CHAPTER-1
1.1. INTRODUCTION
Inflammation is a multi-factorial process. It reflects the reaction of the organism to a range of stimuli and is related to many disorders such as arthritis, asthma, and psoriasis which require prolonged or constant treatment. Cyclooxygenase (COX), the rate limiting enzyme of the prostanoid biosynthetic pathway, catalyzes the conversion of arachidonic acid to important anti-inflammatory mediators such as prostaglandins (PGs), prostacyclin (PGI) and thromboxane (TXA2). The COX enzyme possesses two different catalytic activities: (i) cyclooxygenase activity that catalyzes the oxidation of arachidonic acid to produce hydroperoxy endoperoxide (PGG2), and (ii) peroxidase activity that reduces the endoperoxide (PGG2) to the hydroxyl endoperoxide (PGH2). The PGH2 is malformed to a wide range of enzymatic and nonenzymatic mechanisms into the primary prostanoids.[3]
Heterocyclic ring system containing carbazole and their derivatives aroused great interest for the past and recent years due to wide variety of biological properties such analgesic, anti-inflammatory, anticancer, anti-proliferative, anti-tubercular, antifungal and antimicrobial activities.[17]
Carbazole is an aromatic heterocyclic organic compound. It has a tricyclic structure, consisting of two six membered benzene ring fused on both side with five membered nitrogen containing ring. The carbazole ring present in a variety of naturally occurring medicinally active substances e.g., carbazomycins, oxazinocarbazoles, indolocarbazoles, oxazolynil carbazoles etc.[17]
1.1.1. Heterocyclic compounds
A cyclic natural compound containing each carbon molecules in ring arrangement is alluded to as a carbocyclic compound. In the event that as a base one molecule other than carbon, frames a piece of the ring framework then it is assigned as a heterocyclic compound. Nitrogen, oxygen and sulfur are the most well-known heteroatoms however heterocyclic rings containing other hetero molecules are additionally generally known.[10]
A gigantic number of heterocyclic mixes are known and this number is expanding quickly. In like manner the writing regarding the matter is exceptionally huge. Heterocyclic mixes might be ordered into aliphatic and fragrant. The aliphatic heterocyclics are the cyclic analogs of amines, ethers, thioethers, amides and so on. Their properties are especially impacted by the nearness of strain in the ring. These mixes by and large comprise of little (3-and 4-membered) and normal (5 to 7 membered) ring frameworks.
The fragrant heterocyclic mixes, conversely, are those which have a heteroatom in the ring and carry on in a way like benzene in a portion of their properties. Moreover, these mixes additionally agree to the general administer proposed by Hückel.
This rule states that aromaticity is obtained in cyclic conjugated and planar systems containing (4n + 2) π- electrons. The conjugated cyclic rings contain six π-electrons as in benzene, and this forms a conjugated molecular orbital system which is thermodynamically more stable than the non-cyclically conjugated system.
This extra stabilization results in a diminished tendency of the molecule to react by addition but a larger tendency to react by substitution in which the aromatic ring remains intact.[11]
1.1.2. Chemistry of heterocyclic compounds
Organic compounds can have an assortment of structures. These structures can be non-cyclic or cyclic. The cyclic frameworks containing just carbon molecules are called carbocyclic and the cyclic frameworks containing carbons and no less than one other component are called heterocyclic. In spite of the fact that various heteroatoms are known to be a piece of the heterocyclic rings, the most widely recognized heteroatoms are nitrogen, oxygen or sulfur.[12]
A heterocyclic ring may contain at least one heteroatoms which might possibly be same. Additionally the rings might be soaked or unsaturated. Almost 50% of the known natural mixes contain no less than one heterocyclic ring. Numerous heterocyclic mixes happen normally and are effectively engaged with science e.g., nucleic acids (purine and pyrimidine bases), vitamins (Thiamine B1, Riboflavin B2, Nicotinamide B3, Pyridoxol B6 and Ascorbic corrosive C), heme and chlorophyll, penicillins, cephalosporins, macrolides and so on. The investigation of heterocyclic science is a tremendous and extending territory of science as a result of their applications in drug, agribusiness, photodiodes and different fields.[13]
Heterocyclic compounds are devided in aliphatic and aromatic heterocycles. The aliphatic heterocycles are the cyclic analogues of amines, ethers and thioethers and their properties are subjective by the ring strain. The three and four membered aliphatic heterocyclic rings are more anxious and reactive compared to five and six membered rings. The common aliphatic heterocyclic compounds are aziridine (I), oxirane (II), thiirane (III), azetidine (IV), oxetane (V), thietane (VI), pyrrolidine (VII), tetrahydrofuran (VIII), tetrahydrothiophene (IX) and piperidine (X).
The heterocycles which show aromatic behavior as in benzene are called the aromatic heterocyclic compounds. These compounds follow the Hückel’s rule which states that cyclic conjugated and planar systems having (4n+2) π electrons are aromatic. Some simple aromatic heterocyclic compounds are pyrrole (XI), furan (XII), thiophene (XIII), imidazole (XIV), pyrazole (XV), oxazole (XVI), thiazole (XVII) and pyridine (XVIII).
1.2. Carbazole profile
The pervasiveness of heterocycles in restoratively vital mixes keeps on determining the requirement for new strategies for their arrangement. Carbazole subsidiaries are known to have imperative photograph physical and organic properties. Carbazole (Fig. 1.3.) was detached first from coal tar in 1872 by Graebe and Glazer.
Carbazole is a fragrant heterocyclic natural compound. It has a tricyclic structure, comprising of two six-membered benzene rings combined on either side of a five-membered nitrogen-containing ring. The compound's structure depends on the indole structure, yet in which a second benzene ring is intertwined onto the five-membered ring at the 2– 3 position of indole (comparable to the 9a– 4a twofold bond in carbazole, individually).[7]
Carbazole and its derivatives are an important type of nitrogen containing heterocyclic compounds that are widespread in nature. The chemistry and biology of carbazole have attracted an increasing interest over the last 50 years because it possess a desirable electronic and charge transport properties, as well as large π-conjugated system so various functional groups are easily introduced into structurally rigid carbazolyl ring. These characteristics result in the extensive potential application of carbazole in the field of chemistry (photoelectrical material, dyes, supramolecular recognition) and medicinal chemistry (antitumor, antiinflammatory, antimicrobial, psychotropic, anti-oxidative).[7]
Carbazole ring is present in a variety of naturally occurring medicinally active substances.[11]
1.3. Synthesis of Carbazole
a. Pschorr Reacction
b. A palladium-catalyzed reaction sequence consisting of an intermolecular amination and an intramolecular direct arylation enabled highly regioselective synthesis of functionalized indoles or carbazoles and proved to be amenable to the use of inexpensive 1,2-dichloroarenes as electrophiles.
c. The iridium-catalyzed dehydrogenative cyclization of 2-aminobiphenyls proceeds smoothly in the presence of a copper cocatalyst under air as a terminal oxidant to yield N-H carbazoles. A similar catalytic system can also be used for a dimerization reaction of 2-aminobiphenyl involving 2-fold C-H/N-H couplings.
d. Various carbazoles can be synthesized from substituted biaryl azides at 60°C using Rh2(OCOC3F7)4 or Rh2(OCOC7H15)4 as catalysts.
e. An efficient route to carbazoles and dibenzofurans has been developed. The reaction of o-iodoanilines or o-iodophenols with silylaryl triflates in the presence of CsF to afford N- or O-arylated products is followed by a cyclization using a Pd catalyst to carbazoles and dibenzofurans in good to excellent yields. Various functional groups are tolerated.
1.4. Literature review of Carbazole
1.4.1. Antimicrobial activity
Gu et al. 2014 has reported a series of new N-substituted 1H-dibenzo[a,c]carbazole derivatives were synthesized from dehydroabietic acid, and their structures were characterized by IR, 1H NMR and HRMS spectral data. All compounds were evaluated for their antibacterial and antifungal activities against four bacteria (Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas fluorescens) and three fungi (Candida albicans, Candida tropicalis and Aspergillus niger) by serial dilution technique. Some of the synthesized compounds displayed pronounced antimicrobial activity against tested strains with low MIC values ranging from 0.9 to 15.6 µg/ml. Among them, two compounds exhibited potent inhibitory activity comparable to reference drugs amikacin and ketoconazole.[8]
1.4.2. Antideressant activity
Kim et al. 2016 has discovered a novel 5-HT7R antagonist for treatment of depression, we designed N-acyl-carbazole derivatives which were synthesized and biologically evaluated against 5-HT7R. The compound, 1-(9H-carbazol-9-yl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)hexan-1-one, showed good selectivity over other serotonin receptor subtypes and turned out to be a novel selective 5-HT7R antagonist following functional assays. The compound showed moderate activity on hERG channel and good stability in microsomal stability test. The compound exhibited a good pharmacokinetic profile with 67.8% oral bioavailability and good penetration to the brain. The compound was also tested in in vivo depression animal model and showed antidepressant effect in the forced swimming test. Therefore, the selective 5-HT7R antagonist compound can be considered as a good lead for discovery of novel 5- HT7R antagonists as antidepressants.[13]
1.4.3. Alzheimer disease activity
Thiratmatrakul et al. 2014 discovered a new tacrineecarbazole hybrids were developed as potential multifunctional anti-Alzheimer agents for their cholinesterase inhibitory and radical scavenging activities. The developed compounds showed high inhibitory activity on acetylcholinesterase (AChE) with IC50 values ranging from 0.48 to 1.03 mM and exhibited good inhibition selectivity against AChE over butyrylcholinesterase (BuChE). Molecular modeling studies revealed that these tacrineecarbazole hybrids interacted simultaneously with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The derivatives containing methoxy group showed potent ABTS radical scavenging activity. Considering their neuroprotection, our results indicate that these derivatives can reduce neuronal death induced by oxidative stress and bamyloid (Ab). Moreover, S1, the highest potency for both radical scavenging and AChE inhibitory activity, exhibited an ability to improve both short-term and long-term memory deficit in mice induced by scopolamine. Overall, tacrineecarbazole derivatives can be considered as a candidate with potential impact for further pharmacological development in Alzheimer’s therapy.[22]
1.4.4. 5-HT6 antagonist
Nirogi et al. 2012 has reported the design, synthesis and SAR of novel tetrahydrocarbazole derivatives having 5-HT6 receptor antagonist activity is presented. The racemic compound was found to possess desirable pharmacokinetic properties, adequate brain penetration and activity in animal models of cognition.[16]
Tetrahydro carbazole derivaticve
1.4.5. Leukemia therapy
Ito et al. 2011 has carried out primary screening of 13 carbazole alkaloids isolated from the plant species Murraya euchrestifolia (Rutaceae) on cell growth inhibition of the human leukemia cell line HL-60. Among them, murrayafoline & murrayazolinine (Methyl (E)-2-[(2S,3S,7aS,12bS)-3-ethyl-7a-hydroxy-8-methoxy-2,3,4,6,7,12b-hexahydro-1H-indolo[2,3-a]quinolizin-2-yl]-3 methoxyprop-2-enoate) exhibited significant growth suppression due to apoptosis mediated by the activation of the caspase-9/caspase-3 pathway.[9]
1.4.6. Neuroprotective activity
Bashir et al. 2015 given Carbazoles represent an important class of heterocycles. These have been reported to exhibit diverse biological activities such as antimicrobial, antitumor, antiepileptic, antihistaminic, antioxidative, anti-inflammatory, antidiarrhoeal, analgesic, neuroprotective and pancreatic lipase inhibition properties. A series of carbazole derivatives such as N-substituted carbazoles, benzocarbazoles, furocarbazoles, pyrrolocarbazoles, indolocarbazoles, imidazocarbazoles, etc. have been synthesized. The N-substituted derivatives have gained the attention of researchers due to their therapeutic potential against neurological disorders and cell proliferation. Herein an attempt is made to review the medicinal importance of recently synthesized N-substituted carbazoles.[4]
1.4.7. Antiproliferative activity
Ferlin et al. 2011 given Some modified 11H-pyrido[a]carbazoles (11H-PyC) and their corresponding tetrahydro derivatives (11H-THPyC) were prepared. A common multistep pathway characterized by conventional reactions, including a Fischer-indole-type synthesis, yielded the tetracyclic compounds. To improve cytotoxicity, 11H-PyC and 11H-THPyC derivatives were endowed with a diethylaminoethyl side chain. The antiproliferative activity was assessed in three human tumor cell lines, and a number of derivatives showed a cytotoxic effect in agreement with their capacity to form a molecular intercalative complex with DNA and to interfere with the relaxation activity of DNA topoisomerase II. In contrast, three derivatives that exhibited significant antiproliferative efficacy, showed no inhibition of topoisomerase II, thus suggesting an unexpected and novel mode of action for these ellipticine-like compounds independent of topoisomerase II activity.[6]
1.4.8. Anti tuberculosis activity
Auranwiwat et al. 2014 has reported Two novel carbazole alkaloids, guillauminines A and B, and sixteen known compounds were isolated and identified from the acetone extract of Clausena guillauminii roots. Their structures were elucidated by spectroscopic methods. The cytotoxic, antimalarial and antimycobacterial activities of the isolated compounds were evaluated.[2]
1.4.9. Antitumor activity
Murli et al. 2016 has described about Claisen-Schmidt condensation of 2,3,4,9-tetrahydro-1H-carbazol-1-one with 3-bromo-4- methoxy benzaldehyde afforded the 2-(3'-bromo-4'-methoxybenzylidene)-2,3,4,9-tetrahydro- 1H-carbazol-1-one Compound was allowed to react with different organic reactants, hydroxylamine hydrochloride, malononitrile and guanidine nitrate through condensation cum cycloaddition reactions to afford a series of the respective novel hetero annulated carbazoles such as isoxazolo-, pyrido- and pyrimido carbazoles. The structures of the compounds were established by FT-IR, 1H NMR, 13C NMR, X-ray diffraction and elemental analysis. The compounds have been screened for in vitro anti-tumor activity by MTT assay and displayed enviable selective growth inhibition on MCF-7 cell line compared to A-549 cell line. Apoptotic morphological changes in MCF-7 and A-549 cells were visualized using fluorescent microscopic technique. The preliminary structure activity relationships were also carried out.[11]
1.4.10. Cytotoxic activity
Ahmad et al. 2014 has told about Murraya koenigii (L.) (Rutaceae), which is an indigenous medicinally important herb of Indian origin and now is widely distributed throughout southern Asia. The stem bark, leaves and roots of Malayan Murraya koenigii were selected for phytochemical investigation. Eight carbazole alkaloids was isolated and identified using spectroscopic methods including NMR, IR, UV, MS spectra data. Crude extract and isolated compounds from the roots of this plant were screened for cytotoxic activity and antitumor promoting activity. All crude extracts of the roots including the isolated compounds, mahanimbine, mahanine and murrayafoline-A exhibited significant cytotoxic activity against CEM-SS cell line with IC50 3 μg/ml.[1]
1.4.11. Anti-HIV activity
Głuszynska et al. 2015 has told about Carbazole skeleton, which is the key structural motif of many biologically active compounds including synthetic and natural products. Over the past several years, a large number of research highlighting the significance of carbazole derivatives has been reported in the literature. The present review focuses on the recent progress, from 2010 until now, in knowledge on Anti-HIV biological properties of classical, tricyclic carbazole derivatives.[7]
1.4.12. Antioxidant activity
Taj et al. 2011 has reported a novel tricyclic carbazoles 4aek were synthesized in one-pot employing sydnone derivatives as masked hydrazines by the ring transformation in presence of conc. HCl and cyclohexanone. The title compounds were screened for anti-tubercular, anti cancer, DNA cleavage, antioxidant activity. MIC, GI50, LC50, TGI were evaluated. The title compounds have exhibited significant antitubercular, DNA cleavage and antioxidant activities and partial anticancer activity.[21]
Anticancer activity
Nandy et al. 2014 has tells about Carbazole alkaloids constitute an important class of naturally occurring heterocycles, isolated from the Rutaceae family. First Carbazole alkaloids were isolated as natural products from Murraya koenigii that exhibited strong antimicrobial activity. The stem bark of Murraya koenigii contains dimeric carbazole alkaloids along with six carbazole alkaloids. Traditionally, this plant is used as stimulant, stomachic, febrifuge, analgesic and for the treatment of diarrhoea, dysentry and insect bites. Along with these activities it also shows anticancer property.[15]
1.4.13. Antifungal activity
Thevissen et al. 2009 reported a report that tells Carbazole derivatives are well known for their various pharmacological activities, including anti-HIV, anticancer, antibacterial and antifungal activities. This review will focus on carbazoles that possess antifungal activity against Candida albicans, the major human fungal pathogen. In our search for new fungicidal compounds, we identified a series of substituted carbazoles, termed N-alkylated 3,6-dihalogenocarbazoles, that exhibit fungicidal activity against C. albicans and the emerging pathogen Candida glabrata. The most potent fungicidal compounds of this series were characterized by minimal fungicidal concentration (MFC) between 8.5 and 25M. To analyse the structural determinants for fungicidal activity of these carbazole derivatives we selected 10 such derivatives and performed further analysis. Interestingly, some of these N-alkaylated 3,6-dihalogenocarbazoles were active against Candida biofilms grown in microtiter plates. In this review, we will further discuss the putative therapeutic potential of the antifungal carbazole compounds as antimycotics.[23]
1.4.14. Aim and Objective:
Carbazole nucleus is an important pharmacophore in medicinal chemistry, since a large number of its derivatives posses useful biological properties. Carbazole are known to posses Antimicrobial (Gu et al 2014), Neuroprotective (Bashir et al. 2015), Antituberculosis (Auranwiwat et al.2014), Cytotoxic (Ahemad et al.2014), Antitumor (Murli et al. 2017), Antifungal (Thevissen et al. 2009), Anti-HIV (Gluszynska et al. 2015), Antioxidant (Taj et al. 2011), Antiproliferative (Ferlin et al. 2011).
The carbazole ring is frequent moiety present in various drugs such as Carvidilol (Antihypertensive), Caprofen (Inflammatory), Rimcazole (Neuroleptic), Carazolole (Antitanginal), Elliptinium (Antitumor).
In view of this medicinal importance of carbazole nucleus as potential therapeutic agents. It was thought worthwise to synthesize and characterized certain newer compounds having carbazole nucleus and evaluate for their biological potential.
3.1.3. Inflammation
Inflammation is a multi-factorial process. It reflects the response of the organism to the various stimuli and is related to many disorders such as arthritis, asthma, and psoriasis which require prolonged or repeated treatment. Cyclooxygenase (COX), the rate limiting enzyme of the prostanoid biosynthetic pathway, catalyzes the conversion of arachidonic acid to important anti-inflammatory mediators such as prostaglandins (PGs), prostacyclin (PGI) and thromboxane (TXA2). The COX enzyme possesses two distinct catalytic activities: (i) cyclooxygenase activity that catalyzes the oxidation of arachidonic acid to produce hydroperoxy endoperoxide (PGG2), and (ii) peroxidase activity that reduces the endoperoxide (PGG2) to the hydroxyl endoperoxide (PGH2). The PGH2 is transformed to a wide range of enzymatic and nonenzymatic mechanisms into the primary prostanoids.
It is well known that cyclooxygenase exists in two isoforms, cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). The COX-1 is a constitutive enzyme and is responsible for the production of cytoprotective prostaglandins in the gastrointestinal tract (GI) and proaggregatory thromboxanes in blood platelets. However, COX-2 is an inducible enzyme, which is induced in response to the release of several pro-inflammatory mediators such as TNFa, IL-6, IL-1, LPS, carragenan, TPA, and histamine. Since COX-2 is involved in the inflammation and the resulting pain, inhibiting its enzymatic activity would be of therapeutic value. Many nonsteroidal anti-inflammatory drugs (NSAIDs) were found to interact with these enzymes and inhibit their enzymatic activity. These molecules include aspirin and indomethacin which are non-selective anti-inflammatory agents and inhibit both enzymes COX-1 and COX-2. Aspirin inhibits COX-1 more strongly than COX-23 and inhibition of COX-1 by aspirin reduces the production of PGE2 and PGI2, which has an adverse ulcerogenic effect. The COX-2 expressions was associated with inflammation and other pathologies, such as cancer proliferation and have led to the development of COX-2 selective inhibitors to improve the therapeutic potency and reduce the classical side effects associated with the use of conventional NSAIDs. Therefore, selective COX-2 inhibitors (coxibs) with better safety profile have been marketed as a new generation NSAIDs. But careful prospective examination of coxibs has revealed unexpected cardiovascular adverse effects such as myocardial infarction (MI). Therefore, development of novel compounds having anti-inflammatory activity with an improved safety profile is still of paramount importance.
3.1.4. Procedure
Albino wistar rats of either sex (150-200 gm) were divided into various groups of three animals each. Animals were deprived of food for 12 hrs. prior to experiment and only water is given. First group was used as a control and received 1ml of 1% w/v sodium DMSO suspension in saline, the second group received DMSO suspension of Diclofenac sodium( 20 mg/kg) orally and the third group received sodium DMSO suspension of test compounds at a dose of 20 mg/kg orally. One hour after the administration of the compounds, carrageenan suspension (0.2 ml of 1% w/v suspension in 0.9% saline solution) was injected into the sub planter region of left hind paw of the animals. Immediately, the paw volume was measured using digital vernier calliper (initial paw thickness, Vc). Thereafter, the paw volume was measured after 0 hr, ½ hr, 1hr, 2 hr and 4 hr after carrageenan administration. The difference between initial and subsequent readings gave the change in edema volume for the corresponding time.
Anti-inflammatory activity – [% inhibition = (Vc – Vt)/ Vc × 100]
3.2. RESULT
3.2.1. Chemistry
The desired carbazole derivatives were prepared by multistep reaction summarized in scheme 1. In the first step, 9H-Carbazole and acetone in prensence of chloro acetal chloride afforded the corresponding carbazole derivative (2a). Carbazole derivative was allowed to react with hydrazine hydrate in ethanol and dioxane to gives corresponding pyrazole derivative (3a). IR spectra of all final carbazole derivatives (4a-i) showed a intense peak in the region 1676 -1600 cm-1 due to the C=N stretching vibration which indicate the presence of C=N in carbazole ring. A strong, characteristic band in the region 1230- 1200 cm-1 due to the C-N stretching vibration. Peak appeared at 869-820 cm-1 due to C=S stretching. Band for aromatic C-H stretching vibrations was observed at 3261-3025 cm-1. Peak for aromatic C-H are generally appeared at longer wavelength than the aliphatic C-H. It is due to the higher stretching of pi electrons present in aromatic ring.
For compound 4a C-O-C asymmetric and symmetric stretching vibrations was appeared between 1230 cm-1 and 1028 cm-1 respectively. Vibration characteristic of C-O-C system would not be expected to differ greatly from the C-C-C system, however vibrations involving oxygen atom results in greater dipole moment changes than those involving carbon atoms, more intense IR bands are observed for ether. For compound 4e and 4f O-N-O asymmetric and symmetric stretching vibrations was appeared between 1530-1522 cm-1 and 1326-1322 cm-1 respectively. These two compounds show two intense bands due to asymmetric and symmetric stretching vibrations of the highly polor nitrogen- oxygen bonds. A stretching vibration of C-Br was appeared at 680 cm-1 for compound 4c and stretching vibration of C-Br was appeared at 765 cm-1 for compound 4h. An intense peak was observed in the region of 3261-3322 cm-1 due to N-H stretching vibration which confirms the conversion of substrates into the expected products.
3.2.2. BIOLOGICAL ACTIVITY
Anti-inflammatory activity:
Anti-inflammatory activity was performed by carrageenan induced inflammation in rat paw edema model. This project has been approved by the Institutional Animal Ethical Committee at Hygia Institute of Pharmaceutical Education and Research, Lucknow (Ref. No. HIPER/IAEC/19/18/04). Adult albino rats (wistar strain) of either sex weighing 150-200 gm were used. The animals were divided into three groups (control, standard and test) and each group comprising of three rats. Animals were deprived for 12 hrs prior to experiment and only water is given. First group was used as a control and received 1 ml of 1% w/v sodium DMSO suspension in saline, the second group received DMSO suspension of Diclofenac sodium (20 mg/kg) orally and the third group received sodium DMSO suspension of the test compounds, carrageenan suspension (0.2 ml of 1% w/v suspension in 0.9% saline solution) was injected into the sub planter region of left hind paw of the animals. Immediately, the paw volume was measured using digital vernier calliper (initial paw thickness, Vc). Thereafter, the paw volume was measured after 0 hr, ½ hr, 1 hr, 2hr and 4 hr after carrageenan administration. The difference between initial and subsequent readings gave the change in edema volume for the corresponding time.
3.3. CONCLUSION
The dissertation describes on synthesis and pharmacological evaluation of different carbazole derivative as potential anti-inflammatory compound. Various carbazole derivative where synthesized and evaluated for anti inflammatory using in vivo performed by carrageenan induced inflammation in rat paw edema method respectively.
These compounds were synthesized by reaction between chloro acetyl chloride and carbazole in presence of acetone to afford the corresponding carbazole derivatives. Further carbazole derivatives on treatment with substituted aldehyde in presence of 10% NaOH afforded corresponding carbazole derivatives. The newly synthesized compound were characterize by using spectroscopic (UV, IR, 1HNMR) and chromatographic techniques. Physiochemical studies were carried out to assess the solubility and chemical stability of the synthesized compounds.
Study stated that carbazole in combination with other hetero cycles ring might be used as a lead for finding the potent anti-inflammatory agents. Potency of the newly synthesized compounds was determined on the basis of their reduction in inflammation at different time interval by using carrageenan induced inflammation in rat paw edema model of three rats significantly different from standard drug diclofenac sodium.
Presence of an electron releasing group on the benzene ring also increases the potency. Substituted carbazole derivative (4a and 4f) also increases the therapeutic value of carbazole toward the treatment of inflammation. It is concluded that further research on carbazole core is needed for the discovery of a potent anti- inflammatory agent. Thus we observed that carbazole in combination with other heterocyclic might be used as a lead for further study in developing such compounds as a good lead molecules with better pharmacological profile.