to AR-55a) were synthesized having only piperazine secondary amine at second position of thiazole. The chemical structures of these compounds and results of in vivo anti-inflammatory activity are shown in Table 2 and Table 3 respectively.

 

The IR spectrum of series some 1-(4-substituted)-2-(-4-(piperazine-1-yl) bis-thiazole-5-yl) 2-Methyl-4-Nitro-1H-imidazole-1-yl) ethanone. AR-15a, AR-25a AR-35a, AR-45a and -AR-55a) showed an absorption band at 3150, 3138, 3192, 3182 and 3138 cm¹ indicate the aromatic (Ar-H stretching) respectively. Similarly the absorption band at 1635, 1734, 1669, 1667, and 1737 cm¹ indicates the presence of (C=O stretching) attached to the fifth position of thiazole ring system. Other important absorption band are observed at 1175-1138, 1159-1012, of  (C-N-C stretching of phenylpiperazine) and 1491-1433, 1390, 1446-1464 cm¹  of (-NO_2- group). The ¹H NMR spectrum recorded at 400 MHz of compounds AR-15a to AR-55a showed a singlet at δ ppm, 8.0, 8.20, 7.94, 8.0 and 8.07 integrating for one proton, which is attributed to aromatic proton at fifth position of nitroimidazole. The aromatic protons resonate as multiplets at δ ppm 7.41-7.64, 7.08, 6.99, 7.40-7.62, and 7.50-7.84.  Additionally evidences for the structures of compounds AR-15a-AR-55a were made by recording its mass spectra. The mass spectrum of showed a molecular ion peak at m/z, 739, 807, 719 (M+1) likewise, which is reliable with their molecular formula. The characterization data are given in spectral section for (AR-15a, AR-25a, AR-35a, AR-45a and AR-55a).

 

Biological evaluation of some 1-(4-substituted)-2-(-4-(piperazine-1-yl) bis-thiazole-5-yl) 2-Methyl-4-Nitro-1H-imidazole-1-yl) ethanone were done by in-vitro and in-vivo of anti-inflammatory model as Bis-thaizole derivative found to have very good anti-inflammatory response by HRBC membrane stability., however moderate to poor protection was observed by in-vivo study in carrageenan induce rat paw oedema. 

 

5. ACKNOWLEDGEMENT:

The authors are thankful to President JIIU’s G.M. Vastanvi and Dr. V. Sudarsanam for their encouragement and support. We also wish to thanks to Mr. Prashant Patel director, Cambay Organics Pvt. Cambay, Gujarat, India to provide chemicals and Director SAIF, Punjab University for Spectral analysis.

 

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Received on 13.02.2017         Modified on 21.02.2017

Accepted on 18.03.2017         © AJRC All right reserved