A Comprehensive Review on Recent Advances in Synthesis and Pharmacotherapeutic Potential of Betacarbolines

 

Alivelu  Samala^1*, Srinivasa Murthy M², Krishna Mohan Gottumukkala³

¹Department of Pharmaceutical Chemistry, Holy Mary Institute of Science and Technology, Bogaram, Keesara, Hyderabad, Telangana, India.

²Department of Pharmaceutical Chemistry, Vignan Institute of Pharmaceutical sciences, Near Ramoji Film City, Deshmukhi, Nalgonda, India.

³Centre for Pharmaceutical Sciences, Institute of Science and Technology, JNT University Hyderabad, Kukatpally, Telangana, India.

 

ABSTRACT:

Heterocyclic analogues and their derivatives have attracted strong interest in medicinal chemistry due to their biological and pharmacological properties. β-carboline also known as nor-harmane is a nitrogen containing heterocyclic compound. It belongs to the group of indole alkaloids and consists of pyridine ring that is fused to an indole skeleton. These tricyclic nitrogen heterocyclics are formed in plants and animals as Maillard reaction products between amino acids and reducing sugars or aldehydes. These compounds have special significance in the field of Medicinal chemistry due to their remarkable pharmacological potentialities and their derivatives have attracted a great deal of interest due to their wide range of biological activities such as antimicrobial, antitumor, cytotoxic, antiplasmodial, antioxidant, antimutagenic, antigenotoxic and hallucinogenic properties. It acts on gamma-aminobutyric acid type A and monoamine oxidase A or B receptor, enhances insulin sensitivity and also produces vasorelaxant effect. Harmine prevents bone loss by suppressing osteoclastogenesis. This review is mainly an attempt to present the research work reported in the recent scientific literature focusing on different synthetic methods and pharmacological activities of betacarboline derivatives which may contribute in future to synthesize various analogs and to develop new pharmacologically less toxic medicines.

 

 

 

1. INTRODUCTION AND SCOPE:

β-Carboline also known as norharmane, is a nitrogen containing heterocyclic and consist of a variety of both simple and complex natural and synthetic compounds¹. It is a key pharmacophore present in a large number of natural tricyclic alkaloids. Naturally occurring β-carboline alkaloids and synthetic analogues containing β-carboline subunit are endowed with diverse pharmacological properties including anticancer activity against colon and lung cancers, central nervous system activity in mammals and also as the biological control agent for receptor research on bio-enzyme inhibitors.

 

Some β-carbolines are known to bind with high affinity to the central benzodiazepine receptors with anticonvulsive and anxiolytic properties. Norharmine also prevents bone loss by suppressing osteoclastogenesis^2-11. These advances warrant reviewing the chemistry and biological properties of various betacarboline derivatives

 

1.1 Structure and Occurrence:

β-Carboline belongs to the group of indole alkaloids and consists of pyridine ring that is fused to an indole skeleton. The structure of β-carboline is similar to that of tryptamine, with the ethylamine chain re-connected to the indole ring via an extra carbon atom, to produce a three-ringed structure^{12, 13}.

 

 

β-Carboline alkaloids are an important group of natural and synthetic indole alkaloids which all bear the common feature of a tricyclic pyrido[3,4-b]indole ring structure¹⁴. The first β-carboline alkaloid recognized was harmalin, originally isolated in 1841 from Peganum harmala¹⁵, also known as Syrian rue. The occurrence of β-carbolines in nature is widespread, presumably due to their simple biogenesis from tryptamine (or tryptophan), and today β-carbolines have been isolated from various plant families, fungi, animal tissues and marine sources. The fully aromatic members of this group are named β-carbolines (βCs, 1), whereas the members with partially saturated rings are known as 3,4-dihydro-β-carbolines (DHβCs, 2) and 1,2,3,4-tetrahydro-β-carbolines (THβCs, 3) ( (Figure 1).

 

 

Figure 1. The basic structural units of βCs (1), DHβCs (2) and THβCs (C3)

 

 

 

2. SYNTHESIS OF BETACARBOLINE DERIVATIVES:

The Pictet-Spengler condensation is commonly used to synthesize β-carbolines, due to its analogy to the biosynthesis of these systems. This reaction needs an aryl ethylamine, an aldehyde and an acid catalyst. This reaction can be considered a special case of the Mannich reaction.

 

some groups describe a sequence of Pictet-Spengler condensation followed by oxidation, without the isolation of the intermediate tetrahydrocarbolines (THC), to prepare the carbolines. The reaction mechanism occurs by initial formation of an iminium ion (4) followed by electrophilic addition at the 3-position, in accordance with the expected nucleophilicity of indoles, to give the spirocycle (5). After migration of the best migrating group, deprotonation gives the product (7)^18-22.

 

 

Ya-Ching Shen et al.²³ synthesized a 1-substituted tetrahydro and dihydro beta carbolines by the treatment of tryptamine with substituted benzaldehyde in the presence of CF₃ COOH via Pictet- Spengler cyclisation. Subsequent oxidation of 1, 2, 3, 4-tetrahydro-β –carbolines (7) by DDQ furnished 3, 4-dihydro-β -carboline derivatives (8).

 

 

                                                                                                                                   7                                                                      8

 

The 3-(2-thioxo-1, 3, 4-oxadiazol-5-yl) β-carbolines1a-c were prepared by Maria et al²⁴ from the commercial L-tryptophan. The condensation reaction of (9a-c), formaldehyde 37% ^{25, 26} and the primary amines isopropyl amine, butyl amine, cyclohexylamine and benzylamine, using ethanol as solvent, afforded the Mannich bases (10a-c, 11a-c, 12a-c and 13a-c), respectively. Condensation reaction with pyrrolidine and morpholine secondary amines under the same conditions, afforded the Mannich bases (14a-c and 15a-c), respectively (Scheme 1). The Mannich bases 10-15(a-c) were obtained in range of 52% to 92% yields from (9a-c), and in six steps from commercial L-tryptophan with 15-34% overall yields²⁷.

Scheme. I

 

 

Ya-Ching Shen et al²⁸ synthesized a new series of 1-substituted carbazolyl-1, 2, 3, 4-tetrahydro β-carboline and carbazolyl-3,4-dihydro β-carboline derivatives based on the analog design of manzamine A. These new compounds bear an N-alkyl carbazole conjugated with a β-carboline-like nucleus. The main part of manzamine A illustrated in Figure 16 is similar in both shape and size to final target compounds. The distances between N atom on carbazole and N atoms on carboline-nucleus are almost the same as those in the main part. With the aim of studying the SAR, they focused on the lengh of the N-alkyl side chain on the carbazole ring. Compound (17) was prepared by N-alkylation of carbazole with the appropriate alkyl bromide as depicted in Scheme II. Subsequent synthesis of compound (18) was achieved by Duff reaction, which required hexamethylene tetramine / trifloroacetic acid. Final compounds were furnished from tryptamine by application of Pictet-

 

Spengler cyclization. Subsequent oxidation of 1,2,3,4-tetrahydro-β-carbolines (19) by DDQ yielded 3,4-dihydro-β-carboline derivatives (20).

 

 

Scheme. II

 

To determine an optimal structure for anti-tumor activity, a variety of substituent was introduced onto the amino- or pyridyl- nitrogen atom of 3-amino-β-carboline, or onto the meta-or para-position of the benzyl group of 3-benzylamino-β-carboline according to the known methods by Reiko Ikeda et al²⁹ (Schemes III-VI). The construction of β-carboline frame work was accomplished by Pictet – Spengler reaction of L-tryptophan with formaldehyde. After esterification of the carboxyl group with thionyl chloride and methanol, the1, 2, 3, 4-tetrahydro-β-carboline-3-carboxylic acid methyl ester (22) was dehydrogenated by trichloroisocyanuric acid, TCCA, leading the formation of β-carboline-3-carboxylic acid methyl ester (23).

The total synthesis of 3-amino-β-carboline (27) was completed in 7 steps and 33% overall yield, after Curtius rearrangement of the corresponding carbonyl azide (25) followed by hydrolysis of the benzyl carbamate (26) (Scheme III). As shown in Scheme IV, 3-methyl amino-β-carboline (28) was prepared by LAH reduction of the benzyl carbamate in70% yield. In the same way (30) was synthesized by LAH reduction of the corresponding amides (29) in moderate to high yields (Scheme IV).

 

In addition, the synthesis of 2-methyl-3-benzylamino-β carbolinium salts (33) was illustrated in (Scheme V). The solution of dichloromethane was treated with methyl trifluoromethanesulfonate to quaternize the N-2 atom of the pyridine ring to afford the tri-fluoromethanesulfonate salt (32). The counter anion of (32) was changed to chloride using Amberlite IRA-900 anion exchange resin to form 33 in 43% yield (Scheme V). The meta-or para-substituted 3-benzylamino derivatives (34) were synthesized from (27) by a convenient reductive amination with the corresponding meta-or para- substituted benzaldehydes and sodium cyanoborohydride in high yields, as shown in (Scheme VI).

 

 

Scheme.III

 

Scheme. IV

 

Scheme. V

 

 

Scheme.VI

 

 

Hong-Bin Zhang et al³⁰ synthesized N-substituted tetrahydro-β-carboline–imidazole derivative (45), by using commercial tryptophol (35). After OH and NH groups were protected with tert-butyl (dimethyl) silyl and with phenylsulfonyl groups, respectively, an aldehyde group was installed at the 3-positionof the indole moiety to afford compound (38). Condensation of (38) with (R)-(+)-2-methyl-2-propane sulfonamide led to imine (39). Starting from compound (39), tetrahydro-β-carboline (43) was formed through three sequential steps including reduction of the imine, de -protection of the OH group and ring closure. Next, key intermediate 43 was converted to ( 44a) and (44b) under two different displacement conditions. The acylation of (44a) and (44b) led to (45a) and (45b). Subsequently, N-substituted tetrahydro-β-carboline–imidazole hybrid (46) was formed from (45a) and (45b) using various substituted imidazoles (imidazole, 2-ethyl-imidazole, benzimidazole or 5, 6-dimethyl-benzimidazole) in 72–88% yield (Scheme VII)

 

Scheme VII

 

 

 

For the construction of the eudistomin skeleton Van Maarseveen et al³¹, used methyl α, β- isopropylidene-D-glycerate (47) as the starting compound. After deprotection of the iso- propylidene group by stirring in 80% HOAc for 5 days, the terminal primary alcohol was protected with the di- phenyl-tert-butyl silyl group gave (48). Protection of the remaining hydroxyl group was carried out by treatment with 5, 6-dihydro-4-methoxy-2H-pyran and a catalytic amount p-toluene sulfonic acid in THF, followed by de- protection of the silyl group gave (49b) in 96% yield.

 

A precursor for the C(1)-methyl derivative was commercially available in optically pure form as (R)-(-)-methyl 3- hydroxy-2-methylpropionate (49c). The terminal alcohol functionality in (49a-c) was transformed into a thiol group by using the method developed by Kellogg and co-workers³². After that alcohols (49a-c) were transformed into the tosylates which gave, after purification followed by treatment with Cs2C03 and thiolacetic acid in DMF, the thioacetates (50a-c). (Scheme. VIII) After liberation of the thiols with sodium methoxide in methanol solution and subsequent alkylation under phase-transfer conditions using bromo- chloromethane and benzyl triethylammonium chloride/ powdered KOH, the chloromethyl sulfides (51a-c ) were isolated without further purification in excellent yields.

N-Hydroxytryptamines (Scheme IX) were prepared by treatment of (52) with sodium hydride in 1,2-di- methoxyethane (DME) and subsequent addition of allyl bromide gave a quantitative yield of the 0-allyl derivative of (53), which was methylated by stirring in DMSO with methyl iodide and powered KOH to give (54). Deprotection of the allylgroup was carried out with a cocktail of palladium (II) acetate/ triphenylphosphine/ triethylamine" on formate in refluxing acetonitrile" gave(55) in an overall yield of 98%.

 

Compounds (52) and (55) were treated with sodium hydride in freshly distilled DME. This solution of the oxoanion of (52) or (55) is dropped slowly (3-4 h) under an argon atmosphere into a cooled (0^oC) DME solution of the iodomethyl sulfides prepared in situ from (51a-c) gave (56). As described in a previous paper,"deprotection of the TEOC group was most effectivily carried out by using % akedn fluoride ion generated by tetrabutylammonium chloride and potassium fluoride dihydrate in acetonitrile at elevated temperature (50 ⁰C), gave (57) (Scheme X). Cyclization of (57) gave the racemic mixture (Scheme XI). The cis / trans (58) ratios were determined by analytical HPLC.

 

 

 

 

Scheme. VIII

 

 

Scheme. IX

 

 

Scheme. X

 

 

Scheme XI

 

 

3. MOLECULAR SPECTROSCOPY OF BETACARBOLINES:

A.     Ultraviolet Absorption Spectroscopy:

The characteristic UV- visible spectrum of the alkaloid (59) showed maxima at 207, 258 and 371 nm in the range of 200–550 nm. The spectra showed a clear isosbestic point at 407 nm indicating a clear equilibrium between free and DNA bound form of the structure. These remarkable spectral changes disclosed π-π-stacking interactions between the chromophore of this molecule and the DNA^{33, 34}

 

 

B.     IR data:

The IR spectral showed the distinctive absorption bands of 3325 cm-1 (N-H stretch), 1619 cm-1 (C=C aromatic stretch), 1453 cm-1(C-N stretch), 1163 cm-1 (C-O stretch) ^{35, 36}

 

C.     NMR data:

The 270-MHz ¹HNMR spectrum of urinary (62c) showed the following signals [δ value (number of H; multiplicity, J ), 1.49 (3H,t, J=7.3) [CH3]; 4.56 (2H,q, J=7.3) [CH2]; 7.37 (1H,t) [H-6]; 7.62 (1H,"t") [H-7]; 7.68 (1H,"d") [H-8]; 8.22 (1H,d) [H-S]; 8.92 (1H,s) [H-4]; 9.12 [1H,s(slightly broadened)] [H-1]; 9.81[1= H,(broadened)] [H-9]. The 67,889-MHz.

 

¹³CNMR spectrum of urinary 62c showed the following signals δ-value (multiplicity in undecoupled spectrum of synthetic material,coupling constants observed in synthetic material, 1:14.5 (q, J=126.3Hz) [CH3]; 61.7 (t,146.6Hz) [CH2]; 112.3 (dd,' JCH=164.2Hz, IJCH=7.4Hz) [CH in benzene moiety];117.9(d,'JcH=165.2Hz) [C4];121.0 (dd,'JCH=1Hz, 3JCH=7.4Hz) [CH in benzene moiety]; 122.0 (dd, J CH=160.0Hz,=8.4Hz) [CH in benzene moiety]; 129.1(dd,'JCH=162.1Hz, 3JCH=7.4Hz) [CH in benzene moiety];133.4 (d,'JCH=181.0Hz [C-1]; 137.5,137.7, and141.1 (broadeneds); 166.2(s) [COO]. Two signals are missing due to long relaxation times or overlap of signals

 

The coupling pattern in the 'HNMR spectrum revealed a -CH=CH-CH=CH- moiety (H-5-H-8), which resembled that in carbazole ^{37, 38}.

 

D.     Mass Spectroscopy:

The spectra of all six compounds (63-69) have as their base peak the ion of mass m/e 171 formed in each instance by the expulsion of the alkyl radical. Subsequent fragmentation of the m/e 171 ions is shown in (Scheme XII). An accurate mass determination of the m/e 117 peak in the mass spectrum of l-methyl-l,2,3,4-tetrahydro-β-carboline (63a ,) showed that it was composed of two ions, C₈H₇N (67%) and C₉H₉ (33 %). The mass spectra of the six β-carbolines (63a to 63f) all possessed a diagnostic ion of mass m/e 156. The relative abundance of this ion varied (3% to 35%) but accurate mass measurements confirmed that in each spectrum a fragment ion of composition C₁₁H₁₀N was present. The formation of this ion requires the expulsion of an RNH radical from the molecular ion and in five of the six spectra a metastable ion was present which supported such a loss³⁹.

 

Scheme XII

 

 

4. PHARMACOLOGICAL ACTIVITIES OF BETA CARBOLINES:

Anti cancer activity:

During the last one and half decade, the interest has increased tremendously as traditional βC targets such as PL Kinases, TGFβ, Haspin kinase, Eg5 and phosphodiesterase 5 have been recognized as cancer targets. The first reports on the cytotoxicity of compounds with βC structure came in 1990 when the newly isolated eudistomins (70, 72 and 73) from Marine tunicates showed antileukemic properties against murine leukemic cell lines L1210 and L5178Y ^{23, 40}

 

In 1992, Chris G. Kruse et al reported antiviral and antitumor structure-activity relationship studies on tetracyclic Eudistomines 73, against Murine Leukemia Cells (L1210), Human T-Lymphoblast Cells (Molt/lF) and Human T-LsmDhocvte (MT-4). Some compounds showed high potency for antitumor models ^{24, 41}.

 

In 2005, Shen et al. Examined a series of simple THβC and DHβC derivatives, (74) against the murine cell line P-388 and the human cell lines KB-16 and A-549, and the human colon adenocarcinoma cell line HT-29 and exhibited moderate cytotoxicity^{25, 42}. In 2009, Santos et al., synthesized a tetracyclic compounds resembling arborescidines and tested them for antitumor activity towards human lung fibroblasts (MRC-5), human gastric adenocarcinoma (AGS), human lung cancer (SK-MES-1), human bladder carcinoma (J82) and human leukemia (HL-60) cells⁵⁴. From the arborescidine resembling compounds, compound (75) showed most activity having IC50 values in micromolar range. The research group also tested all the intermediate compounds they had synthesized and found that the non-cyclic compound (76) actually gave better response to almost all tested cell lines with IC50 values ranging from 8.8 to 18.1 μM for lung fibroblasts, gastric adenocarcinoma, lung cancer and bladder carcinoma (IC50 of standard etoposide: 0.36–3.93 μM)^{26, 43}.

 

In 2011, Shen et al. published a new study in which they had increased the size of the substituent in C1 and had a series of THβCs and DHβCs. The series was evaluated for antitumor activity against human tumor cells including KB, DLD, NCI-H661, Hepa, and HepG2/A2 cell lines. In this study, the THβCs, (77) showed significant cytotoxicity ^{30, 44}

 

 

 

 

 

 

 

In 2012 Julio Alvarez-Builla et al.⁴⁵ synthesized a series of new pyridazino[10,60:1,2]pyrido[3,4-b]indol-5-inium derivatives,78 and tested for their cytotoxic activity in vitro against L1210 leukaemia and for their effect on the L1210 cell cycle. Finally they noticed that the most cytotoxic compounds have effect in the G1 phase of the cell cycle while the reference compounds exert their effect in the G2M phase.

 

In 2015, Siwen Li et al⁴⁶, modified harmine to increase the therapeutic efficacy and to decrease the systemic toxicity. Specifically, they synthesized two tumor targeting harmine derivatives 2DG-Har-01 and MET-Har-02 by modifying substituent in position -2, -7 and -9 of harmine ring with two different targeting group2-amino-2- deoxy-D-glucose (2DG) and Methionine (Met), respectively. Their therapeutic efficacy and toxicity were investigated both in vitro and in vivo. Finally they suggested that the two new harmine derivatives displayed much higher therapeutic effects than non-modified harmine. In particular, MET-Har-02, (80) was more potent than 2DG-Har-01, (79) with promising potential for targeted cancer therapy.

In 2016, Hong-Bin Zhang et al.⁴⁷ proved that the imidazo-lium salt derivatives 81, bearing a 2-ethyl-imidazole, benzimidazole or 5,6-dimethyl-benzimidazole ring and a 3-naphthylmethyl or 1-(naphthalen-2-yl)ethan-1-one at position-3 of the imidazole ring, were vital for modulating cytotoxic activity. Some of the derivatives exhibited cytotoxic activity selectively against MCF-7 and SW480 cell lines with IC50 values 5.3-fold and 1.6- fold more sensitive compared to DDP.some other Compounds can also induce G1 phase cell cycle arrest and apoptosis in MCF-7 cells

 

 

 

 

 

 

Other pharmacological activities:

Recently their antiparasitic and antiviral properties are of greater interest compared to their defined CNS activity. Surprisingly, the results of clinical trials confirm the increased levels of β-carbolines in the plasma of chronic alcoholics and heroin-dependent humans. They are also reported to increase the voluntary intake of alcohol⁴⁸.

 

β-carbolines such as methyl-6,7-dimethoxyl-4-ethyl- β-carboline-3-carboxylate (DMCM) are convulsant and anxiogenic drugs. They bind to the benzodiazepine receptor site but have reverse effects: they are called ‘benzodiazepine inverse agonists⁴⁹ and Claus braestrup et al in 1980 reported that Urinary and brain Beta-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors ³⁸

 

Antiviral Activities of β -Carbolines In Vitro and InVivo: The discovery of β -carboline metabolites as potent antiviral agents has accelerated the synthetic and pharmacological studies of β -carboline derivatives. In 1984, Rinehart et al. first reported that the activities of eudistomins E (82), K (83) and L (84) against herpes simplex virus-1 (HSV-1), in vitro, were in the range of 25-250 ng/12.5 mm disc⁵⁰.

 

 

Eudistomin E R1=Br R2=OH R3=H (82)

Eudistomin K R1=H R2=H R3=Br (83)

Eudistomin L R1=H R2=Br R3=H (84)

 

Antimicrobial and antimalerial activities of β -Carbolines In Vitro: Currently, only a few studies have been published on the antimicrobial activities of β-carboline alkaloids. The eudistomins H (86), I (87), O (85) and P (88) exhibited modest antimicrobial activities against Saccharomyces cerevisiae and antimalarial activities of manzamines against malaria parasite Plasmodium falciparum ^{51, 52} and Leishmania donovani⁵¹, the causative agent for visceral leishmaniasis, were also reported. Furthermore, some β-carboline derivatives, isolated from Eurycoma longifolia, were found to be effectively antimalarial against three Plasmodium falciparum clones, W2, D6 and TM91C235 ⁵³.

 

Antithrombotic Activities of β -Carbolines In Vitro and In Vivo: Only a few investigations have been published on the antithrombotic activities of β -carboline derivatives. Tang et al.^54-56 first reported that perlolyrine (89) and its analogues exhibited potent anti-aggregation activities in vitro and antithrombotic activities in vivo. SAR analysis suggested that the β -carboline structure might be an important basis for their antihrombotic activities.

 

Antioxidant activity: Koteppa Pari at al.⁵⁷ reported in 2000 that β-Carbolines (90), accumulate in human tissues may serve a protective role against oxidative stress and in 2007, Moura DJ et al.⁵⁸ reported that in vivo antioxidative properties of the aromatic (harmane, harmine, harmol) and dihydro-beta-carbolines (harmaline and harmalol) by using Saccharomyces cerevisiae strains proficient and deficient in antioxidant defenses. Their antimutagenic activity was also assayed in S. cerevisiae and the antigenotoxicity was tested by the comet assay in V79 cell line, when both eukaryotic systems were exposed to H(2)O(2). They showed that the alkaloids have a significant protective effect against H(2)O(2) and paraquat oxidative agents in yeast cells, and that their ability to scavenge hydroxyl radicals contributes to their antimutagenic and antigenotoxic effects.

 

Antileishmanial activity: Leishmaniasis has an overwhelming impact on global public health especially in tropical and subtropical countries and the currently available Antileishmanial drugs have serious side effects and low efficacy. Natural and synthetic compounds have been tested in the past few years against Leishmania and the beta-carboline class of compounds has shown great results in antiparasitic chemotherapy. R B Pedroso et al synthesized a series of 1-substituted beta-carboline-3-carboxylic acid and screened for in vitro activity against L. amazonensisin 2011, Compound 91 showed the best activity against promastigote and axenic amastigote forms with IC₅₀ of 2.6 and 1.0 μM, respectively⁵⁹.

 

 

 

Eudistomin H R1=Br R2=H (86)

 

Eudistomin I R1=H R2=H (87)

Eudistomin P R1=OH R2=Br (88)

 

 

 

 

 

5. CONCLUSION:

β -Carbolines are regarded as a promising class of bioactive heterocyclic compounds that exhibit a range of biological activities like as antimicrobial, antitumor, cytotoxic, antiplasmodial, antioxidant, antimutagenic, antigenotoxic and hallucinogenic properties. This comprehensive overview summarizes the synthesis of different substituted β –Carbolines along with their pharmacological activities.

6. ACKNOWLEDGEMENTS:

The author is thankful to the Principal and Management of Holy Mary Institute of Science and Technology (College of Pharmacy), Bogaram, Keesara, Hyderabad, Telangana, India for providing the necessary facilities.

 

7. DECLARATION OF INTEREST:

The authors report no conflict of interest.

 

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Accepted on 29.05.2018        © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(8): 3547-3560.