Bardzo tanie apteki z dostawą w całej Polsce kupic levitra i ogromny wybór pigułek.

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International Journal of Drug Design and Discovery
Volume 1 Issue 2 April– June 2010. 115-123
Synthesis and in vitro Biological Activity of Organic Charge-transfer
Complexes of lansoprazole, fluconazole, gabapentin and
gabalactum with Chloranilic and Picric Acids

Lingappa Mallesha and Kikkeri N. Mohana*
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India. ABSTRACT: Novel Charge-transfer (CT) complexes were synthesized in order to determine their antimicrobial and
antioxidant activity relationships to improve the efficacy. The purity of the synthesized complexes was judged by their
elemental analyses, and their chemical structures were confirmed by UV-visible, FT-IR and 1H NMR spectral studies.
Among the synthesized compounds, 2a and 2b showed good antimicrobial activity. Compound 1a showed moderate
antioxidant activity compared to standard drug by diphenylpicrylhydrazyl (DPPH) assay method.
KEYWORDS: Charge - transfer complexes; Fluconazole, Lansoprazole; Gabapentin; Antimicrobials; Antioxidant activity
Introduction
inhibits the growth of H. pylori at concentrations of several The health problem demands to search and synthesize a micrograms per milliliter. This inhibition appeared to be new class of antimicrobial compounds which are effective specific to H. pylori since the growth of more than 27 other against pathogenic microorganisms and develop resistance bacterial species was not affected by lansoprazole even at to the antibiotics used in the current regime1-2. 100 mg/ml. Since lansoprazole acts only against H. pylori, Antioxidants are substances that even at low concentration elucidating the mechanism of its bactericidal action will significantly delay or prevent oxidation of easily facilitate the development of drugs to treat H. pylori oxidizable substrates3. The applications of antioxidants are infections13. It is exhibited antifungal activity against industrially widespread in order to prevent the oxidative Candida albicans14. It is widely used for the treatment of degradation of polymers, auto-oxidation of fats, synthetic acid-related gastric diseases due to their ability to inhibit and natural pigments discoloration, etc. There is an acid secretion15. Fluconazole (Flu) is a synthetic antifungal increased interest of using antioxidants for medical agent that can be used for the treatment of a variety of purposes in the recent years4-6. Charge-transfer (CT) candida albicans and other fungal infections. For the complexes are being regarded as important materials due breastfeeding mother in particular, it can be used to treat to their ample applications7. Protonic charge transfer recurrent candida infections of the nipples. It is frequently complexes were first introduced by Matsunaga and used for the prophylaxis of fungal infections in recipients coworkers8. The transfer of an electron and a proton of allogeneic hematopoietic cell transplantation (HCT)16. produces a new type of adduct and the complex formation Gabapentin (Gpn) has been introduced as an anti-epileptic may indeed be dramatic9. Chloranilic acid (CA) and picric drug which is orally active17. Gpn is structurally related to acid (PA) form salts or charge transfer complexes with the neurotransmitter-aminobutyric acid (GABA) which has many organic compounds particularly with aromatic and been widely studied for its significant inhibitory action in aliphatic amines10-11. Picric acid is also used in medicinal the central nervous system18. More recently, Gpn has been formulations in the treatment of malaria, trichinosis, advanced for the treatment of neuropathic pain19. Gpn is a new generation antiepileptic drug that is used as add-on therapy as well as monotherapy20 in patients with partial Lansoprazole (Lan) is a benzimidazole derivative, is a seizures21-22. The mechanism of action of gabapentin widely-used proton-pump inhibitor. In addition, it has been remains unclear, although it is apparently dissimilar to that reported to have an independent gastroprotective action. It of other antiepileptic agents23. In recent years, there has been intense interest in the polymorphs of gabapentin and * For correspondence: Kikkeri N. Mohana, in the synthesis of gabapentin analogues. The crystal structure of gabapentinium picrate (3b) has been recently
116 International Journal of Drug Design and Discovery Volume 1 Issue 2 April - June 2010
In connection with such studies, the present paper reports
formulated as [(Lan)(CA)] (1a), [(Lan)(PA)] (1b),
the molecular complexes formed during the reaction of [(Flu)(CA)] (2a), [(Flu)(PA)] (2b), [(Gpn)(CA)] (3a),
lansoprazole (1), fluconazole (2), gabapentin (3) and
[(Gpn)(PA)] (3b), [(gabalactum)(CA)] (4a) and
gabalactum (4) as electron donors with chloranilic acid (5)
[(gabalactum)(PA)] (4b) respectively. The elemental
and picric acid (6) as electron acceptors. These complexes
analyses data showed good agreement between the were characterized by different spectral analyses. experimentally determined values and the theoretically Antimicrobial and antioxidant results of the complexes calculated values within the limits of permissible error. were reported in this paper. The synthesized compounds These charge transfer complexes are stable in air, soluble give significant contribution in the general area of study. in DMSO and DMF. The elemental analyses data confirm Further, the study focuses on the nature of interaction and the stoichiometry and hence the molecular formula of the biological activity of the compounds. On the basis of their synthesized complexes. New bands were detected in the activity, the synthesized compounds were identified as UV-visible spectra of the CT complexes. These bands are viable leads for further studies. The complexes of 1 and 2
not exhibited by either donor or acceptors alone. The with 4 and 5 were synthesized with a view to improve the
appearance of longer wavelength absorption band in the visible region in UV-visible spectrum owing to the charge transfer transition confirms the formation of molecular Results and discussion
complexes. The electronic absorption spectra of synthesized complexes in DMSO were shown in Fig. 1. Reaction of electron donors with electron acceptors The physical data of synthesized complexes are given in resulted in the formation of stable charge-transfer Table 1. complexes with a donor–acceptor ratio of 1:1, and were Fig. 1 Electronic absorption spectra of complexes: (1a) Lansoprazolium chloranilate, (1b) Lansoprazolium
picrate, (2a) Fluconazolium chloranilate, (2b) Fluconazolium picrate, (3a) Gabapentinium chloranilate and (3b) Table 1 Physical data of synthesized complexes.
Complexes
Mol. Formula
M. P (0C) Yield
(%) λmax (nm)
Lingappa Mallesh and Kikkeri N. Mohana : Synthesis and in vitro Biological Activity of …
The Infrared spectra of the molecular complexes of zone of inhibition in the range of 17-19 mm and 15-17 mm CA, PA with donors indicates that ν(C–Cl) of CA and compared with other synthesized complexes. ν(NO2) of PA are shifted to lower wavenumber values The antifungal activity of the synthesized complexes upon complexation. The stretching frequency of C=O bond were evaluated and compared with standard drug nistatin. of the acceptor displays a shift to a higher wavenumber
values upon complexation. Infrared spectra of the Complexes, 2a and 2b showed better antifungal activity
with the zone of inhibition 96 mm and 94 mm against synthesized complexes show a strong band, indicating N – F.solani, compared with 1a, 1b, 3a, 3b, 4a and 4b,
H…O- stretching vibration of the intermolecular hydrogen respectively. Among the synthesized complexes, inhibitory bond. The protonation of the NH group of the donor activity in the order 2a > 2b > 1a > 1b > 3a > 3b > 4a > 4b
through transfer of proton from CA. On the other hand, the against the tested fungi. The CT-complexes of donors with intermolecular hydrogen bond occurs in the PA from the chloranilic acid is more antimicrobial activity compared OH group to the basic central nitrogen atom of the donor. New signals are observed in 1H NMR for the synthesized with salts of picric acid. Antimicrobial screening results of the tested complexes are shown in Table 2. complexes, assigned to N –H proton, which resulted from the protonation of N atom of donors. The O–H signals of Absorbance of the stable radical DPPH• was measured the free CA and PA were disappeared on complex at 517 nm for different concentrations of newly formation. These data is agreed quite well with the synthesized complexes. The percentage inhibition and IC50 elemental analyses, UV-visible and FT-IR studies. values were tabulated in Table 3. Since IC50 value is a The investigation of antibacterial screening data measure of inhibitory concentration, a lower IC50 value revealed that synthesized complexes were evaluated and would reflect greater antioxidant activity of the sample. compared with standard drug, streptomycin. The Hence all the tested complexes except 1a, 1b, 3a and 3b
complexes showed moderate active inhibitory against
displayed lowest antioxidant activity with highest IC50 pathogenic bacterial strains compared with standard drug. (>100 µg/ml), when compared with the IC50 value of standard Generally, 1a, 1b and 3a showed moderate inhibitory
antioxidant ascorbic acid (8.5 µg/ml). Complex 2a and 2b
activity which is in the order of 1a > 1b > 3a against gram
showed moderate antioxidant activity. Complexes, 1a (IC
positive (zone of inhibition 14-16 mm, 12-15 mm and 11- = 36.6 µg/ml), 1b (IC
12 mm respectively) and gram negative (zone of inhibition 50 = 38.2 µg/ml), 3a (IC50 = 38.1
14-15 mm, 13-14 mm and 10-13 mm respectively) µg/ml) and 3b (IC50 = 49.2 µg/ml) showed in vitro DPPH•
bacteria. Complexes, 3b, 4a and 4b showed weak activity
radical-scavenging activity. Complexes, 4a and 4b have
with the zone of inhibition in the range of 8-10 mm, 4-8 showed no scavenging activity at 20 µg/ml. Further, CT- mm and 3-7 mm compared with standard drug. Whereas complexes of donors with chloranilic acid are more the Complexes, 2a and 2b exhibited better activity with the
antioxidant activity compared with picric acid salts. Table 2 In vitro antibacterial and antifungal activities of synthesized complexes.
Zone of inhibition in mm
F. solani in
Complexes
Gram-positive bacteria
Gram-negative bacteria
% inhibition
B. subtillu
S. aureus
X. malvacearum
Streptomycin
Nystatin
118 International Journal of Drug Design and Discovery Volume 1 Issue 2 April - June 2010
Table 3 Results of DPPH radical scavenging assay.
% Scavenging (Mean ± SEM) of duplicates
IC50 µg/ml
complexes
20 µg/ml
40 µg/ml
60 µg/ml
80 µg/ml
100 µg/ml
Ascorbic acid
NA = IC50 >100 µg/ml, - showed no scavenging activity.
The initial structure activity relationship (SAR) can be evaluated. The synthesized complexes were confirmed by drawn for the compounds, 1a, 1b, 2a, 2b, 3a, 3b, 4a and
elemental analyses, UV-visible, FT-IR and 1H NMR 4b. Compounds 2a and 2b showed good inhibitory
spectral studies. Fluonazolium chloranilate (2a) and
antimicrobial activity compared to standard drug due to the fluconazolium picrate (2b) demonstrated good inhibition
presence of triazole ring and electron donating hydroxyl against all the strains tested. The antioxidant activity group. Compounds 3b, 4a and 4b showed weak inhibition
revealed that complex, lansoprazolium chloranilate (1a) is
against tested strains due to the presence of electron moderate antioxidant activity compared with standard withdrawing nitro groups in 3b, carbonyl groups in 4a and
4b. Electron donating ethoxy group in 1a, 1b and amine
group in 3a showed moderate antimicrobial activity.
Experimental
Compounds 1a, 1b, 3a and 3b showed IC50 value within
50 µg/ml. The presence of fluoro group in 2a, 2b and
Chemistry
carbonyl group in 4a, 4b did not showed IC50 value at 100
All solvents and reagents were purchased from Sigma- µg/ml. The SAR study of π-acceptors such as CA and PA Aldrich, India. Melting points were determined by Veego reveals that the CA salts showed good activity due to the Melting Point VMP III apparatus. Elemental analyses were presence of more hydroxyl groups compared to PA salts. recorded on VarioMICRO superuser V1.3.2 Elementar. The above SAR correlation studies reveal that, the nature The UV-visible spectra were recorded on Analytikjena of the functional linkage (alkyl/aryl) influences the Specord 50 UV–vis spectrophotometer with quartz cell of antimicrobial and antioxidant activities. 1.0 cm path length in DMSO. The FT-IR spectra were recorded using KBr discs on FT-IR Jasco 4100 infrared Conclusion
spectrophotometer. 1H NMR spectra were recorded on In conclusion, novel complexes of lansoprazole, Bruker DRX -500 spectrometer at 400 MHz using d6- fluconazole, gabapentin and gabalactum with chloranilic DMSO as solvent and TMS as an internal standard. CT- and picric acids were synthesized in good yield, and their complexes 1a, 1b, 2a, 2b, 3a, 3b, 4a and 4b were
antimicrobial and antioxidant activities have been synthesized by the method summarized in Scheme 1.
Lingappa Mallesh and Kikkeri N. Mohana : Synthesis and in vitro Biological Activity of …
120 International Journal of Drug Design and Discovery Volume 1 Issue 2 April - June 2010
Scheme 1 Synthetic protocol of the compounds.
Synthesis of lansoprazolium chloranilate (1a)
Synthesis of lansoprazolium picrate (1b)
The complex, 1a was synthesized by mixing lansoprazole
The complex, 1b was synthesized by adding lansoprazole
(1.50 g, 4 mmol) in ethanol (10 ml) with chloranilic acid (1.50 g, 4 mmol) in ethanol (10 ml) with picric acid (0.92 (0.84 g, 4 mmol) in the same solvent. The mixture was g, 4 mmol) in the same solvent. The mixture was stirred at stirred at room temperature for 2 h, where the solid room temperature for 1 h, where the solid precipitated after precipitated after the reduction of the volume of the the reduction of volume of the solvent to the half. The solvent. The separated precipitate was filtered off, washed precipitate was filtered off, washed several times with several times with diethyl ether (2 × 0.5 ml) and dried in recrystallization using methanol solvent. 1H NMR purified by recrystallization using methanol solvent. 1H (DMSO-d NMR (DMSO-d6, 400MHz) δ: 8.56 (d, 1H), 8.55(s, 2H) 6, 400MHz) δ: 8.50 (d, 1H), 7.53-7.51(m, 2H), 7.33(d, 1H), 7.23-7.21 (m, 2H), 5.06 (q, 2H), 4.83 (s, 2H), 7.55-7.51(m, 2H), 7.41(d, 1H), 7.27-7.23 (m, 2H), 7.22 (s, 3.15 (s, 2H), 2.28(s, 3H). FT-IR (KBr, ν/cm−1): 3431 (O- 2H), 5.09(q, 2H), 4.85 (s, 2H), 2.28(s, 3H). FT-IR (KBr, H), 3075(C-H), 2967 (N-H), 1640 (C=O), 1503 (C=C), ν/cm−1): 3647 (O-H), 3073(C-H), 2818 (N-H), 1624 1110 (C-O), 1032(C-N), 981(C-F), 837 (C-Cl). Anal. (C=O), 1558 (C=C), 1362 (NO2), 1113 (C-O), 1035(C-N), Calcd. for C22H16Cl2F3N3O6S (in %): C-45.69, H-2.79, N- 1012(C-F). Anal. Calcd. for C22H17F3N6O9S (in %): C- 44.15, H-2.86, N-14.04. Found. C-44.35, H-3.12, N-14.17. Lingappa Mallesh and Kikkeri N. Mohana : Synthesis and in vitro Biological Activity of …

Synthesis of fluconazolium chloranilate (2a)
product was purified by recrystallization using methanol solvent. 1H NMR (DMSO-d The complex, 2a was synthesized according to the method
described for the complex, 1a employing 2 (1.23 g, 4
C6H2), 7.62 (s, 3H, N H3), 2.90 (s, 2H, CH2), 2.34 (s, 2H, mmol) and CA (0.84 g, 4 mmol) to afford 2a. 1H NMR
CH2), 1.33-1.40 (m, 10H, cyclohexyl methylenes group). (DMSO-d6, 400 MHz) δ: 8.45(s, 2H), 7.88(s, 2H), 7.22(d, FT-IR (KBr, ν/cm−1): 3341 (O-H), 3235 (N-H), 1608 1H), 7.14(d, 1H), 6.87(s, 1H), 4.74(s, 2H), 4.58(s, 2H), (C=O), 1161 (C-O), 1039 (C-N). Anal. Calcd. for 3.83(s, 1H). FT-IR (KBr, ν/cm−1): 3446 (O-H), 3186(C-H), C15H20N4O9 (in %): C-45.00, H-5.04, N-13.99. Found. C- 3118 (N-H), 1615 (C=O), 1462 (C=C), 1163 (C-O), 1053(C-N), 1014(C-F), 817(C-Cl). Anal. Calcd. for Synthesis of gabalactum chloranilic acid (4a)
C19H14Cl2F2N6O5 (in %): C-44.29, H-2.74, N-16.31. Found. C-44.13, H-3.01, N-16.17. The complex, 4a was synthesized according to the method
described for the complex, 3a employing 4 (1.54 g, 0.01
Synthesis of fluconazolium picrate (2b)
mol) and CA (2.1 g, 0.01 mol) to afford 4a. 1H NMR
The complex, 2b was synthesized according to the method
(DMSO-d6, 400 MHz) δ: 7.41 (s, 2H, N H2), 2.91 (s, 2H, described for the complex, 1b employing 2 (1.23 g, 4
CH2), 2.47 (s, 2H, CH2), 1.37 (m, 10H, cyclohexyl mmol) and PA (0.92 g, 4 mmol) to afford 2b. 1H NMR
methylenes group). FT-IR (KBr, ν/cm−1): 3282 (O-H), (DMSO-d6, 400 MHz) δ: 8.45(s, 2H), 7.88(s, 2H), 7.22(d, 2929 (N-H), 1615 (C=O), 1161 (C-O), 1039 (C-N), 749 1H), 7.14(d, 1H), 6.87(s, 1H), 4.74(s, 2H), 4.58(s, 2H), (C-Cl). Anal. Calcd. for C15H17Cl2NO5 (in %): C-49.74, H- 3.83(s, 1H). FT-IR (KBr, ν/cm−1): 3446 (O-H), 3186(C-H), 4.73, N-3.87. Found. C-49.31, H-4.51, N-4.01. 3118 (N-H), 1615 (C=O), 1462 (C=C), 1163 (C-O), Synthesis of gabalactum picric acid (4b)
1053(C-N), 1014(C-F), 817(C-Cl). Anal. Calcd. for C The complex, 4b was synthesized according to the method
19H15F2N9O8 (in %): C-42.62, H-2.82, N-23.55. Found. described for the complex, 3b employing 4 (1.54 g, 4
mmol) and PA (4.59 g, 4 mmol) to afford 4b. 1H NMR
Synthesis of gabapentinium chloranilate (3a)
(DMSO-d6, 400 MHz) δ: 8.56 (s, 2H, C6H2), 7.43 (s, The complex, 3a was synthesized by mixing Gpn (1.72 g,
3H, N H2), 2.95 (s, 2H, CH2), 1.94 (s, 2H, CH2), 1.38 (m, 0.01mol) in distilled water (20 ml) with chloranilic acid 10H, cyclohexyl methylenes group). FT-IR (KBr, ν/cm−1): (2.1 g, 0.01 mol) in the same solvent. The mixture was 2929 (O-H), 2924 (N-H), 1615 (C=O), 1161 (C-O), 1039 stirred at room temperature for 1 h, where the solid (C-N). Anal. Calcd. for C15H18N4O8 (in %): C- 47.12, H- precipitated after the reduction of the volume of the 4.75, N-14.65. Found. C-47.44, H-4.87, N-14.85. solvent. The separated precipitate was filtered off, washed several times with diethyl ether (2 × 0.5 ml) and dried in vacuum over CaCl2. The product was purified by
recrystallization using methanol solvent. 1H NMR Antimicrobial assay
(DMSO-d6, 400 MHz) δ: 8.39 (s, 3H, N H3), 2.92 (s, 2H, Antibacterial activity of the synthesized complexes was CH2), 2.37 (s, 2H, CH2), 1.29-1.41 (m, 10H, cyclohexyl determined against gram-positive bacteria (Bacillus methylenes group). FT-IR (KBr, ν/cm−1): 3438 (O-H), subtillis, Staphylococcus aureus) and gram-negative 2929 (N-H), 1615 (C=O), 1195 (C-O), 1021 (C-N), 749 bacteria (Escherichia coli, Xanthomonas malvacearum) in (C-Cl). Anal. Calcd. for C15H19Cl2NO6 ( in %): C-47.38, DMSO by disc diffusion method on nutrient agar medium 25. H-5.04, N-3.68. Found. C-47.28, H-5.20, N-3.64. The sterile medium (Nutrient Agar medium, 15 ml) in each petriplates was uniformly smeared with cultures of gram Synthesis of gabapentinium picrate (3b)
+ve and gram –ve bacteria. Sterile discs (10 mm diameter) The complex, 3b was synthesized by adding an excess of a
were made in each of the petriplates, to which 50 µl of the saturated solution of picric acid (4.59 g contain 50 % different complexes were added. The treatments were also moisture, 0.01 mol) in distilled water (20 ml) with Gpn including 50 µl of DMSO and streptomycin as negative (1.72 g, 0.01 mol) in the same solvent. The mixture was and positive control for comparison. For each treatment, stirred at room temperature for 30 min, where the solid three replicates were maintained. The plates were precipitated after the reduction of volume of the solvent to incubated at 25 ± 2 ºC for 24 h and the size of the resulting the half. The precipitate was filtered off, washed several zone of inhibition, if any, was determined. The data were times with diethyl ether, and then dried over CaCl subjected to analysis of variance (ANOVA). 122 International Journal of Drug Design and Discovery Volume 1 Issue 2 April - June 2010
Antifungal assay
[4] Vaya, J.; Aviram, M. Curr. Med. Chem. Immunol. The synthesized complexes were screened for their antifungal activity against fusarium oxysporum in DMSO [5] Amic, D.; Davidovic, D.; Beslo, D.; Trinajstic, N. Croat. by pour plate method26. Potato Dextrose Agar (PDA) media was prepared and about 15 ml of PDA was poured [6] Middleton, E.; Kandaswami, C.; Theoharides, C. into each Petri plate and allowed to solidify. 5 mm disc of seven days old culture of the test fungi was placed at the center of the Petri plates and incubated at 26 °C for 7 days. [7] Pal, P.; Saha, A.; Mukherjee, A. K.; Mukherjee, D. C. After incubation the colony diameter was measured in millimeter, and three replicates were maintained for each [8] (a) Saito, G.; Matsunaga, Y. Bull. Chem. Soc. 1974, 47, treatment. Activity of each complex was compared with 1020. (b) Morukama, K. Acc. Chem. Res. 1977, 70, 294. standard drug, nystatin. All the synthesized complexes (c) Kasha, M. Basic Life Sci. 1991, 58, 231. were tested (at the dosage of 500 µl of the novel complexes/petriplate, where concentration was 0.1 mg/ml) [9] Strohbusch, F.; Marshall, D.; Eyring, E. M. J. Phys. [10] Matulis, V. E.; Lyakhov, A. S.; Gaponik, P.N.; DPPH radical scavenging assay
Voitekhovich, S. V.; Ivashkevich, O. A. J. Mol. Structure. The free radical scavenging activity of the newly synthesized complexes was studied in vitro by 1, 1- [11] Gaballa, A. S.; Wagner, C.; Teleb, S. M.; Nour, E. M.; diphenyl-2-picrylhydrazyl (DPPH) assay method27. Stock Elmosallamy, M. A. F.; Kaluderovic, G. N.; Schmidt, H.; solution of the drug was diluted to different concentrations Steinborn, D. J. Mol. Structure 2008, 876, 301. in the range of 20 μg/ml to 100 μg/ml in methanol. DPPH [12] Bingham, Eula, Cohrssen, Barbara, Powell, Charles, H. methanol solution (1 ml, 0.3 mmol) was added to 2.0 ml of Patty’s Toxicology; 5th ed., John Wiley and Sons: New drug solutions of different concentrations and allowed to react at room temperature. After 30 min, the absorbance values were measured at 517 nm and converted into [13] Iwahi, T.; Satoh, H.; Nakao, M.; Iwasaki, T.; Yamazaki, percentage antioxidant activity. Methanol was used as the T.; Kubo, K.; Tamura, T.; Imada, A. Agents Chemother. solvent and ascorbic acid was used as standard in 1-100 μg/ml solution. The inhibitory concentration (IC50) value, [14] Biswas, S. K.; Yokoyama, K.; Kamei, K.; Nishimura, K.; representing the concentration required to exhibit 50 % antioxidant activity was calculated. All experiments were carried out in duplicate and the inhibition ratio (I %) of the [15] Fellemius, E.; Berglindh, T.; Sachs, G.; Elander, B.; tested complexes was calculated according to the following Sjostrand, S. E.; Wallmark, B. Nature 1981, 290, 159. [16] Goodman, J. L.; Winston, D. J.; Greenfield, R. A.; Chandrasekar, P. H.; Fox, B.; Kaizer, H. N. Engl. J. Med. 1992, 326, 845. Where Ac is the absorbance of the control and As is the [17] Chadwick, D.W.; Anhut, H.; Greiner, M. J.; Alexander, J.; Murray, G. H.; Garofalo, E. A.; Pierce, M.W. Neurology 1998, 51, 1282. Acknowledgements
[18] Bowery, N.G. Annu. Rev. Pharmacol. Toxicol. 1993, 33, One of the authors (LM) grateful to University Grants Commission, New Delhi, for financial support under UGC-RFSMS scheme and like to thank University of Mysore for [19] Rosenberg, J. M.; Harrell, C.; Ristic, H.; Werner, R. A.; Derosayro, A. M. Clin. J. Pain. 1997, 13, 251. [20] Placidi, F.; Mattia, D.; Romigi, A.; Bassetti, M. A.; References
Spanedda, F.; Marciani, M. G.; Placidi, F. Mattia, D.; Romigi, A.; Bassetti, M. A.; Spanedda, F.; Marciani, M. [1] Koca, M.; Servi, S.; Kirilmis, C.; Ahmedzade, M.; Kazaz, G. Clin. Neurophysiology 2000, 111, 1637. C., Ozbek, B.; Otuk, G. Eur. J. Med. Chem. 2005, 40, [21] Lima, J. M. L. Curr. Pharm. Des. 2000, 6, 873. [22] Morton, L. D.; Pellock, J. M. Curr .Pharm. Des. 2000, 6, [2] Ram, V. J. J. Heterocycl. Chem. 1988, 25, 253. [3] Halliwell, B. Biochem. Pharmacol. 1995, 49, 1341. Lingappa Mallesh and Kikkeri N. Mohana : Synthesis and in vitro Biological Activity of …
[23] Gee, N. S.; Brown, J. P.; Dissanayake, V.U. K.; Offord, [26] Khan, Z. K. In vitro and vivo screening techniques for J.; Thurlow, R.; Woodruff, G.N. J. Biol. Chem. 1996, bioactivity screening and evaluation, in: Proceedings of the international workshop UNIDO-CDRI, 1997; pp 943– 946. [24] Hongqi Li, Yathirajan, H. S.; Mallesha, L.; Mohana, K. N.; Narayana, B. Acta Cryst. E 2009, 65, o783. [27] Mensor, L. L.; Menezes, F. S.; Leitao, G. G.; Reis, A. S.; Santos, T.C.; Coube, C. S.; Leitao, S. G. Phytother. Res. [25] Anon, The Indian Pharmacopoeia, 3rd ed., 1996.

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