Synthesis and characterization of novel benzimidazole embedded 1,3,5-trisubstituted pyrazolines as antimicrobial agents
J. Serb. Chem. Soc. 82 (9) 985–993 (2017)
UDC 547.772+547.785.5:615.281/.282–188
JSCS–5017 Original scientific paper
Synthesis and characterization of novel benzimidazole embedded 1,3,5-trisubstituted pyrazolines as antimicrobial agents
GOPAL K. PADHY , JAGADEESH PANDA and AJAYA K. BEHERA * Organic Synthesis Laboratory, School of Chemistry, Sambalpur University, Jyoti Vihar, Burla 768019, India, Maharajah’s College of Pharmacy, Phool Baugh, Vizianagaram 535002, India and Raghu College of Pharmacy, Dakamarri, Visakhapatnam 531162, India (Received 4 June 2016, revised 3 April, accepted 17 July 2017)
Abstract : Efficient syntheses of some new substituted pyrazoline derivatives linked to substituted benzimidazole scaffold were performed by multistep reaction sequences. All the synthesized compounds were characterized using elemental analysis and spectral studies (IR, 1D/2D NMR techniques and mass spectrometry). The synthesized compounds were screened for their antimicro-bial activity against selected Gram-positive and Gram-negative bacteria, and fungi strain. The compounds with halo substituted phenyl group at C5 of the 1-phenyl pyrazoline ring ( , and ) showed significant antibacterial acti-vity. Among the screened compounds, showed most potent inhibitory acti-vity ( MIC = 64 µg mL -1 ) against a bacterial strain. The tested compounds were found to be almost inactive against the fungal strain C. albicans , apart from pyrazoline-1-carbothiomide , which was moderately active. Keywords : chlacone; pyrazoline; diastereotopic protons; antibacterial activity; antifungal activity.
INTRODUCTION
In the current scenario, bacterial infections bring about a serious threat to human lives due to their rapid resistance to existing antibiotics. Thus, exploration of new types of antibacterial agents has become extremely vital. Benzimidazole derivatives are very useful for the development of molecules of pharmaceutical interest due to their pharmacological activities, including antimicrobial, anti-cancer, antidiabetic and plasmin inhibitor. Moreover, N -benzyl-substituted benzimidazoles have been synthesized showing promising antibacterial activities, among which amidine I and 2-(piperidin-4-yl)benzimidazole II are examples (Fig. 1). * Corresponding author. E-mail: [email protected] https://doi.org/10.2298/JSC160604089P __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
In the current scenario, bacterial infections bring about a serious threat to human lives due to their rapid resistance to existing antibiotics. Thus, exploration of new types of antibacterial agents has become extremely vital. Benzimidazole derivatives are very useful for the development of molecules of pharmaceutical interest due to their pharmacological activities, including antimicrobial, anti-cancer, antidiabetic and plasmin inhibitor. Moreover, N -benzyl-substituted benzimidazoles have been synthesized showing promising antibacterial activities, among which amidine I and 2-(piperidin-4-yl)benzimidazole II are examples (Fig. 1). * Corresponding author. E-mail: [email protected] https://doi.org/10.2298/JSC160604089P __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ (CC) 2017 SCS PADHY, PANDA and BEHERA
NNClClCl I NHHN Cl NNClCl NHHN II N NS O ON SCNBr
III
N NON N O Cl IV Fig. 1. Structures of some benzimidazoles and pyrazolines with antibacterial activity.
The pyrazoline motif is a core structure in numerous biologically active compounds. Some representatives of this heterocycle exhibited antimicro-bial, anticancer, anti-inflammatory, and monoamine oxidase inhib-itory activities. Series of novel thiazolyl-pyrazoline, such as III and mor-pholinoquinoline clubbed pyrazoline IV were recently reported as potent antibacterial agents (Fig. 1). The combination of N -benzylbenzimidazole and pyrazoline fragments in one molecule is expected to be a perspective approach to design promising antimicrobial agents. Thus, a novel series of N -benzyl attached benzimidazolyl pyrazolines was designed, synthesized and evaluated against different bacteria and fungi. EXPERIMENTAL
Chemistry
The chemicals used were laboratory grade and procured from Merck (India), Fischer Scientific (India) and Finar (India). IR spectra were obtained on a Bruker ALPHA-T FT-IR spectrometer (KBr pellets using opus software). H- and C-NMR spectra were recorded on a Bruker AVANCE III 500 MHz (AV 500) spectrometer using TMS as an internal standard in DMSO- d /CDCl . The mass spectra were recorded on a Varian Inc 410 Prostar Binary LC– –MS and an Agilent 6410 LC–MS spectrometer. Melting points were determined by the open tube capillary method and are uncorrected. Progress of the reaction and purity of the products __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
The chemicals used were laboratory grade and procured from Merck (India), Fischer Scientific (India) and Finar (India). IR spectra were obtained on a Bruker ALPHA-T FT-IR spectrometer (KBr pellets using opus software). H- and C-NMR spectra were recorded on a Bruker AVANCE III 500 MHz (AV 500) spectrometer using TMS as an internal standard in DMSO- d /CDCl . The mass spectra were recorded on a Varian Inc 410 Prostar Binary LC– –MS and an Agilent 6410 LC–MS spectrometer. Melting points were determined by the open tube capillary method and are uncorrected. Progress of the reaction and purity of the products __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ (CC) 2017 SCS NOVEL BENZIMIDAZOLE-SUBSTITUTED PYRAZOLINES AS ANTIMICROBIAL AGENTS was checked by thin layer chromatography (TLC). The spots were located under iodine vap-ours/UV light. The physical, analytical and spectral data for the compounds are given in the Supplementary material to this paper.
General procedure for synthesis of 3-aryl-1-(1-benzyl-1 H -benzo[ d ]imidazol-2-yl)-2-propen-1- -ones ( – ) Chalcones – (10 mmol) were dissolved in 40 mL dry acetone and then anhydrous K CO (15 mmol) was added to the solution. Later benzyl chloride (40 mmol) was added to the mixture and the contents were heated under reflux. The progress of the reaction was moni-tored by TLC (benzene–ethyl acetate, 4:1). After completion of the reaction (22–26 h), the reaction mixture was cooled and then poured into crushed ice. The obtained solid were filtered and recrystallized form alcohol. It should be noted that compounds – crystallised out from the reaction mixture after cooling, and they were then collected by filtration. Compounds and were previously reported. However, neither of them has been examined for their anti-microbial activities.
General procedure for the synthesis of 1-benzyl-2-(5-aryl-1-phenyl-4,5-dihydro-1 H -pyrazol- -3-yl)-1 H -benzimidazoles ( – ) To a solution of chalcones – (2 mmol) in acetic acid, phenylhydrazine (3 mmol) was added dropwise. The reaction mixture was heated under reflux. The progress of the reaction was monitored by TLC (benzene–ethyl acetate, 5:1). After completion of reaction (6–8 h), the reaction mixture was cooled and then poured into crushed ice. The obtained solid pyrazolines were washed with diethyl ether and recrystallized from acetone. General procedure for synthesis of 5-aryl-3-(1-benzyl-1 H -benzimidazol-2-yl)-4,5-dihydro- -1 H -pyrazole-1-carbothioamides ( – ) A mixture of chalcones – (2 mmol), thiosemicarbazide (6 mmol) and NaOH (4 mmol) was refluxed in ethanol (15 ml). The progress of the reaction was monitored by TLC (ben-zene–ethyl acetate, 5:1). After completion of reaction (4–6 h), the reaction mixture was cooled. The precipitate formed was filtered and washed with acetone. Microbiology
The compounds – were evaluated for their in vitro antimicrobial activity against bac-terial strains, viz . Bacillus subtilis
MTCC 441,
Staphylococcus aureus
MTCC 3160,
Pseudo-monas aeruginosa
MTCC 4673 and
Escherichia coli
MTCC 739, and the fungi
Candida albicans
MTCC 183. The reference cultures were procured from the Institute of Microbial Technology (IMTECH), Chandigarh, India-160036. Minimum inhibitory concentrations (
MIC ) were determined using nutrient broth (NB) for the bacteria and Sabouraud dextrose broth (SDB) for fungi by the two-fold serial dilution method.
The cultures were incubated for 24 h for the bacteria and 48 h for the fungi at 35 °C and the growth was monitored. The lowest concentration required to arrest the growth of microorganism was regarded as the mini-mum inhibitory concentration (
MIC ). Ciprofloxacin and fluconazole were used as positive control for the bacteria and fungi, respectively. DMSO was used as the negative control. The determinations of the antimicrobial activities of the compounds were performed in duplicate. RESULTS AND DISCUSSION
Chemistry
The target compounds described in this study were prepared as outlined in Scheme 1. Condensation of o -phenylenediamine with lactic acid under Phillips __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
The target compounds described in this study were prepared as outlined in Scheme 1. Condensation of o -phenylenediamine with lactic acid under Phillips __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ (CC) 2017 SCS PADHY, PANDA and BEHERA conditions led to 2-(1-hydroxyethyl)benzimidazole ( ), chromic oxidation of the latter followed by neutralization with ammonia led to 2-acetylbenzimidazole ( ). The required synthons 3-aryl-1-(1 H -benzimidazol-2-yl)-2-propen-1-ones ( – ) were prepared by Claisen–Schmidt condensation of 2-acetylbezimidazole with substituted aromatic aldehydes in presence of NaOH. Condensation of the 3-aryl-1-benzimidazolyl-2-propen-1-one derivatives – with benzyl chloride gave the corresponding 3-aryl-1-(1-benzyl-1 H -benzimidazol-2-yl)-2-propen-1- -ones – . The reaction of – with phenylhydrazine in the presence of acetic acid afforded 1-benzyl-2-(5-aryl-1-phenyl-4,5-dihydro-1 H -pyrazol-3-yl)-1 H -ben-zimidazoles – , whereas when – were condensed with thiosemicarbazide in presence of NaOH, 5-aryl-3-(1-benzyl-1 H -benzimidazol-2-yl)-4,5-dihydro- -1 H -pyrazole-1-carbothioamides were obtained in good yields. Scheme 1. Synthetic route to 1-benzyl-2-(1-substituted-5-aryl-4,5-dihydro-1 H -pyrazol-3-yl)- -1 H -benzimidazoles. Reagents and conditions: i) 4 M HCl, reflux, 8 h; ii) K Cr O , dil. H SO , r.t., 2h; iii) Ar-CHO, 10 % aq NaOH, ethanol, r.t., 4–8 h; iv) benzyl chloride, dry acetone, anhydrous K CO , reflux, 22–26 h; v) phenylhydrazine, acetic acid, reflux, 6–8 h; vi) thiosemicarbazide, NaOH, ethanol, reflux, 4–6 h. __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
The target compounds described in this study were prepared as outlined in Scheme 1. Condensation of o -phenylenediamine with lactic acid under Phillips __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ (CC) 2017 SCS PADHY, PANDA and BEHERA conditions led to 2-(1-hydroxyethyl)benzimidazole ( ), chromic oxidation of the latter followed by neutralization with ammonia led to 2-acetylbenzimidazole ( ). The required synthons 3-aryl-1-(1 H -benzimidazol-2-yl)-2-propen-1-ones ( – ) were prepared by Claisen–Schmidt condensation of 2-acetylbezimidazole with substituted aromatic aldehydes in presence of NaOH. Condensation of the 3-aryl-1-benzimidazolyl-2-propen-1-one derivatives – with benzyl chloride gave the corresponding 3-aryl-1-(1-benzyl-1 H -benzimidazol-2-yl)-2-propen-1- -ones – . The reaction of – with phenylhydrazine in the presence of acetic acid afforded 1-benzyl-2-(5-aryl-1-phenyl-4,5-dihydro-1 H -pyrazol-3-yl)-1 H -ben-zimidazoles – , whereas when – were condensed with thiosemicarbazide in presence of NaOH, 5-aryl-3-(1-benzyl-1 H -benzimidazol-2-yl)-4,5-dihydro- -1 H -pyrazole-1-carbothioamides were obtained in good yields. Scheme 1. Synthetic route to 1-benzyl-2-(1-substituted-5-aryl-4,5-dihydro-1 H -pyrazol-3-yl)- -1 H -benzimidazoles. Reagents and conditions: i) 4 M HCl, reflux, 8 h; ii) K Cr O , dil. H SO , r.t., 2h; iii) Ar-CHO, 10 % aq NaOH, ethanol, r.t., 4–8 h; iv) benzyl chloride, dry acetone, anhydrous K CO , reflux, 22–26 h; v) phenylhydrazine, acetic acid, reflux, 6–8 h; vi) thiosemicarbazide, NaOH, ethanol, reflux, 4–6 h. __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ (CC) 2017 SCS NOVEL BENZIMIDAZOLE-SUBSTITUTED PYRAZOLINES AS ANTIMICROBIAL AGENTS
The structure of the synthesized compounds were assigned based on elemental and spectroscopic analysis, IR, H-NMR, C-NMR and mass spec-trometry (Supplementary material to this paper). The IR data were very inform-ative and fully supported the proposed structures of the reported compounds. In the IR spectra of chalcones – , the (C=O) stretching was found in the expected region at 1652–1662 cm –1 . Furthermore, the presence of (C=N) and (C–N) stretching frequencies at 1594–1597 cm –1 and 1283–1330 cm –1 in the IR spectra of – confirmed the subsequent cyclization of the chalcone to the pyrazoline derivatives. In addition, derivatives – –22 showed typical absorption bands due to (–NH ) at 3290–3355 cm –1 and 3218–3250 cm –1 . The H-NMR spectrum compounds – exhibited two doublets with J values between 15–20 Hz, confirming the trans coupling and indicating the ole-finic protons in the E form. The C-NMR spectra of – confirmed the pre-sence of the α , β -unsaturated carbonyl system of chalcones by the presence of a peak at δ – were racemates, their structures were unambig-uously assigned with the help of spectral studies. The H-NMR spectra of com-pounds – displayed three sets of signals with an ABX pattern for the pyra-zoline ring protons. The sterochemical nature of the hydrogens H A , H B and H X was ascertained from a study of the coupling constants ( J ). The vicinal coupling constant between H A and H X was found to be 2.7–10.0 Hz ( J AX ), which indi-cates that these hydrogens are cis to each other, while the trans relationship between H B and H X was evident from the coupling constants of J BX in the 10.0– –15.0 Hz range. The coupling value of J AB in 17.5–20.0 Hz range between H A and H B evidently indicates their geminal placement at C4. The CH protons of pyrazoline are diastereotopic and appeared as a pair of doublets of doublets at δ A ) and δ B ), due to the vicinal coupling with the H X proton and the geminal coupling with each other. The CH proton (H X ) appeared as a doublet of doublets at δ A and H B ) at position 4 of the pyrazoline ring. The two methylene protons of benzyl group on geminal coupling showed two separate doublets at δ C ) and δ D ), indicating the diastereotopic nature of the methylene hydrogen. This was further confirmed by the appearance of three sets of signals at δ δ of benzyl) and δ C-NMR spectra of pyrazolines. It should be noted that in the spectra of compounds and the signal of C4 of pyrazoline was overshadowed by residual peaks of DMSO- d . Compounds – exhibited two separate broad singlets at δ δ protons. All the other additional peaks observed were in agreement with the respective aromatic substituents and benzimidazole __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
The structure of the synthesized compounds were assigned based on elemental and spectroscopic analysis, IR, H-NMR, C-NMR and mass spec-trometry (Supplementary material to this paper). The IR data were very inform-ative and fully supported the proposed structures of the reported compounds. In the IR spectra of chalcones – , the (C=O) stretching was found in the expected region at 1652–1662 cm –1 . Furthermore, the presence of (C=N) and (C–N) stretching frequencies at 1594–1597 cm –1 and 1283–1330 cm –1 in the IR spectra of – confirmed the subsequent cyclization of the chalcone to the pyrazoline derivatives. In addition, derivatives – –22 showed typical absorption bands due to (–NH ) at 3290–3355 cm –1 and 3218–3250 cm –1 . The H-NMR spectrum compounds – exhibited two doublets with J values between 15–20 Hz, confirming the trans coupling and indicating the ole-finic protons in the E form. The C-NMR spectra of – confirmed the pre-sence of the α , β -unsaturated carbonyl system of chalcones by the presence of a peak at δ – were racemates, their structures were unambig-uously assigned with the help of spectral studies. The H-NMR spectra of com-pounds – displayed three sets of signals with an ABX pattern for the pyra-zoline ring protons. The sterochemical nature of the hydrogens H A , H B and H X was ascertained from a study of the coupling constants ( J ). The vicinal coupling constant between H A and H X was found to be 2.7–10.0 Hz ( J AX ), which indi-cates that these hydrogens are cis to each other, while the trans relationship between H B and H X was evident from the coupling constants of J BX in the 10.0– –15.0 Hz range. The coupling value of J AB in 17.5–20.0 Hz range between H A and H B evidently indicates their geminal placement at C4. The CH protons of pyrazoline are diastereotopic and appeared as a pair of doublets of doublets at δ A ) and δ B ), due to the vicinal coupling with the H X proton and the geminal coupling with each other. The CH proton (H X ) appeared as a doublet of doublets at δ A and H B ) at position 4 of the pyrazoline ring. The two methylene protons of benzyl group on geminal coupling showed two separate doublets at δ C ) and δ D ), indicating the diastereotopic nature of the methylene hydrogen. This was further confirmed by the appearance of three sets of signals at δ δ of benzyl) and δ C-NMR spectra of pyrazolines. It should be noted that in the spectra of compounds and the signal of C4 of pyrazoline was overshadowed by residual peaks of DMSO- d . Compounds – exhibited two separate broad singlets at δ δ protons. All the other additional peaks observed were in agreement with the respective aromatic substituents and benzimidazole __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ (CC) 2017 SCS PADHY, PANDA and BEHERA ring. The mass spectra and elemental analyses were also in agreement with the proposed structures. Furthermore, the carbon–proton correlation of pyrazoline was confirmed by an HSQC experiment. The H A and H B protons ( δ δ δ δ Antimicrobial activity
The synthesized compounds – were screened for their in vitro antimic-robial activity. The results of antimicrobial activities of the benzimidazole deri-vatives are presented in Table I. The antimicrobial screening data revealed that all the newly synthesized compounds exhibited weaker antimicrobial activities compared to those of the control drugs. For bacterial strains, the MIC values of the compounds ranged between 128–1024 μg mL –1 for the chalcones – , between 64–1024 μg mL –1 for the 1-phenylpyrazolines – and between 128– –512 μg mL –1 for the pyrazoline-1-carbothioamides – . Among all the tested compounds, compound showed good activity (64 µg mL –1 ) against the tested bacterial strains. The MIC value of ciprofloxacin was 6.25–12.5 μg mL –1 for all TABLE I.
In vitro antimicrobial activity of the synthesized compounds , MIC / µg mL -1 Compound Gram-positive bacteria Gram-negative bacteria Fungi
S. aureus B. subtilis E. coli P. aeruginosa C. albicans
512 512 ˃1024 ˃1024 ˃1024 ˃1024 512 ˃1024 ˃1024 ˃1024
256 256 512 512 ˃1024
128 256 256 512 ˃1024
128 128 256 256 ˃1024
256 512 512 256 ˃1024 ˃1024 512 ˃1024 ˃1024 ˃1024
64 128 256 128 512
128 64 256 128 512
64 128 64 256 256 ˃1024 512 ˃1024 ˃1024 512 ˃1024 ˃1024 512 ˃1024 512
512 256 ˃1024 512 512
256 128 512 512 128
128 128 256 512 256 Ciprofloxacin 6.25 6.25 6.25 12.5 – Fluconazole – – – – 6.25 __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
128 128 256 512 256 Ciprofloxacin 6.25 6.25 6.25 12.5 – Fluconazole – – – – 6.25 __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ (CC) 2017 SCS
NOVEL BENZIMIDAZOLE-SUBSTITUTED PYRAZOLINES AS ANTIMICROBIAL AGENTS the tested bacterial strains. Chalcones – and 1-phenylpyrazolines and were almost inactive against C. albicans but pyrazoline-1-carbothioamide showed moderate activity against the fungi strain. The MIC value of fluconazole was 6.25 μg mL –1 for the fungi C. albicans . Subsequently, preliminary SAR studies were performed to deduce how the structure variation and modification could affect the antimicrobial activity. The antimicrobial activities of the compounds are related to the presence of electron withdrawing or donating substituents on the benzene ring. Compounds contain-ing electron withdrawing –F, –Cl and –Br exhibited good antimicrobial activity, whereas non-substituted compounds and compounds substituted with electron donating groups did not exhibit the same potency. For example, compound showed an MIC of 64 µg mL –1 against S. aureus and
E. coli , whereas compound showed an MIC of 256 and 512 µg mL –1 , respectively. The reason for above antibacterial activities could be explained by electron density, which plays an important role for the optimum activity. CONCLUSIONS
In this paper, the synthesis and characterization of three new chalcones, five 1-phenylpyrazolines and five pyrazoline-1-carbothioamides containing the N -ben-zylbenzimidazole moiety are presented. The structures of the new compounds were confirmed by spectral data (IR, H-NMR, C-NMR and mass spectro-metry) and elemental analysis. All the compounds were investigated for their antimicrobial activity against
B. subtilis , S. aureus , P. aeruginosa , E. coli and
C. albicans . The data indicated weak antibacterial activity, except for compound (which presented good activity against S. aureus and
E. coli ), (which pre-sented moderate activity on S. aureus and
P. aeruginosa and (which presented moderate action on B. subtilis and
P. aeruginosa ). The weak antibacterial activity could be because the tested compounds were in a racemic form. Based on the
MIC values presented by the tested compounds, it could be concluded that, in gen-eral, the derivatives containing a fluorine, chlorine and bromine atom had better antibacterial activity against the tested strains. The tested compounds were found to be either inactive, or moderately active ( ), against the fungal strain C. albicans.
Acknowledgements.
The authors gratefully acknowledge the Sophisticated Instrument-ation Facility (SAIF), IIT Madras and SAIF, IIT Bombay, India, for providing the spectral data. Gopal is thankful to Sri. P. Ashok Gajapathi Raju, Chairman, MANSAS, Vizianagaram and Dr. P. Udaya Shankar, Principal Maharajah’s College of pharmacy, Vizianagaram for pro-viding the necessary infrastructure and facility . __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
The authors gratefully acknowledge the Sophisticated Instrument-ation Facility (SAIF), IIT Madras and SAIF, IIT Bombay, India, for providing the spectral data. Gopal is thankful to Sri. P. Ashok Gajapathi Raju, Chairman, MANSAS, Vizianagaram and Dr. P. Udaya Shankar, Principal Maharajah’s College of pharmacy, Vizianagaram for pro-viding the necessary infrastructure and facility . __________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ (CC) 2017 SCS PADHY, PANDA and BEHERA
И З В О Д
СИНТЕЗА И КАРАКТЕРИЗАЦИЈА
НОВИХ
БЕНЗИМИДАЗОЛА
КОЈИ
САДРЖЕ
ТРИСУПСТИТУИСАНИ
ПИРАЗОЛИН
КАО
АНТИМИКРОБНИХ
ЈЕДИЊЕЊА
GOPAL K. PADHY , JAGADEESH PANDA и AJAYA K BEHERA Organic Synthesis Laboratory, School of Chemistry, Sambalpur University, Jyoti Vihar, Burla 768019, India, Maharajah’s College of Pharmacy, Phool Baugh, Vizianagaram 535002, India и Raghu College of Pharmacy, Dakamarri, Visakhapatnam 531162, India
Извршена је ефикасна синтеза нових супституисаних деривата пиразолина везаних са бензимидазолским прстеном , применом вишефазне реакционе секвенције . Сва синте - тисана једињења окарактерисана су елементалном анализом , спектроскопским мето - дама (IR, 1D/2D NMR) и масеном спектрометријом . Испитана је антимикробна актив - ност синтетисаних једињења према одабраним сојевима Грам - позитивних и Грам - нега - тивних бактерија и одабраних сојева гљивица . Једињења која поседују халоген - супсти - туисану ароматичну групу на C5 1- фенилпиразолинског прстена ( – ) показују зна - чајну антибактеријску активност . Од испитиваних једињења , дериват показује највећу инхибиторну активност ( MIC = 64 μ g mL -1 ). Испитивана једињења су показала готово потпуно одсуство активности према C. albicans , осим пиразолин -1- карботиоамида који је показао умерену активност . ( Примљено јуна ревидирано априла , прихваћено јула REFERENCES 1.
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