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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 12  |  Issue : 1  |  Page : 35-43

Design, synthesis, and biological evaluation of novel diclofenac analogs as promising anti-inflammatory agents


Department of Pharmaceutical Chemistry, KLE College of Pharmacy, Hubli, Karnataka, India

Date of Web Publication18-Jan-2019

Correspondence Address:
Dr. Mahesh B Palkar
Department of Pharmaceutical Chemistry, KLE College of Pharmacy, Vidya Nagar, Hubli - 580 031 Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kleuhsj.kleuhsj_151_18

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  Abstract 


INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesics and antipyretics in the treatment of pain, fever, and rheumatoid arthritis. Major side effect with treatment of NSAIDs is gastric irritation. 1,3,4-thiadiazole is an imperative scaffold since several of these derivatives are known to be associated with multiple biological activities such as anti-inflammatory, antibacterial, anti-cancer, anti-tubercular, and immunosuppressive. Literature survey reveals that certain compounds bearing this nucleus possess significant anti-inflammatory activity with reduced ulcerogenic effect.
MATERIALS AND METHODS: In the present research work, we have synthesized thirteen 2-(2-[2,6-dichlorophenylamino] phenyl) acetohydrazide derivatives (4a–4m) and four 2,6-dichloro-N-(2-[6-phenylimidazo[2,1-b][1,3,4]thiadiazol-yl] methyl] phenyl) benzenamine derivatives (6a–6d) derived from diclofenac. All these newly synthesized compounds were screened for in vivo acute anti-inflammatory activity by carrageenan-induced rat paw edema method at a dose of 10 mg/kg bw.
RESULTS AND DISCUSSION: Structures of these novel compounds were characterized based on their physicochemical and spectral analysis. Perusal of the activity data strongly suggests that compound 4d was most promising with significant anti-inflammatory activity, while moderate to good activity was observed for compounds 4a, 4c, g, 4i, and 4l. Among the imidazo (2,1-b) 1,3,4-thiadiazole series (6a–6d), compound 6b exhibited excellent anti-inflammatory activity, while compounds 6a, 6c and 6d displayed reasonably to good anti-inflammatory activity as compared to standard drug diclofenac.
CONCLUSION: Among the series of synthesized compounds, two derivatives (4d and 6b) have displayed the most encouraging results and could be further exploited for developing newer anti-inflammatory agents with better efficacy and safety, which necessitates further investigations.

Keywords: 1,3,4-thiadiazole, anti-inflammatory activity, Diclofenac, Schiff base


How to cite this article:
Chikkamath MK, Hampannavar GA, Palkar MB. Design, synthesis, and biological evaluation of novel diclofenac analogs as promising anti-inflammatory agents. Indian J Health Sci Biomed Res 2019;12:35-43

How to cite this URL:
Chikkamath MK, Hampannavar GA, Palkar MB. Design, synthesis, and biological evaluation of novel diclofenac analogs as promising anti-inflammatory agents. Indian J Health Sci Biomed Res [serial online] 2019 [cited 2019 Jun 19];12:35-43. Available from: http://www.ijournalhs.org/text.asp?2019/12/1/35/250387




  Introduction Top


Inflammation is a localized physical condition wherein part of the body becomes reddened, swollen, hot and often painful, especially as a reaction due to injury or infection.[1] Although inflammation is a body defense mechanism, it is also an early phase of some serious diseases such as cancer, cardiovascular diseases, and Alzheimer's dementia. Inflammation has become stamp of authentication for cancer. Hence, it is a challenge for a medicinal chemist to develop potent anti-inflammatory agents with enhanced safety profile.[2],[3]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesics and antipyretics in the treatment of pain, fever, and rheumatoid arthritis. The pharmacological activities of NSAIDs are related to the suppression of prostaglandin (PG) biosynthesis from arachidonic acid by inhibiting the enzyme PG endoperoxidase, popularly known as cyclooxygenase (COX) and 5-lipoxygenase.[4] COX exists in two isoforms, COX-1 and COX-2. Inhibition of both the isoforms by classical NSAIDs with preferential binding affinity for enzyme COX-1 causes serious side effects. These findings led to the hypothesis that the inhibition of COX-1 is associated with the adverse effects of classical NSAIDs, whereas inhibition of COX-2 is responsible for their anti-inflammatory effects [Figure 1].
Figure 1: Structures of non-selective and selective cyclooxygenase inhibitors

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Diclofenac which is often used as NSAID has a common side effect of gastric irritation, due to the nonselective inhibition of COX enzymes.[5],[6]

Over the years, many researchers have attempted to modify Diclofenac moiety to synthesize potential and therapeutic agents with anti-bacterial, anti-tubercular, and anti-tumor activity.[7],[8],[9] Recently, Bhandari et al., synthesized and studied the pharmacological activities (anti-inflammatory, analgesic, and ulcerogenecity) of novel S-substituted phenacyl-1, 3, 4-oxadiazole-2-thione and Schiff bases of diclofenac.[10] In contemporary, Palkar et al., have reported the synthesis, pharmacological screening and in silico studies of a new class of diclofenac analogs as promising anti-inflammatory agents.[11] 1, 3, 4-thiadiazole is an imperative scaffold since several of these derivatives are known to be associated with multiple biological activities such as anti-allergic, antibacterial, anti-cancer, anti-tubercular, and immunosuppressive.[12] Literature reports revealed that certain compounds bearing this nucleus possess significant anti-inflammatory activity with reduced ulcerogenic effect. The substituted derivatives serve both as biomimetic and reactive pharmacophores, which are of considerable pharmaceutical interest.[13],[14],[15]

On the other hand, molecular hybridization-based drug design approach has been exploited by many researchers to develop new hybrid chemical entities as promising drug candidates. The concept of molecular hybridization has gained more attention wherein two or more biologically active compounds of synthetic and/or natural origin are linked with an expectation to get enhanced possibility of new therapeutics.

Based on the above facts and in continuation of our research program on the development of novel and safer anti-inflammatory agents,[11] we have designed [Figure 2] and developed newer anti-inflammatory agents derived from diclofenac acid and evaluated them for their possible anti-inflammatory activity.
Figure 2: Literature reported and designed molecules derived from Diclofenac

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  Materials and Methods Top


Chemicals and chemistry protocols

All research chemicals were purchased from Sigma–Aldrich (St. Louis, Missouri, USA) or Lancaster Co. (Ward Hill, MA, USA) and used as such for the reactions. Diclofenac used in this research work was obtained from Elegant Drug Pvt, Ltd. Hubballi. Carrageenan was purchased from Sigma Aldrich Chemicals (St. Louis, Missouri, USA). The hydrogen-1 nuclear magnetic resonance (1H-NMR) was recorded on Bruker AVANCE II 400 (Bruker, Rheinstetten/Karlsruhe, Germany) using appropriate solvent. Chemical shifts are reported in δ ppm units with respect to TMS as an internal standard. The synthesized title compounds were purified by using column chromatography. The acute in vivo anti-inflammatory activity was carried out using digital plethysmometer (Ugo-Basile, Italy).

Synthetic work

Synthesis of methyl 2-(2-(2,6-dichlorophenylamino) phenyl)acetate)(2)

The methyl ester of diclofenac was prepared as per procedure reported earlier in the literature.[5],[16] This compound was obtained as a white crystalline solid. Yield: 71.78%. mp 96–98°C. UV (CH3 OH, λmax): 271.5 (ε: 8173.37). IR spectra (KBr, νmax, cm-1): 3447 (N-H), 3082 (C-H), 1730 (C = O), 1238 (C-O-C), 783 (C-Cl). 1H-NMR (CDCl3, δ, ppm): 8.69 (s, 1H, N-H), 7.52–6.93 (m, 7H, Ar-H), 3.82 (s, 3H, OCH3), 2.75 (s, 2H, CH2).

Synthesis of 2-(2-(2,6-dichlorophenylamino) phenyl) acetohydrazide (3)

Compound 2 (0.01 mol, 3.10 g) and hydrazine hydrate (0.02 mol, 1 g) were refluxed in absolute ethanol (50 ml) for 24 h (monitored by thin layer chromatography [TLC]). The synthesis of compound 3 was carried out as per the previous literature report.[11] The mixture was concentrated, cooled and poured in ice cold water. White amorphous solid thus separated out was filtered, dried and recrystallized from ethanol and water to afford compound 3. Yield: 61.45%. mp 157–159°C. UV (CH3 OH, λmax): 280.5 (ε: 15944.24). IR spectra (KBr,νmax, cm-1): 3448, 3437 (NH2), 3396 (N-H), 3022 (C-H), 1690 (C = O), 770 (C-Cl). 1H-NMR (CDCl3, δ, ppm): 8.95 (s, 1H, CONH), 8.44 (s, 1H, N-H), 7.63–6.87 (m, 7H, Ar-H), 4.26 (s, 2H, NH2), 2.64 (s, 2H, CH2).

General procedure for the synthesis of 2-(2-(2,6-dichlorobenzyl) phenyl)-N'-ethylideneaceto hydrazidederivatives (4a-4 m)

To a constantly stirred solution of compound (3, 0.1 mol) in anhydrous toluene, the appropriately substituted aldehyde (0.1 mol) was added and the reaction mixture was refluxed for 4 h in anhydrous conditions (monitored by TLC). Then, the reaction mixture was cooled to the room temperature, filtered, and the Schiff base is collected. The product was recrystallized using absolute ethanol as per the earlier report.[17] The physical data and spectral data of title compounds (4a-4m) are depicted in [Table 1] and [Table 2], respectively.
Table 1: Physico-chemical data of title compounds (4a-4m)

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Table 2: Spectral data of title compounds 4a-4m

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Procedure for synthesis of 5-(2-(2,6-dichlorophenylamino) benzyl)-1, 3, 4-thiadiazol-2-amine (5)

The equimolar quantity of diclofenac (1, 0.051 mol), thiosemicarbazide (0.051 mol) and conc. sulfuric acid (0.0102 mol) were thoroughly mixed at 10–15°C and heated at 90°C for 1 h with constant stirring. After cooling to RT, polyphosphoric acid (0.0408 mol) and water (50 mL) were added. The reaction mixture was further refluxed for 7 h (monitored by TLC) at 105–110°C as per the previous literature report.[18] After cooling, the mixture was basified between pH 6.8 and 7.3 by careful dropwise addition of NaOH solution with constant stirring. The precipitate was filtered and recrystallized from ethanol to get the crude product of 5-(2-(2,6-dichlorophenylamino) benzyl)-1, 3, 4-thiadiazol-2-amine (5). Yield: 52.2%. mp 178–182°C. IR spectra (KBr,νmax, cm-1): 3425 (NH2), 3338 (N-H), 3043 (C-H), 1597 (C = N), 769 (C-Cl). 1H-NMR (CDCl3, δ, ppm): 8.24 (s, 1H, N-H), 7.97–7.18 (m, 7H, Ar-H), 4.42 (s, 2H, NH2), 2.57 (s, 2H, CH2).

Synthetic scheme*

*Reagents and conditions: (a) Absolute methanol, conc. H2 SO4, reflux, 4 h; (b) Hydrazine hydrate (99%), absolute ethanol, reflux, 24 h; (c) Substituted aldehydes, anhydrous toluene, reflux, 4 h; (d) Polyphosphoric acid, conc. H2 SO4, thiosemicarbazide, reflux, 3 h; (e) α-bromo ketones, anhydrous ethanol, reflux, 25–30 h [Figure 3].
Figure 3: Synthetic scheme for Diclofenac analogs

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General procedure for synthesis of 2,6-dichloro-N-(2-((6-phenylimidazo [2,1-b] [1, 3, 4] thiadiazol-2-yl) methyl) phenyl) benzenamine derivatives (6a-6d)

A mixture of equimolar quantities of compound (5, 0.01 mol) and substituted α-bromo phenyl ketone (0.01 mol) was refluxed in absolute ethanol (75 mL) for 25–30 h (monitored by TLC). The reaction mixture was cooled overnight at room temperature. Excess solvent was removed under reduced pressure and the solid hydrobromide salt separated was filtered, washed with a cold ethanol and dried. Neutralization of hydrobromide salts with cold aqueous solution of Na2 CO3 yielded the corresponding free bases (6a-6d). The synthesis of compounds (6a-6d) was carried out as per the previous literature report.[19] Further, these compounds were purified by column chromatography using 200–400 mesh silica gel and eluted with ethyl acetate: hexane (2:8) as the mobile phase. The physicochemical data of title compounds (6a-6d) are depicted in [Table 3].
Table 3: Physico-chemical data of title compounds (6a-6d)

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Pharmacological activities

Animals

Albino mice of either sex weighing 20–25 g were used for acute toxicity studies and analgesic activity. Healthy male albino adult rats weighing 150–230 g were used for various pharmacological screenings. Animals were procured from Venkateshwara Enterprises, Bangalore, India, (245/CPCSEA) and housed individually in polypropylene cages, maintained under standard conditions of alternating 12 h light and dark cycles at a constant temperature (25 ± 2°C and 35%–60% relative humidity). The pharmacological evaluations were conducted after obtaining ethical clearance from the Animal Ethical Committee of KLEU's College of Pharmacy, Hubli (India). Animals were fed with standard rat pellet diet procured from Hindustan Lever Ltd., Mumbai, India and water ad libitum.

Preparation of test compounds

After suspending the test compounds in 0.5% aqueous solution of sodium carboxymethylcellulose (sodium CMC), were administered to animals orally. The control group animals received appropriate volumes of vehicle and reference drugs. The experimental animal handling procedure followed was similar for all groups of animals.

Acute toxicity

The acute toxicity study was carried out as per the Organization for Economic Co-operation and Development guidelines, revised guideline no 423.[20] Approval of the Institutional Animal Ethical Committee was obtained before the experimentation on the animals. Acute toxicity studies experimented on the albino mice of either sex weighing between 25 and 30 gm. Mice were starved for 24 h with water ad libitum before the test. On the day of the experiment, animals were administered with different compounds to different groups in an increasing dose of 10, 20, 100, 200, 1000, and 2000 mg/kg bw orally. The animals were then observed continuously for 3 h for general behavioral, neurological, autonomic profiles and then every 30 min for next 3 h and finally for next 24 h or until death.

Anti-inflammatory activity

In vivo acute anti-inflammatory activity was evaluated using the carrageenan-induced rat paw edema assay model.[21] Male albino rats (170–220 g) were fasted with free access to water at least 12 h before experiments. Control group received 1 ml of 0.5% sodium CMC, standard group received 13.5 mg/kg bw of diclofenac and test groups received 10 mg/kg bw of synthesized compounds (4a–4m and 6a–6d). The rats were dosed orally, 1 h later; a subplantar injection of 0.05 ml of 1% solution of carrageenan in sterile distilled water was administered to the left hind footpad of each animal. The paw edema volume was measured with a digital plethysmometer at 0, 2nd, 4th h after carrageenan injection. Paw edema volume was compared with the vehicle control group and percent reduction was calculated as 1-(edema volume in the drug-treated group/edema volume in the control group) ×100. The anti-inflammatory activity data of the title compounds (4a–4m and 6a–6d) are represented in [Table 4] and [Table 5], respectively.
Table 4: Anti-inflammatory activity data of title compounds (4a-4m) by carrageenan induced rat paw edema method

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Table 5: Anti-inflammatory activity of the title compounds (6a-6d) by carrageenan induced rat paw edema method

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  Results and Discussion Top


Chemical synthesis

The synthesis of novel series of 2-(2- [2,6-dichlorobenzyl] phenyl)-N'-ethylideneaceto hydrazide derivatives (4a-4m) were achieved through the versatile and efficient synthetic route as outlined in general Scheme. All the newly synthesized compounds gave satisfactory analysis for the proposed structures, which were confirmed on the basis of physicochemical and spectral data that are summarized in [Table 1] and [Table 2], respectively.

The methyl ester of diclofenac (2) was prepared from diclofenac by esterification. The purity of the compound was confirmed by melting point, TLC. Structure of compound 2 was confirmed by IR and H1NMR spectral data. IR spectra showed the characteristic peak of N-H at 3447 cm-1, C-H stretching at 3082 cm-1, C = O at 1729 cm-1, C-O-C at 1238 cm-1, C-Cl at 784 cm-1. This was further supported by H1NMR spectral data with δ value at 3.72 (s, 2H, CH2), 3.82 (s, 3H, CH3), 6.39 (s, 1H, N-H), 6.93–7.52 (m, 7H, Ar-H) thus confirming the structure. In the NMR spectra (1 H NMR) the signals of the respective protons of the synthesized compounds were verified on the basis of their chemical shifts, multiplicities, and coupling constants. In 1H-NMR spectra, the synthesized compounds showed prominent signals for the aromatic protons as multiplets between δ 6.77 and 8.10 ppm.

This methyl ester (2) was reacted with hydrazine hydrate, gave carbohydrazide (3). The purity of the compound was confirmed by melting point, TLC. Structure of compound 3 was confirmed by IR and H1NMR spectral data. IR showed the characteristic peak of N-H at 3325 cm-1, C-H stretching at 3022 cm-1, C = O at 1637 cm-1, C-Cl at 770 cm-1. This was further supported by H1NMR spectral data with δ value at 3.64 (s, 2H, CH2), 3.95 (s, 2H, NH2), 6.50–7.13 (m, 7H, Ar-H), 7.26 (s, 1H, N-H), and 7.44 (s, 1H, CONH) reveals the confirmation of structure.

Treatment of this carbohydrazide (3) with different types of aromatic aldehydes in absolute alcohol gave the title compounds (4a–4m).

5-(2- [2,6-dichlorophenylamino] benzyl)-1, 3, 4-thiadiazol -2-amine (5) derived from diclofenac was synthesized by reaction of mixture of conc. sulfuric acid, polyphosphoric acid and thiosemicarbazide with carbohydrazide of diclofenac (3). The purity of the compound (5) was confirmed by melting point, TLC, and IR, 1H-NMR spectral data. Melting point 122°C, percentage yield 42%, Molecular formula C15H12Cl2N4S. IR spectra showed a characteristic peak of N-H at 3448.21 cm-1, C-Cl stretch at 783 cm-1. This was further supported by 1H-NMR spectral data.

The synthesis of 2-substituted-6-phenylsubstituted imidazo (2,1-b)-1, 3, 4-thiadiazole derivatives (6a–6d) were carried out by the condensation of an appropriate α-bromo-phenyl ketones (a-d) with 5-(2-(2,6-dichlorophenylamino) benzyl)-1, 3, 4-thiadiazol-2-amine (5) under reflux conditions in absolute ethanol for 16–20 h, followed by the addition of P2O5 and refluxed further for 6–10 h to get hydrobromide salts, which on neutralization with saturated Na2 CO3 solution yielded free bases (as illustrated in general Scheme). This reaction precedes via intermediate iminothiadiazole, which spontaneously undergo ring closure to under reflux temperature to afford the desired fused heterocycles with good yields. The completion of reaction and purity of products were established by chromatographic analysis. The physicochemical data of compounds (6a-6d) is presented in [Table 3].

Pharmacological activity

Acute toxicity

Acute toxicity studies were carried out to reveal the level of toxicity and LD50 of the synthesized compounds. The synthesized compounds did not produce any toxicity (morbidity and mortality) up to dose level of 2000 mg/kg body weight. Hence, we have arbitrarily selected 10 mg/kg bw as the effective dose of the test compounds for the study of acute anti-inflammatory activity.

Acute in vivo anti-inflammatory activity

The in vivo anti-inflammatory activity was performed for compounds (4a–4m) and (6a–6d) using carrageenan-induced rat paw edema model by adopting the earlier reported method of Winter et al.[21] Carrageenan-induced edema is a nonspecific inflammation resulting from a complex of diverse mediators. Since edema of this type is highly sensitive to NSAIDs, carrageenan has been accepted as a useful agent for studying anti-inflammatory screening. During the second phase of inflammation, anti-inflammatory properties of test agents are detected as a result of inhibition of PG amplification. This model reliably predicts the anti-inflammatory efficacy of the NSAIDs. The data of anti-inflammatory activity is presented in [Table 4] and [Table 5], which revealed moderate to good anti-inflammatory activity for the synthesized compounds. In particular, compound 4d (73.3% and 70.4%) was most active, while compounds 4a (64.4% and 62.1%), 4c (65.1% and 64.1%), 4g (67.2% and 65.1%), and 4i (66.7% and 64.2%) displayed good-to-moderate inhibitory activity at the 2nd and 4th h, respectively. The anti-inflammatory activity of these compounds was comparable to that of the standard drug Diclofenac (65.5% and 61.4%) at the 2nd and 4th h. In the case of compounds 6 (a-d), compound 6b (71.82% and 70.1%) exhibited the most promising activity at the 2nd and 4th h among the series. The brief structure-activity relationship studies of these compounds indicated that the presence of electron releasing groups in the phenyl ring has greatly enhanced the anti-inflammatory activity, whereas compounds containing electron withdrawing groups exhibited moderate to poor anti-inflammatory activity.


  Conclusion Top


In this research project, we synthesized some novel series of Schiff base (4a–4m) and imidazo-(2,1-b) -1, 3, 4-thiadiazole (6a-d) derived from Diclefenac as described in Scheme. All the newly synthesized compounds were purified either by recrystallisation or column chromatography using silica gel (230–400 mesh). The structures of final compounds were established by spectral data IR, 1H-NMR. All the newly synthesized compounds gave satisfactory analysis of the proposed structures, which were confirmed on the basis of physicochemical and spectral data. In addition, the compounds are subjected to mass spectra for final molecular weight confirmation (results awaited). Acute toxicity studies of the synthesized compounds did not produce any toxic effect at the maximum dose of 2000 mg/kg body weight. All the newly synthesized compounds (4a–4m and 6a–d) were screened for anti-inflammatory activity using carrageenan-induced rat paw edema method. The anti-inflammatory activity of the synthesized compounds revealed that compound 4d (73.3% and 70.4%) and 6b (71.8% and 70.1%) were most active as compared to the reference diclofenac. Whereas compounds 4a, 4c, 4g, and 4i displayed good-to-moderate inhibitory activity. In conclusion, among the series of synthesized compounds, two derivatives (4d and 6b) have displayed the most encouraging results and could be further exploited for developing newer anti-inflammatory agents with better efficacy and safety, which necessitates further investigations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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