{Microwave-assisted synthesis of new pyrazole derivatives bearing 1,2,3-triazole scaffold as potential antimicrobial agents} J. Serb. Chem. Soc. 82 (4) 357–366 (2017) UDC 547.772.2+547.791:542.913+ JSCS–4971 537.5–962:615.28–188 Original scientific paper 357 Microwave-assisted synthesis of new pyrazole derivatives bearing 1,2,3-triazole scaffold as potential antimicrobial agents DONGAMANTI ASHOK*, RANGU KAVITHA, SRINIVAS GUNDU and VELAGAPURI HANUMANTHA RAO Green and Medicinal Chemistry Laboratory, Department of Chemistry, Osmania University, Hyderabad- 500 007, India (Received 5 February, revised 7 December 2016, accepted 17 January 2017) Abstract: A new series of (E)-3-(3-(4-substituted phenyl)-1-phenyl-1H-pyr- azol-4-yl)-1-(2-hydroxy-4-((1-aryl-1H-1-2,3-triazol-4-yl)methoxy)phenyl)- prop-2-en-1-one derivatives was synthesized. The synthesis of the title com- pounds involved the 1,3-dipolar Cu(I)-catalyzed alkyne–azide cycloaddition (CuAAC) reaction of (E)-3-(3-(4-substituted phenyl)-1-phenyl-1H-pyrazol-4- -yl)-1-(2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-ones with aro- matic azides. The structures were confirmed by NMR, FT-IR, mass and ele- mental analysis. All the synthesized compounds (6a–j) were evaluated for their antimicrobial activity. Compounds 6a, 6d and 6e demonstrated promising inhibitory effects on both bacterial and fungal strains. Keywords: pyrazole; chalcone; 1,2,3-triazole; microwave irradiation; antimic- robial activity. INTRODUCTION Infectious diseases caused by microbes, such as bacteria and fungi, are one of the leading causes of morbidity and mortality. The major reason for the inc- rease in microbial infections is the resistance developed by these microbial org- anisms.1 Thus, the development of new antimicrobial or antipathogenic agents that act upon new microbial targets is a necessity.2 Pyrazole scaffolds possess a wide range of bioactivities, including antiviral,3 anti-inflammatory,4 anticonvulsant,5 anticancer,6 insecticidal,7 and antifungal.8,9 In recent years, several drugs developed from pyrazole derivatives, such as cele- coxib that demonstrates anti-inflammation effects and inhibits COX-2, rimon- abant that functions as a cannabinoid receptor inverse agonist and is utilized in obesity treatment, fomepizole that inhibits alcohol dehydrogenase and sildenafil that inhibits phosphodiesterase (Fig. 1). * Corresponding author. E-mail: ashokdou@gmail.com doi: 10.2298/JSC160205016A 358 ASHOK et al. Fig. 1. Commercially available bioactive pyrazole and triazole drugs. On the other hand, 1,2,3-triazoles have received attention due to their ease of synthesis by click chemistry bearing attractive features as well as their numerous biological activities.10–14 1,2,3-Triazole derivatives have gained interest for their various biological activities, such as chemotherapeutic agents,15,16 and potent antimicrobial,17 anti-inflammatory,18,19 local anaesthetic,20 anticonvulsant,21 antineoplastic,22 antimalarial23 and antiviral activity.24 Among the best known examples of triazole-containing drugs, tazobactam, a commercially available β-lactamase inhibitor, plays an eminent role in combination with broad-spectrum antibiotics (Fig. 1). Considering the above facts, it seemed worthwhile to integrate both pyrazole and 1,2,3-triazole pharmacophore units in one molecular platform to generate a newer scaffold for biological evaluation. Pharmacophore hybridization is believed to be analogous to conventional combination therapy wherein the two drugs are covalently linked and available as a single entity.4 In continuation to ongoing research activities25–27 to discover and develop potential new antimic- robial agents, an efficient method for the synthesis of (E)-3-(3-(4-substituted- phenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(2-hydroxy-4-((1-aryl-1H-1,2,3-triazol-4- -yl)methoxy) phenyl)prop-2-en-1-one derivatives in excellent yields is reported herein. RESULTS AND DISCUSSION The synthetic approach adapted to obtain the target compounds is depicted in Schemes 1 and 2. The selective preparation of the starting material 1-(2-hydroxy- -4-(prop-2-yn-1-yloxy)phenyl)ethanone28 (3) was realized by the nucleophilic substitution reaction of 1-(2,4-dihydroxyphenyl)ethanone (1) with propargyl bro- mide (2) in the presence of K2CO3 (Scheme 1). The selective mono-pro- pargylation of the hydroxy group without altering the o-hydroxy acetyl function- ality was performed in high yields when starting from compound 1 rather than the other positional isomers. The synthesis of the title compounds 6a–j was accomplished by two synthetic strategies as shown in Scheme 2. In order to develop a high yield protocol for the synthesis of the title com- pounds by click chemistry, the yields of compound 6g were investigated using CuSO4·5H2O/sodium ascorbate and CuI in different solvents, such as THF/H2O, t-BuOH/H2O and DMF/H2O, under both conventional conditions and MWI. In SYNTHESIS AND ANTIMICROBIAL EFFECTS OF PYRAZOLE–TRIAZOLE HYBRIDS 359 the above optimization study, higher yields using CuI in DMF/H2O (1:3) under MWI were attained (Table I). Scheme 1. Synthesis of 1-(2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl)ethanone (3). Scheme 2. Synthetic route for the preparation of pyrazole-based 1,2,3-triazole hybrids (6a–j). In route-1 (Scheme 2), the (E)-3-(3-(4-substituted phenyl)-1-phenyl-1H-pyr- azol-4-yl)-1-(2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one derivat- ives (5a and b) were synthesized by Claisen–Schmidt condensation of compound 3 with substituted 1H-pyrazole-4-carboxaldehydes (4a and b) in presence of KOH under conventional conditions and microwave irradiation. These com- pounds (5a and b) via a Huisgen 1,3-dipolar cycloaddition reaction with aromatic 360 ASHOK et al. azides using CuI in DMF under MWI gave compounds 6a–j. In route-2 (Scheme 2), compound 3 in a click reaction with aromatic azides using CuI in DMF under MWI followed by reaction with substituted 1H-pyrazole-4-carboxaldehydes (4a and b) in the presence of KOH under conventional conditions and microwave irradiation gave compounds 6a–j. TABLE I. Optimization study for the synthesis of compound 6g under different catalyst and solvent conditions Entry Catalyst Solvent Conventional Microwave irradiation Time, h Yield, %a Time, min Yield, %a 1 CuSO4/sod. ascorbate THF/H2O (1:2) 72 21 20 25 2 CuSO4/sod. ascorbate THF/H2O (1:3) 72 27 20 32 3 CuSO4/sod. ascorbate DMF/H2O (1:2) 24 35 15 40 4 CuSO4/sod. ascorbate DMF/H2O (1:3) 24 54 14 61 5 CuSO4/sod. ascorbate t-BuOH/H2O (1:2) 24 40 16 46 6 CuSO4/sod. ascorbate t-BuOH/H2O (1:3) 24 44 16 49 7 CuI THF/H2O (1:2) 72 30 20 42 8 CuI THF/H2O (1:3) 72 34 20 44 9 CuI DMF/H2O (1:2) 14 47 10 69 10 CuI DMF/H2O (1:3) 12.5 67 8.5 91 11 CuI t-BuOH/H2O (1:2) 24 41 16 52 12 CuI t-BuOH/H2O (1:3) 24 50 16 63 aIsolated yields By comparing the above routes, the target compounds were synthesized in excellent yields in route-1 (Table II) to give overall yields of 81–92 % in shorter reaction time, while in route-2, the overall yields were much lower in the range of 34–48 % and a longer time (24–48 h)was necessary to complete the reaction. TABLE II. Comparison of the yields of compounds 5a,b and 6a–j under different synthetic conditions Compound M.p., °C Conventional MWI Time, h Yield, %a Time, min Yield, %a 5 a 150–152 12 49 8 89 5 b 128–130 10 51 7 90 6 a 142–144 14 54 10 87 6 b 101–103 12.5 48 8 81 6 c 171–173 12 50 9 84 6 d 162–164 13 49 9.5 87 6 e 184–186 12 53 8 90 6 f 133–135 13 52 9 89 6 g 147–149 12.5 54 8.5 91 6 h 197–199 13 57 10 92 6 i 142–144 12.5 46 10 91 6 j 134–136 12 52 10 92 aIsolated yields SYNTHESIS AND ANTIMICROBIAL EFFECTS OF PYRAZOLE–TRIAZOLE HYBRIDS 361 The formation of pyrazole derivatives containing 1,2,3-triazoles 6a–j was confirmed by IR, NMR and mass analysis (the spectral data are given in Supple- mentary material to this paper). The IR spectrum of compound 6g showed abs- orption bands at 3111 and 1631 cm–1 due to OH and C=O groups, respectively. The 1H-NMR spectrum of 6g showed three singlets at δ 2.40, 3.86 and 5.35 ppm corresponding to CH3, OCH3 and OCH2 protons. The appearance of a doublet at δ 7.78 ppm (J = 15.29 Hz) was due to the β-proton of the α,β-unsaturated carbonyl group. Two singlets at δ 8.65 and 9.46 ppm correspond to triazole and pyrazole protons, respectively. A broad singlet due to the OH protons was observed at δ 13.52 ppm.29 In the 13C-NMR spectrum of 6g, the CH3, OCH3 and OCH2 carbons resonated at δ 20.2, 55.4 and 60.7 ppm, respectively. The carbo- nyl carbon appeared at δ 190.8 ppm. The mass spectra of 6g showed the mole- cular ion peak at m/z = 584 [M+H]+. Antibacterial activity The synthesized compounds 5a and b and 6a–j were screened in vitro for their antibacterial activity against Bacillus subtilis (ATCC 6633) and Staphylo- coccus aureus (ATCC 6538), as examples of Gram-positive bacteria, and Esche- richia coli (ATCC 11229) and Proteus vulgaris (ATCC 13315), as examples of Gram-negative bacteria. The agar well-diffusion method was used to assay the antibacterial activity against the test strains on Mueller–Hinton agar plates. Gen- tamicin was employed as the standard antibacterial drug. The results obtained as zone of inhibition in mm and minimum inhibitory concentration (MIC) in µg mL–1 are presented in Table III. Investigation of the antibacterial efficiency of the synthesized compounds involved varying the substitution with electroneg- ative chloro- and electron-donating methyl group on phenyl ring of the pyrazole nucleus and variable substitutions on phenyl ring of triazole nucleus. It is evident from Table III that compound 6a with chloro substitutions on both the pyrazole and triazole nucleus exhibited the highest antibacterial inhibitory efficacy with inhibition zones of 28, 27 and 31 mm and an MIC of 3.125 µg mL–1 against B. subtilis, S. aureus and E. coli, respectively, and 26 mm with an MIC 6.25 µg mL–1 against P. vulgaris compared to standard drug gentamicin. After 6a, came com- pound 6d, with zones of inhibition in range of 24–28 mm (MIC 6.25–12.5 µg mL–1), with chloro substitution on the pyrazole scaffold and trifluoromethyl group on the triazole nucleus, and 6e, with inhibition zones in range of 22–24 mm (MIC 12.25 µg mL–1) with chloro substitution on the pyrazole scaffold and a benzyl group on triazole nucleus. This indicates that electron withdrawing groups and an electronegative chlorine atom on the phenyl ring strongly affect the anti- bacterial activity. The remaining compounds displayed moderate antibacterial potency with inhibition zones in the range 15–21 mm and with MIC values of 25–50 µg mL–1. 362 ASHOK et al. TABLE III. Antimicrobial activity of the synthesized compounds Compound Gram positive bacteria Gram negative bacteria Fungal strains B. subtilis S. aureus E. coli P. vulgaris A. niger C. albicans 5a 19a (25)b 15 (50) 21 (25) 17 (25) 15(25) 16(50) 5b 23 (12.5) 18 (25) 19 (25) 16 (50) 12(50) 18(50) 6a 28 (3.125) 27 (3.125) 31 (3.125) 26 (6.25) 24(6.25) 25(6.25) 6b 20 (25) 17 (25) 17 (50) 21 (25) 16(50) 18(25) 6c 19 (12.5) 19 (25) 21 (25) 24 (12.5) 21(25) 19(12.5) 6d 26 (6.25) 24 (12.5) 27 (12.5) 28 (6.25) 21(12.5) 18(12.5) 6e 24 (12.5) 22 (12.5) 23 (25) 23 (12.5) 19(12.5) 21(12.5) 6f 21 (12.5) 21 (25) 23 (12.5) 19 (25) 13(50) 19(25) 6g 16 (50) 16 (50) 21 (25) 18 (50) 15(50) 14(50) 6h 18 (25) 21 (12.5) 23 (25) 23 (50) 18(25) 13(50) 6i 15 (50) 18 (25) 16 (50) 20 (50) 18(50) 16(25) 6j 21 (25) 15 (50) 18 (25) 15 (50) 12(50) 16(50) Gentamicin 32 (1.56) 29 (1.56) 34 (1.56) 30 (3.125) – – Fluconazole – – – – 34(3.125) 31(1.56) aZone of inhibition in mm; bMIC in µg mL-1 Antifungal activity The compounds were evaluated for their in vitro antifungal activity against Aspergillus niger (ATCC 9029) and Candida albicans (ATCC 10231) fungal strains. The agar well diffusion method was used to evaluate the antifungal acti- vity against test strains on PDA plates. Fluconazole was used as the standard antifungal drug. The results are given in Table III, from which it is evident that compound 6a displayed the best antifungal activity with zones of inhibition of 24 and 25 mm, and an MIC of 6.25 µg mL–1 against A. niger and C. albicans, res- pectively. Compounds 6d (21 and 18 mm) and 6e (19 and 21 mm) were able to induce appreciable promising growth inhibitory activity with an MIC 12.5 µg mL–1 against A. niger and C. albicans. Thus, it was hypothesized that com- pounds with a chlorine atom and electron withdrawing groups on the phenyl ring of pyrazole and the triazole moieties would exhibit the highest antimicrobial inhibitory potency. EXPERIMENTAL Materials All the used materials were obtained commercially, mostly from Sigma–Aldrich, and used without further purification. Equipment Melting points were determined in open capillaries and are uncorrected. The purity of the compounds was checked by TLC on silica gel 60 F254 (Merck). The 1H-NMR and 13C-NMR spectra were recorded on Bruker Avance II 400 spectrometer using TMS as an internal standard. The IR spectra were recorded in KBr on a Shimadzu FTIR 8400S spectrophoto- meter. The mass spectra were recorded on Shimadzu LCMS-2020 mass spectrometer. Ele- SYNTHESIS AND ANTIMICROBIAL EFFECTS OF PYRAZOLE–TRIAZOLE HYBRIDS 363 mental microanalysis was performed on a Perkin Elmer CHN-2400 analyzer. All the micro- wave irradiation experiments were realized in a CEM Discover microwave system and react- ion temperatures were monitored by an equipped IR sensor. Analytical and spectral data are presented in Supplementary material to this paper. General procedure for the synthesis of (E)-3-(3-(4-substituted phenyl)-1-phenyl-1H-pyrazol- -4-yl)-1-(2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one derivatives (5a and b) Conventional heating method. To a mixture of 1-(2-hydroxy-4-(prop-2-yn-1-yloxy)phe- nyl)ethanone (3, 1 mmol) and powdered KOH (2 mmol), substituted 1H-pyrazole-4-carbox- aldehydes (4a and b, 1 mmol) was added and the reaction mixture was heated at 80 °C for 10– 12 h. After completion of the reaction (as indicated by TLC), the reaction mixture was poured into ice-cold water and neutralized with 10 % HCl solution. The thus-obtained solid was filtered and purified by column chromatography on silica gel using hexane/ethyl acetate (9:1 volume ratio) as eluent to afford compound 5. Microwave irradiation method. To a mixture of 1-(2-hydroxy-4-(prop-2-yn-1-yloxy)- phenyl)ethanone (3, 1 mmol) and powdered KOH (2 mmol) in a glass vial, a substituted 1H- pyrazole-4-carboxaldehydes (4a and b, 1 mmol) was added and the vial was tightly sealed. The mixture was then irradiated for 7–8 min at 90 °C, at an irradiation power of 180 W. After completion of the reaction (as indicated by TLC), the vial was cooled, the reaction mixture was poured into ice-cold water and neutralized with 10 % HCl solution. The thus-obtained solid was filtered and purified by column chromatography on silica gel using hexane/ethyl acetate (9:1) as eluent to afford compound 5. General procedure for the synthesis of (E)-3-(3-(4-substituted phenyl)-1-phenyl-1H-pyrazol- -4-yl)-1-(2-hydroxy-4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)prop-2-en-1-one derivatives (6a–j) using CuI catalyst Conventional method. To a well stirred mixture of (E)-3-(3-(4-substituted phenyl)-1- -phenyl-1H-pyrazol-4-yl)-1-(2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one der- ivatives (5a and b, 1 mmol) and CuI (0.05 equiv.) in H2O/DMF (3:1) (6 mL), an aromatic azide was added and the reaction mixture was stirred at room temperature for 12–14 h. After completion of the reaction (as indicated by TLC), the reaction mixture was poured into ice- cold water. The thus-obtained solid was filtered and purified by column chromatography on silica gel using hexane/ethyl acetate (7:3, v/v) as eluent to afford compound 6. Microwave irradiation method. A mixture of a (E)-3-(3-(4-substituted phenyl)-1-phenyl- -1H-pyrazol-4-yl)-1-(2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one derivative (5a and b, 1 mmol) and CuI (0.05 equiv.) was suspended in H2O/DMF (3:1 volume ratio, 2 mL) in a glass vial equipped with a small magnetic stirring bar. To this, an aromatic azide was added and the vial was tightly sealed. The mixture was then irradiated for 8–10 min at 60 °C, at an irradiation power of 100 W. After completion of the reaction (as indicated by TLC), the vial was cooled, and the reaction mixture poured into ice-cold water. The thus-obtained solid was filtered and purified by column chromatography on silica gel using hexane/ethyl acetate (7:3, v/v) as eluent to afford compound 6. General procedure for the synthesis of (E)-3-(3-(4-substituted phenyl)-1-phenyl-1H-pyrazol- -4-yl)-1-(2-hydroxy-4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)prop-2-en-1-one derivatives (6a–j) using CuSO4/sodium ascorbate catalyst Conventional method. To a well stirred mixture of (E)-3-(3-(4-substituted phenyl)-1- -phenyl-1H-pyrazol-4-yl)-1-(2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one der- ivative (5a and b, 1 mmol), CuSO4·5H2O (0.05 equiv.) and sodium ascorbate (0.05 equiv.) in 364 ASHOK et al. H2O/DMF (2:1 volume ratio, 10 mL), an aromatic azide was added and the reaction mixture was stirred at room temperature for 24 h. After completion of the reaction (as indicated by TLC) the reaction mixture was poured into ice-cold water. The thus-obtained solid was fil- tered and purified by column chromatography on silica gel using hexane/ethyl acetate (7:3) as eluent to afford compound 6. Microwave irradiation method. A mixture of a (E)-3-(3-(4-substituted phenyl)-1-phenyl- -1H-pyrazol-4-yl)-1-(2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one derivative (5a and b, mmol) CuSO4·5H2O (0.05 equiv.) and sodium ascorbate (0.05 equiv.) were suspended in H2O/DMF (2:1 volume ratio, 2 mL) in a glass vial equipped with a small magnetic stirring bar. To this, an aromatic azide was added and the vial was tightly sealed. The mixture was then irradiated for 15 min at 60 °C, at an irradiation power of 100 W. After completion of the reaction (as indicated by TLC), the vial was cooled and the reaction mixture poured into ice- cold water. The thus-obtained solid was filtered and purified by column chromatography on silica gel using hexane/ethyl acetate (7:3) as eluent to afford compound 6. Biological assay Antimicrobial activity. The in vitro antimicrobial studies were performed by the agar well diffusion method against test organisms.30,31 Nutrient broth (NB) plates were swabbed with 24 h-old broth culture (100 mL) of the test bacteria. Using a sterile cork borer, wells (6 mm) were made into each Petri plate. Different concentrations of test samples dissolved in DMSO were added into the wells using sterile pipettes. Simultaneously, the standard antibio- tics, gentamicin for antibacterial activity, fluconazole for antifungal activity were tested against the pathogens. The plates were incubated at 37 °C for 24 h for the bacteria and at 28 °C for 48 h for the fungi. After appropriate incubation, the diameter of zone of inhibition of each well was measured. The broth dilution test was used to determine the minimum inhi- bitory concentration (MIC) of the samples.32,33 Freshly prepared nutrient broth was used as the diluent. The 24 h-old culture of the test bacteria B. subtilis, S. aureus, E. coli and P. vul- garis and the test fungi A. niger and C. albicans were diluted 100-fold in nutrient broth (100 μL bacterial cultures in 10 mL NB). Increasing concentrations of the test samples were added to the test tubes containing the bacterial and fungal cultures. All the tubes were incubated at 37 °C for 24 h for the bacteria and at 28 °C for 48 h for the fungi. The tubes were examined for visible turbidity using NB as the control. The lowest concentration that inhibited visible growth of the tested organisms was recorded as the MIC. CONCLUSION In summary, a new series of compounds 6a–j was synthesized by convent- ional and microwave irradiation methods. In the microwave irradiation method, reactions were completed in a short reaction time under mild reaction conditions and convenient operation in high yields. All the titled compounds were screened for their in vitro antimicrobial activity. Compound 6a was found to be the most potent and compounds 6d and 6e were found to be moderately potent compared to the standard drug gentamicin against the pathogenic bacteria, while com- pounds 6a, 6d and 6e exhibited potent activity against the pathogenic fungi com- pared to the standard drug fluconazole with their respective concentrations. Anti- microbial screening results revealed that, compound 6a of the synthetic library could be considered as a promising antimicrobial drug candidate. SYNTHESIS AND ANTIMICROBIAL EFFECTS OF PYRAZOLE–TRIAZOLE HYBRIDS 365 Acknowledgements. The authors are thankful to The Head of Department of Chemistry, Osmania University, for providing the laboratory facilities and the Director, Central Facilities for Research and Development (CFRD), Osmania University, for providing the IR and NMR spectral analysis. Financial support for RK from UGC, New Delhi, India, is gratefully acknowledged. SUPPLEMENTARY MATERIAL Spectral and analytical data of the synthesized compounds are available electronically at the pages of journal website: http://www.shd.org.rs/JSCS/, or from the corresponding author on request. И З В О Д СИНТЕЗА НОВИХ 1,2,3-ТРИАЗОЛСКИХ ДЕРИВАТА ПИРАЗОЛА, ПОД УСЛОВИМА МИКРОТАЛАСНОГ ЗРАЧЕЊА, КАО ПОТЕНЦИЈАЛНИХ АНТИМИКРОБНИХ ЈЕДИЊЕЊА DONGAMANTI ASHOK, RANGU KAVITHA, SRINIVAS GUNDU и VELAGAPURI HANUMANTHA RAO Green and Medicinal Chemistry Laboratory, Department of Chemistry, Osmania University, Hyderabad-500 007, India Синтетисана је серија нових деривата (E)-3-(3-(4-супституисани фенил)-1-фенил- -1H-пиразол-4-ил)-1-(2-хидрокси-4-((1-арил-1H-1,2,3-триазол-4-ил)метокси)фенил)- проп-2-ен-1-она. Синтеза деривата укључује Cu(I)-катализовану 1,3-диполарну алкин– –азид циклоадицију (CuAAC) реакцијом (E)-3-(3-(4-супституисани фенил)-1-фенил-1H- -пиразол-4-ил)-1-(2-хидрокси-4-(проп-2-ин-1-илокси)фенил)проп-2-ен-1-она и арома- тичних азида. Структуре производа су потврђене NMR и FTIR спектроскопијом, масе- ном спектрометријом и микроанализом. Испитана је антимикробна активност свих син- тетисаних деривата 6a–j. 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