Iraqi J Pharm Sci, Vol.28(1) 2019 Etodolac hydrazone derivatives with anti-inflammatory action DOI: https://doi.org/10.31351/vol28iss1pp106-112 106 Synthesis, Characterization and Preliminary Anti-inflammatory Evaluation of New Etodolac Derivatives Omeed M. Hassan* and Susan W. Sarsam*,1 *Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, Baghdad, Iraq Abstract Three new hydrazone derivatives of Etodolac were synthesized and evaluated for their anti-inflammatory activity by using egg white induced paw edema method. All the synthesized target compounds were characterized by CHN- microanalysis, FT-IR spectroscopy, and 1HNMR analysis. The synthesis of the target (P1-P3) compounds was accomplished following multistep reaction procedures. The synthesized target compounds were found to be active in reducing paw edema thickness and their anti-inflammatory effect was comparable to that of the standard (Etodolac). Keywords: Etodolac hydrazone derivatives, Anti-inflammatory, Paw edema method. كمضادات لاللتهابلاليتودوالك جديدة مشتقاتوتقييم اولي ل وتشخيص تحضير 1*،سوزان وديع سرسم و *اميد محسن حسن . كلية الصيدلة، جامعة بغداد، بغداد، العراقفرع الكيمياء الصيدالنية، * الخالصة المستحث ببياض المخلب وذمة طريقة باستخدام لاللتهابات المضادة وتم تقييم فعاليتها ثالثة مشتقات هيدرازون جديدة لاليتودوالك تحضير تم ، مطياف األشعة تحت الحمراءوالهيدروجين والنيتروجينلكربون دقيق لذرات العناصر اال بالتحليل شخصت حضرةالم المركبات جميع. البيض وجدت المركبات المحضرة بان لها .باتباع طرق تفاعالت متعددة الخطوات P1-P3وتم تحضير المركبات .جهاز الرنين النووي المغناطيسيو .كفعالية في تقليل سمك ورم المخلب وان تأثيرها المضاد لاللتهابات كان مشابها لاليتودوال المخلب. لاللتهابات، طريقة وذمة مشتقات ايتودوالك هيدرازون، مضادة: كلمات مفتاحية Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous group of compounds that are used for the treatment of various inflammatory conditions, pain and fever (1). The principal mechanism of action of NSAIDs involves the inhibition of cyclooxygenase (COX) enzyme also known as prostaglandin-endoperoxide synthase (PTGS). COX is the enzyme that catalyzes the synthesis of prostanoids (Thromboxane and Prostaglandins) from arachidonic acid(2). COX- inhibitors are believed to act as an analgesic (3), anti- inflammatory and antipyretic by decreasing prostaglandin synthesis(4). This decrease in prostaglandin synthesis is associated with the occurrence of several unwanted effects accompanied with the use of NSAIDs, especially gastrointestinal (GI) irritation and ulceration. Additionally, several NSAIDs have a free carboxylic acid group (5); therefore, oral administration is linked with the side effects on the gastric system (6), which are due to direct GI irritation. NSAIDs can be categorized by the site of action into nonselective (COX) inhibitors which target COX I and COX II and selective (COX) inhibitors that selectively target COX II though decrease gastric side effect that comes with COX I inhibitors (7). Etodolac (2-(1,8-diethyl-1,3,4,9- tetrahydropyrano[3,4-b]indol-1-yl) acetic acid) (Figure.1) which is a NSAID, is a derivative of pyrano - indoleacetic acid . It is recommended for the treatment of pain and inflammation caused by osteoarthritis and rheumatoid arthritis. Figure (1) Chemical structure of etodolac The carboxylic acid group of NSAIDs can be replaced with other groups while these agents still exert a potent anti-inflammatory activity (8). 1Corresponding author: E-mail: sarsam14@yahoo.com Received: 27/11/2018 Accepted: 2/2/2019 Iraqi Journal of Pharmaceutical Sciences https://doi.org/10.31351/vol28iss1pp106-112 Iraqi J Pharm Sci, Vol.28(1) 2019 Etodolac hydrazone derivatives with anti-inflammatory action 107 Hydrazones are an important class for new drug development and an exceptional class of organic compounds in the Schiff base family. They are synthesized by heating an appropriately substituted hydrazide with aldehydes or ketones in solvents like ethanol, methanol, tetrahydrofuran, butanol, with few drops of glacial acetic acid as a catalyst (9). Hydrazone have a wide range of biological activities like anti-bacterial, antiviral, antidepressant, cardioprotective activities and anticancer activities (10), alongside with anti-inflammatory action. This study focused on the synthesis of new Etodolac hydrazone derivatives and the evaluation of their anti-inflammatory activity. Materials and Methods Etodolac and different aldehydes were bought from HyperChem / China, while other chemicals and solvents (Ethanol, methanol, acetone, glacial acetic acid, concentrated H2SO4, hydrazine hydrate, n-hexane, petroleum ether, and ethyl acetate) were bought from commercial sources and used without further purification. Thin layer chromatography (TLC plates (254F) /Merck- Germany) was used to check reaction completion and purity of the product under UV light (254 nm).Melting points were measured (uncorrected) by using the capillary tube on Stuart SMP30 Electronic Melting Point Apparatus. CHN elemental microanalysis was carried out on Euro EA Elemental analyzer (Italy). IR spectra were recorded on FTIR-600 Spectrophotometer (Biotech engineering management, UK)) using KBr disc. 1HNMR spectra were recorded on BRUKER model Ultra shield 300 MHz spectrophotometer using DMSO-d6 as a solvent. Synthesis of etodolac ester [methyl 2-(1,8-diethyl- 1,3,4,9-tetrahydropyrano [3,4-b] indol-1-yl) acetate] (compound A) A mixture of Etodolac (0.021 moles, 6g) and methanol (40 mL) in a 250 ml round bottom flask was stirred till a clear solution is achieved. The obtained solution was cooled to 0oC by using an ice bath and 3 mL of concentrated sulfuric acid (H2SO4) was added dropwise with continuous stirring, then, the mixture was set to reflux with stirring at 75C for 5 h. After completion of the reaction (monitored by TLC (acetone: petroleum ether 5:5)), the solution was cooled down to room temperature, then it was thrown over 75 mL of cold distilled water, followed by the addition of saturated sodium bicarbonate solution (5% w/v) in order to neutralize the excess acid. A yellowish precipitate of Etodolac methyl ester was produced. The precipitate was collected by filtration, washed with chilled distilled water and dried, then recrystallized from ethanol. Yellowish powder, yield = 67%, m.p. (128-130oC). Rf = 0.78 (Acetone 5: Petroleum Ether 5). IR (KBr disc), (v cm-1):3379: (NH) str. of Indole, 3062: Aromatic (C- H) str., 2968: (C-H) asymm. str. of CH3 and CH2, 2875: (C-H) symm. str. of CH3 and CH2, 1709: (C=O) str. of ester, 1236: (C-O-C) str. of ether.1H NMR: (300 MHz, DMSOd6 , =ppm): 0.62 (3H, t, -CH2-CH3 at C1), 1.26 (3H, t, -CH2-CH3 at C8), 1.9- 2.11 (2H, m, -CH2-CH3 at C1), 2.5-3.04 (6H, m, - CH2-CH3 at C8, -CH2-COOCH3 at C1and -CH2 at C4), 3.56 (3H, s, -COOCH3), 3.80 (2H, dd, -CH2 at C3), 6.79- 7.00 (2H, m, Ar-H5, H6), 7.23 (1H, d, Ar- H7), 10.48 (1H, s, Indole, N-H). Synthesis of etodolac hydrazide (2-(1,8-diethyl- 1,3,4,9-tetrahydropyrano[3,4-b] indol-1yl) aceto- hydrazide) (compound B) To a solution of compound A (0.02 moles, 6 g) in absolute ethanol (70 mL), an excess amount of hydrazine hydrate 80% (0.2 moles, 10mL) was added, and the mixture was refluxed at 80 C for 6 h. At the end of the reflux time, the mixture was left to be cooled down to room temperature (r.t.), then cold distilled water was added to the mixture, a white precipitate was formed which was left overnight. The obtained precipitate was filtered, washed several times with cold distilled water, dried and recrystallized from ethanol. White powder, yield = 88%, m.p. (187-189 oC). Rf = 0.41 (Acetone 5: Petroleum Ether 5). IR (KBr disc), (v cm-1): 3354, 3313: (NH) str. of Indole and hydrazide, 3062: Aromatic (C-H) str., 2970: (C-H) asymm. str. of CH3 and CH2, 2875: (C-H) symm. str. of CH3 and CH2,1655: (C=O) str. of amide, 1620: (NH) bend., 1242: (C-O-C) str. of ether.1H NMR: 0.61 (3H, t, - CH2-CH3 at C1), 1.25 (3H, t, -CH2-CH3 at C8), 2.04 (2H, q, -CH2-CH3 at C1), 2.61-2.9 (6H, m, CH2- CONHNH2, -CH2-CH3 at C8, -CH2 at C4), 3.95 (2H, dd, -CH2 at C3), 4.25 (2H, b.s. NH-NH2),6.80-6.98 (2H, m, Ar-H5, H6), 7.22 (1H, d, Ar-H7), 8.92 (1H, s, NH-NH2), 10.54 (1H, s, Indole N-H). Synthesis of aryl hydrazones 2-(1,8-diethyl-1,3,4,9- tetrahydropyrano[3,4-b] indol-1yl) acetohydrazide derivatives (P1 - P3) Three drops of glacial acetic acid were added to an ethanolic solution of each of the following aldehydes (scheme 1): (1) [3,5-dimethoxy-4- hydroxybenzaldehyde (0.005 moles, 0.91g)], (2) [4- hydroxy-3-nitrobennzaldehyde (0.005 moles, 0.84g)], (3) [2-pyridine carboxaldehyde (0.005moles, 0.6g)], placed in round bottom flask equipped with magnetic stirrer. Compound B (0.005moles, 1.55g) dissolved in absolute ethanol (20mL) was added to a stirred solution of each of the above mentioned aldehydes mixtures separately. Then each reaction mixture was refluxed at 80 C for 8 h. At the end of the reaction (monitored by TLC), 50 mL of cold ice water was added to the mixture. The precipitate formed was collected, dried and recrystallized from solvents (80% ethanol for P2, 70%, 75% ethanol for P1 and P3 respectively) to get the intended products. Iraqi J Pharm Sci, Vol.28(1) 2019 Etodolac hydrazone derivatives with anti-inflammatory action 108 (P1) 2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4- b]indol-1-yl) - N' - ( 4 – hydroxyl -3 , 5 - dimethoxy – benzylidene ) acetohydrazide. White powder, Yield = 81%, m.p. (173- 175 oC). Rf = 0.46 (Ethyl acetate 6: n-Hexane 4). IR (KBr disc), (v cm-1):3555-3210: (OH) str. broad band, 3377, 3271: (NH) str. of Indole and hydrazone,3060: Aromatic (C-H) str.,2964: (C-H) asymm. str. of CH3 and CH2. 2875: (C-H) symm. str. of CH3 and CH2, 1641: (C=O) str. of amide.1589: (C=N) str., 1512: Ar. (C=C) str., 1213: (C-O-C) str. of ether. 1H NMR: 0.59,0.68(3H, tt, - CH2-CH3 at C1), 1.25 (3H, t, -CH2-CH3 at C8), 2.07 (2H, q, -CH2-CH3 at C1), 2.66 (2H, q, -CH2-CH3 at C8),2.77-3.04 (4H, m,-CH2CONH,-CH2 at C4), 3.74, 3.79 (6H, 2s, 2–OCH3), 3.99 (2H, dd, -CH2 at C3), 6.85-7.0, 7.19-7.29 (5H, 2m, Ar-H), 7.88, 8.08 (1H, ss, N=CH), 8.85 (1H, bs, OH), 10.50 (1H, s, Indole N-H), 11.0, 11.22 (1H, ss, -CO-NH).CHN: C26H31N3O5, M.wt:465.55, Calculated C;(67.08), H; (6.71),N; (9.03). Observed C;(68.88), H;(6.483), N; (8.743). (P2) 2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4- b] indol-1-yl)-N'-(4-hydroxy-3-nitro-benzylidene) acetohydrazide. Pale yellow powder, Yield=77%, m.p. (122-125 oC). Rf = 0.83 (Ethyl acetate 4: n-Hexane 6). IR (KBr disc), (v cm-1):3417, 3249: NH str. of Indole and hydrazone overlapping with (OH) str. of Phenol,3089: Aromatic (C-H) str., 2964: (C-H) asymm. str. of CH3 and CH2, 2875: (C-H) symm. str. of CH3 and CH2, 1666: (C=O) str. of amide, 1622: (C=N) str., 1522: Ar. (C=C) str. and asymm. (NO2) str., 1323: symm. (NO2) str., 1257: (C-O-C) str. of ether. 1H NMR: 0.59, 0.66 (3H, tt, -CH2-CH3 at C1), 1.25(3H, t, -CH2-CH3 at C8), 2.10 (2H, q, CH2-CH3 at C1), 2.66 (2H, q, CH2-CH3 at C8), 2.83-2.99 (4H, m, -CH2CONH at C1, -CH2 at C4), 3.98 (2H, dd, - CH2 at C3), 6.84-6.97 (2H, m, Ar-H5, H7), 7.12- 7.28 (2H, m, Ar-H6, H5´), 7.83 (1H, dd, Ar-H6´), 7.93, 8.08(1H, ss, N=CH), 8.18 (1H, s, Ar-H2´), 8.93 (1H, bs, OH), 10.48 (1H, s, Indole N-H), 11.17, 11.34 (1H, ss, -CO-NH). CHN: C24H26N4O5, M.wt:450.50. Calculated C; (63.99), H; (5.82), N; (12.44). Observed C; (62.634), H; (6.027), N; (12.938). (P3) 2-(1, 8-diethyl-1,3,4,9-tetrahydropyrano[3,4- b]indol-1-yl)-N'-(pyridin-2-ylmethylene) acetohydrazide. Off-white powder, Yield = 54%, m.p. (148-153 oC). Rf = 0.61 (Ethyl acetate 6: n-Hexane 4)). IR (KBr disc), (v cm-1):3298, 3247: (NH) str. of Indole and hydrazone, 3053: Aromatic (C-H) str., 2964: (C-H) asymm. str. of CH3 and CH2, 2873: (C- H) symm. str. of CH3 and CH2, 1672: (C=O) str. of amide, 1606: (C=N) str., 1556: Ar. (C=C) str., 1230: (C-O-C) str. of ether. 1H NMR: 0.59, 0.68 (3H, tt, - CH2-CH3 at C1), 1.26 (3H, t, -CH2-CH3 at C8), 2.11 (2H, q, CH2-CH3 at C1), 2.61-2.73, 2.82-3.01 (6H, 2m, CH2-CH3 at C8, -CH2CONH at C1, -CH2 at C4), 4.06 (2H, dd, -CH2 at C3), 6.82-7.00 (2H, m, Ar-H5, H6), 7.23 (1H, d, Ar-H7), 7.33-7.45 (1H, m, Ar- H4´), 7.50-7.59 (1H, m, Ar-H3´), 7.78-7.92 (1H, m, Ar-H2´), 8.03, 8.22 (1H, ss, N=CH), 8.53-8.63 (1H, m, Ar-H5´), 10.50 (1H, s, Indole N-H), 11.40, 11.51 (1H, ss, -CO-NH).CHN:C23H26N4O2, M.wt:390.49, Calculated C; (70.75), H; (6.71), N; (14.35), Observed C; (69.722), H; (7.006), N; (14.868). Evaluation of the anti-inflammatory activity (11) Albino rats of both sexes weighing (190 ± 10 g) were delivered by the animal house of the College of Pharmacy, University of Baghdad, and are kept in the same place under consistent conditions. Animals Iraqi J Pharm Sci, Vol.28(1) 2019 Etodolac hydrazone derivatives with anti-inflammatory action 109 were fed commercial chaw and had access to water freely. Animals were divided into five groups (each group consists of 6 rats) including standard (Etodolac), control (DMSO) and P1, P2 and P3 groups. Dose determination of the final synthesized compounds (Table 1) was done according to the equation below, Egg white induced edema model (12) was used to study the anti-inflammatory activity of the target compounds. This was achieved by the administration of an intraperitoneal (i.p) injection of each of the final products, Etodolac or control, individually to the five animal groups. Thirty minutes after that subcutaneous injection (S.C.) of 0.05 mL of undiluted egg-white was injected into the plantar side of the left hind paw of the rats of each group. Vernea was used to measure paw thickness at six-time intervals (0, 30, 60, 120, 180, and 240 min.), where zero time was the time at which the products, standard, and control were administered intra-peritoneally. 𝐃𝐨𝐬𝐞 𝐨𝐟 𝐑𝐞𝐟𝐞𝐫𝐚𝐧𝐜𝐞 𝐂𝐨𝐦𝐩𝐨𝐮𝐧𝐝 𝐌𝐨𝐥𝐞𝐜𝐮𝐥𝐚𝐫 𝐰𝐞𝐢𝐠𝐡𝐭 𝐨𝐟 𝐫𝐞𝐟𝐞𝐫𝐞𝐧𝐜𝐞 𝐜𝐨𝐦𝐩𝐨𝐮𝐧𝐝 = 𝐃𝐨𝐬𝐞 𝐨𝐟 𝐭𝐞𝐬𝐭𝐞𝐝 𝐜𝐨𝐦𝐩𝐨𝐮𝐧𝐝 𝐌𝐨𝐥𝐞𝐜𝐮𝐥𝐚𝐫 𝐰𝐞𝐢𝐠𝐡𝐭 𝐨𝐟 𝐭𝐞𝐬𝐭𝐞𝐝 𝐜𝐨𝐦𝐩𝐨𝐮𝐧𝐝 Table (1) Doses determined for the synthesized final products Product no. M.wt. Dose mg/kg Etodolac (Std.) 287.359 10 (a) P1 465.550 16.20 (b) P2 450.495 15.68(b) P3 390.487 13.59(b) (a)The standard dose for Etodolac in mg/kg. (b)The determined dose which is equivalent to Etodolac dose. Multiple comparisons between the synthesized target compounds against control and reference drug were done using one-way ANOVA test, then to see the significance between each pair of compounds, post hoc Tukey test was used, which offers an advantage over the use of independent t- test for more powerful accuracy for calculating the p-value. Graph Pad Prism 8.0.0 program was used to carry out the statistical analysis. Results and Discussion Chemistry The synthetic pathways used for the preparation of the target Etodolac hydrazone derivatives (P1-P3) are summarized in scheme (1). Etodolac methyl ester Compound (A) was synthesized by the reaction of Etodolac with methanol along with the use of few drops of concentrated H2SO4. Compound (B) was synthesized by the reaction of Etodolac methyl ester with hydrazine hydrate (NH2NH2.H2O). The synthesis of the final Etodolac hydrazone derivatives involves the reaction of Etodolac hydrazide with different types of aldehydes by using glacial acetic acid as a catalyst. Iraqi J Pharm Sci, Vol.28(1) 2019 Etodolac hydrazone derivatives with anti-inflammatory action 110 ArCHO: are listed below; Scheme (1) The synthesis of target compounds (P1-P3). The structures of all the synthesized compounds were characterized by FT-IR, 1HNMR and CHN elemental microanalysis. The infrared spectra of the hydrazone derivatives (P1-P3) showed the characteristic absorption band at (1641-1672) cm-1 due to (C=O) stretching of amide as well as the appearance of bands at (1589-1622) cm-1attributed to the(C=N) stretching of the imine. Additionally, two other absorption bands were displayed at (3298- 3417) cm-1 and (3247-3271) cm-1attributed to (N-H) stretching of indole and hydrazone, respectively. The 1HNMR spectra of the target compounds (P1 - P3) confirmed the synthesis of hydrazone derivatives. Characteristic signals of hydrazone were shown in the region (7.83-8.22 ppm) as two singlets attributed to the azomethine proton N=CH, another characteristic signal of hydrazone due to – CO-NH proton was displayed as two singlets resonating at 11.00-11.54 ppm, in addition to the loss of signal at 4.25 ppm for the two hydrazide protons NH-NH2. Generally, hydrazones may exist as E and Z geometrical isomers (12). This explains the appearance of each of azomethine N=CH and CO- NH proton as two singlets. Evaluation of the anti-inflammatory activity Comparison of reference drug (Etodolac) versus control (DMSO) At baseline and after 30 minutes, there was no significant difference between control and etodolac in paw edema reduction, but after 60 minutes the difference becomes significant in which etodolac offer more reduction in the percent paw thickness compared to the control. Further reduction was continued significantly at 120 minutes, up to 240 minutes as shown in Figure (2) below; Figure (2) Effect of etodolac (reference), and dimethyl sulfoxide (control) on egg-white induced paw edema in rats measured in percentage. Note: Time (30) min. is the time of egg-white injection. Comparison of the effect of synthesized compounds P1, P2 and P3 versus control No significant difference was found between the target compounds compared to the control at baseline and after 30 minutes. However, compound (P3) produced a significant difference in the reduction of paw thickness at 60, 180 and 240 minutes compared to the control. Whereas, a significant difference compared to the control in percent reduction of paw thickness was shown for compound (P2) at 120 and 240 minutes. These results are shown in table (2) and figure (3). Iraqi J Pharm Sci, Vol.28(1) 2019 Etodolac hydrazone derivatives with anti-inflammatory action 111 Table (2) Effect of dimethyl sulfoxide (control) and target compounds (P1-P3) on egg-white induced paw edema Data are expressed in mm paw thickness as mean ± SEM. n= number of animals. Time (0) is the time of i.p. injection of tested compounds, and DMSO (2ml/kg) Time (30) is the time of injection of egg-white (induction of paw edema). Significantly different compared to control: p-value *< 0.033 (GP system) Comparison of the effect of synthesized compounds P1, P2 and P3 versus etodolac There was no significant difference in the reduction of paw thickness between the synthesized target compounds compared to Etodolac at baseline and after 30, 60, 120, 180and 240 minutes. All the synthesized compounds produce reduction in paw thickness which was comparable to the standard (Etodolac) as presented in table (3) and figure (3). Table (3) Effect of etodolac (reference) and target compounds (P1-P3) on egg-white induced paw edema Data are expressed in mm paw thickness as mean ± SEM. n= number of animals. Time (0) is the time of i.p. injection of tested compounds, and Etodolac. Time (30) is the time of injection of egg-white (induction of paw edema). Note: In this case all compounds with no significant difference compared to Etodolac Figure (3) Effect of etodolac, dimethyl sulfoxide (DMSO), compounds P1, P2, and P3 on egg-white induced paw edema in rats. Results are expressed as mean ± SEM & Percent. (n=6 for each group). Note: Time (30) is the time of egg-white injection. Time (min) Control n=6 P1 n=6 P2 n=6 P3 n=6 P a w th ic k n e ss (m m ) 0 3.77±0.10 3.78±0.13 3.65±0.09 3.70±0.07 30 5.51±0.09 5.24±0.16 4.98±0.10 5.04±0.18 60 6.03±0.18 5.68±0.14 5.53±0.08 5.36±0.14* 120 5.80±0.22 5.56±0.12 5.08±0.08* 5.22±0.13 180 5.52±0.18 5.31±0.11 4.92±0.14 4.85±0.08* 240 5.23±0.12 4.97±0.14 4.57±0.09* 4.58±0.09* Time (min) Etodolac n=6 P1 n=6 P2 n=6 P3 n=6 P a w T h ic k n e ss (m m ) 0 3.51±0.11 3.78±0.13 3.65±0.09 3.70±0.07 30 4.70±0.09 5.24±0.16 4.98±0.10 5.04±0.18 60 5.33±0.12 5.68±0.14 5.53±0.08 5.36±0.14 120 5.24±0.08 5.56±0.12 5.08±0.08 5.22±0.13 180 5.00±0.17 5.31±0.11 4.92±0.14 4.85±0.08 240 4.64±0.13 4.97±0.14 4.57±0.09 4.58±0.09 Iraqi J Pharm Sci, Vol.28(1) 2019 Etodolac hydrazone derivatives with anti-inflammatory action 112 Conclusion Three new etodolac hydrazone derivatives (P1-P3) were synthesized, and their structures were characterized by FT-IR, 1HNMR and CHN microanalysis. The compounds synthesized in this study exhibited anti-inflammatory action when tested on rats by using egg white induced paw edema and showed comparable effect as the used standard drug (Etodolac) with no significant difference. References 1. Mohammed ZAHD and MH. Synthesis of 5- Fluorouracil Derivatives as Possible Mutual Prodrugs with Meloxicam and Ibuprofen for Targeting Cancer Tissues. Iraqi J. Pharm. Sci. 2011;20(2). 2. Matsumura Y. Chapter 14 – Synthesis and Pharmacological Properties of Fluorinated Prostanoids. Fluorine and Health. (1st ed.), Elsevier B.V.;2008. p 623-659. 3. Meek IL, van de Laar MAFJ, Vonkeman HE. Non-steroidal anti-inflammatory drugs: An overview of cardiovascular risks. Pharmaceuticals. 2010;3(7): 2146–2162. 4. Hawkey CJ. COX-1 and COX-2 inhibitors. Best Pract Res Clin Gastroenterol. 2001;15(5): 801– 820. 5. Nugrahani I, Utami D, Permana B, Ibrahim S. Development of the NSAID-L-proline amino acid zwitterionic cocrystals. J Appl Pharm Sci. 2018;8(4): 57–63. 6. Liu W, Li Y, Yue Y, Zhang K, Chen Q, Wang H, et al. Synthesis and biological evaluation of curcumin derivatives containing NSAIDs for their anti-inflammatory activity. Bioorganic Med Chem. ; 2015;25(15): 3044–3051. 7. Altilio T, Otis-Green S, Hedlund S, Fineberg Cohen I. Pain Management and Palliative Care. Handbook of health social work,(1st ed.) 2006. p 635-672. 8. Ullah N, Huang Z, Sanaee F, Rodriguez- Dimitrescu A, Aldawsari F, Jamali F, et al. NSAIDs do not require the presence of a carboxylic acid to exert their anti-inflammatory effect –why do we keep using it? J Enzyme Inhib Med Chem. 2016;31(6): 1018–1028. 9. Kumar N, Chauhan LS, Dashora N, Sharma CS. Anticonvulsant potential of Hydrazone derivatives : Sch Acad J Pharm. 2014;3(5): 366– 373 10. Dadaş Y, Coşkun GP, Bingöl-Özakpınar Ö, Özsavcı D, Küçükgüzel ŞG. Synthesis and Anticancer Activity of Tolmetin Thiosemicarbazides. Marmara Pharm J. 2015;19(3): 259–267. 11. Dragojevic-Simic V, Jacevic V, Dobric S, Djordjevic A, Bokonjic D, Bajcetic M, et al. Anti-inflammatory activity of fullerenol C60(OH)24nano-particles in a model of acute inflammation in rats. Dig J Nanomater Biostructures. 2011;6(2): 819–827. 12. Cikla P, Ozcavci D, Sener A and Turan S. Synthesis, cytotoxicity and pro-apoptosis activity of Etodolac hydrazide derivatives as anti-cancer agents. Arch Pharm. 2013; 367(5), 367-379. 13. Omar T. NA. Synthesis and Preliminary Pharmacological Evaluation of Esters and Amides Derivatives of Naproxen as Potential Anti-Inflammatory Agents. Iraqi j. of Pharm. Sci. 2013;22(1):120–7.