{Hindered phenolic aminothiazoles - synthesis, $\alpha$-glucosidase, $\alpha$-amylase inhibitory and antioxidant activities} J. Serb. Chem. Soc. 82 (10) 1087–1095 (2017) UDC 547.789.1+547.56+542.913:547.918: JSCS–5025 66.097.8:615.279–188 Original scientific paper 1087 Hindered phenolic aminothiazoles – Synthesis, α-glucosidase and α-amylase inhibitory and antioxidant activities SANDHYA VYJAYANTHY SATHEESH, AKHILA VIJAYAN RADHA, KRISHNAPRIYA KRISHNAN NAIR GIRIJA, KALLIKAT NARAYANAN RAJASEKHARAN and PRIYA RANI MAHESWARI* Department of Chemistry, University of Kerala, Kariavattom Campus, Trivandrum, Kerala, 695581, India (Received 5 October 2016, revised 1 July, accepted 5 July 2017) Abstract: Base-catalysed heterocyclization of either N-aryl-N'-[imino(nitro- amino)methyl]thioureas or N-aryl-N'-cyanothioureas by reaction with 2-bromo- 1-(2,6-di-t-butyl-4-hydroxyphenyl)ethanone afforded 4-amino-2-(arylamino)- -5-(3,5-di-t-butyl-4-hydroxybenzoyl)thiazoles, designed as molecular hybrids of hindered phenolic and 2-aminothiazole moieties. These compounds were screened for their inhibition activity on carbohydrate hydrolyzing enzymes. Thus, [4-amino-2-(phenylamino)-5-thiazolyl](3,5-di-t-butyl-4-hydroxyphenyl)- methanone exhibited α-glucosidase inhibition activity with an IC50 value of 117 µM while the standard compound acarbose showed an IC50 value of 48.3 µM and {4-amino-2-[(4-methylphenyl)amino]-5-thiazolyl}(3,5-di-t-butyl-4- -hydroxyphenyl)methanone showed good α-amylase inhibition activity with an IC50 value of 283 µM compared to acarbose (IC50 532 µM). The antioxidant activities of the hindered phenolic thiazoles were also investigated and the 2-[(4-methoxyphenyl)amino] derivative showed an antioxidant activity better than that of butylated hydroxyanisole in the 2,2-diphenyl-1-picrylhydrazyl rad- ical scavenging assay, better than that of either vitamin C or curcumin in the ferric ion-reducing antioxidant potential assay and comparable with that of but- ylated hydroxyanisole in the β-carotene bleaching assay. Keywords: 2,4-diaminothiazolyl; 3,5-di-t-butyl-4-hydroxyphenyl; hindered phenol; enzyme inhibition. INTRODUCTION Diabetes mellitus is a chronic endocrine disease that affects the metabolism of carbohydrates. The goal of diabetes treatment is to maintain a nearly normal level of glycemic control subsequent to food intake so as to maintain the postprandial hyperglycaemia.1 This could be achieved by inhibiting the carbo- * Corresponding author. E-mail: priyajyothym@gmail.com https://doi.org/10.2298/JSC161005084S ___________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. 1088 SATHEESH et al. hydrate hydrolyzing enzymes involved in the breakdown of carbohydrates, such as α-glucosidase and α-amylase. Hence, carbohydrate digestive enzyme inhi- bitors are widely investigated in the identification of lead compounds for the treatment of diabetes.2 In addition, the role oxidative stress and inflammation play in the development of diabetes mellitus has now been recognized and the significance of antioxidants in the control of diabetes mellitus was studied.3–5 Hindered phenols in which the phenolic hydroxyl group is juxtaposed with a sterically demanding group, such as a t-butyl group, have found wide application as antioxidants and permissible food preservatives.6 Typical examples of hin- dered phenols used in food preservation are 2-t-butyl-4-methylphenol (butylated hydroxytoluene, BHT), 2-t-butyl-4-methoxyphenol (butylated hydroxyanisole, BHA) and t-butylhydroquinone (TBHQ). A recent report highlighted the import- ance of free phenolic groups in flavone, isoflavone and chalcone derivatives on their α-glucosidase inhibitory activity.7 The incorporation of a 2,6-di-t-butyl- phenolic unit to improve the bioactivities of flavonoids by designing hindered phenol–flavonoid hybrids and the antioxidant activity of hydrazones bearing a 2,6-di-t-butylphenolic unit have also been reported recently.8 The 2-aminothi- azole moiety is isosteric with a phenolic unit and devoid of the acidity of the latter and hence, it finds much use in drug design.9 In connection with our inter- est in the anticancer10,11 and neuroprotective12 activities of 2,4-diaminothiazoles, it was noted that only a few reports exist on the antioxidant activity of aminothi- azoles.13,14 With this background, it was hypothesized that 2,4-diaminothiazoles bearing a hindered phenol moiety could show promising antioxidant activities. Accordingly, the design and synthesis of hitherto unreported 4-amino-2-(aryl- amino)-5-(3,5-di-t-butyl-4-hydroxybenzoyl)thiazoles as molecular hybrids inc- orporating di-t-butylphenol and 2,4-diaminothiazole moieties, along with their α- -glucosidase and α-amylase inhibitory and antioxidant activities are reported herein. EXPERIMENTAL Chemistry Melting points are uncorrected and were determined by the open capillary method. The thin layer chromatographic analyses were performed using silica gel 60 F254 TLC aluminium sheets purchased from Merck, Mumbai, India. The elemental analyses were performed on a Vario EL III elemental analyzer. The IR spectra were recorded on JASCO, Bomem MB and Shimadzu FTIR spectrophotometers. The NMR spectra were recorded on Bruker DPX-400 and 500 MHz spectrometers and FAB mass spectra were recorded on Jeol SX-102 FAB mass spectrometer. HRMS-ESI spectrum was performed at a resolution of 61800 using a Thermo Scientific Exactive mass spectrometer. All chemicals were from Sigma–Aldrich and Merck. The required N-aryl-N'-[imino(nitroamino)methyl]thioureas 1a–e were obtained from nitro- guanidine and aryl isothiocyanates 2a–e as reported earlier.15 Reported procedures with slight modifications were used to prepare 1-(2,6-di-t-butyl-4-hydroxyphenyl)ethanone from 2,6-di-t- -butylphenol16 and its bromination17 to obtain 2-bromo-1-(2,6-di-t-butyl-4-hydroxyphenyl)- ethanone 4. ___________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. PHENOLIC AMINOTHIAZOLES 1089 Analytical and spectral data of the synthesized compounds are given in Supplementary material to this paper. General procedure for synthesis of 4-amino-2-(arylamino)-5-(3,5-di-t-butyl-4-hydroxy- benzoyl)thiazoles 5a–e Method A: from N-aryl-N'-[imino(nitroamino)methyl]thioureas 1a–e. To a stirred solution of N-aryl-N'-[imino(nitroamino)methyl]thioureas (1a–e, 1 mmol) in N,N-dimethyl- formamide (DMF, 3mL) at room temperature, 2-bromo-1-(2,6-di-t-butyl-4-hydroxyphenyl)- ethanone (4, 1 mmol) was added and stirred. After 15 min, triethylamine (3 mmol) was added and the mixture was further stirred at room temperature for 75 min. The resulting deep brown reaction mixture was poured slowly with stirring into ice cold water. The brownish yellow precipitate of 4-amino-2-(arylamino)-5-(3,5-di-t-butyl-4-hydroxybenzoyl)thiazoles 5a–e obtained was collected by filtration, washed with water and dried. Method B: from N-aryl-N'-cyanothioureas (3a–e) prepared in situ. Cyanamide (1 mmol) and powdered potassium hydroxide (1.1 mmol) were stirred in DMF (2 mL) for 5 min at room temperature and to this mixture, aryl isothiocyanate (2a–e, 1 mmol) in DMF was added drop- wise with stirring over 5 min. After further stirring at room temperature for 90 min, the mix- ture containing N-aryl-N'-cyanothioureas (3a–e) was treated with 2-bromo-1-(2,6-di-t-butyl-4- -hydroxyphenyl)ethanone (4, 1 mmol) and the stirring was continued for a further 30 min. Tri- ethylamine (1.2 mmol) was then added followed by stirring for 30 min. The so-obtained red- dish brown mixture was poured into ice cold water and the crude 4-amino-2-(arylamino)-5- -(3,5-di-t-butyl-4-hydroxybenzoyl)thiazoles 5a–e were collected, washed with water and dried. The crude products obtained by methods A and B were purified either by crystallization from ethanol or by dry column flash chromatography on thin layer chromatography grade silica gel eluted with hexane–ethyl acetate. α-Glucosidase inhibition activity The mode of α-glucosidase inhibition was studied according to Apostolidis et al.18 Briefly, about 50 µL of homogenized sample solutions of varying concentrations (5–250 µM) and 100 µL of 0.1 M phosphate buffer (pH 6.9) containing α-glucosidase solution (1.0 U mL-1) was incubated in 96 well plates at 25 °C for 10 min. After pre-incubation, 50 μL of p-nitro- phenyl α-D-glucopyranoside solution (7.5 mg in 5 ml; 5 mM) in 0.1 M phosphate buffer (pH 6.9) was added to each well at timed intervals. Before and after incubation at 25 °C for 5 min, the absorbance at 405 nm was measured using an Enspire multimode reader (Perkin Elmer). Acarbose was used as the positive control and the results are expressed as percent inhibition, calculated as: (1–Asample/Acontrol)×100 (1) where A is the absorbance. α-Amylase inhibition activity The inhibitory activity of α-amylase enzymes (from Aspergillus oryzae) was performed using a reported procedure with a slight modification.18 Briefly, different concentrations of the stock solutions of the samples (100–600 µM) were incubated with an α-amylase solution (0.5 mg/ml) in 0.02 M phosphate buffer (pH 6.9 with 0.006 M NaCl, 500 μL) at 25 °C for 10 min. After pre-incubation, 500 μL of a 1 % starch solution in 0.02 M sodium phosphate buffer (pH 6.9 with 0.006 M sodium chloride) was added to each tube at timed intervals. The reaction was stopped with 500 µL of 3,5-dinitrosalicylic acid (1 %) as a colour reagent. The tubes were then incubated in a boiling water bath for around 5 min, cooled to room temperature and ___________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. 1090 SATHEESH et al. diluted to 10 mL with distilled water. The absorbance was measured at 540 nm using acarbose as the standard. The percentage of inhibition was calculated using the formula (1). Antioxidant capacity assays 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity. The DPPH radical scav- enging efficacy of the compounds was evaluated based on a reported procedure.19 Briefly, ali- quots of the test samples leading to a concentration range of 100–600 µM were mixed with a methanolic solution of DPPH (1.5 mL; 25 mg L-1), kept in the dark for 30 min and the absorb- ance was measured at 517 nm against the control. BHA and curcumin served as standards. The percentage radical scavenging activity, calculated as the scavenging effect (SE) from formula (1), was plotted against concentration to obtain the concentration values resulting in 50 % inhibition (IC50). Ferric ion reducing potential (FRAP) assay The FRAP activity was measured according to the method of Benzie and Strain.20 Acetate buffer (300  mM; pH 3.6), 2,4,6-tripyridyl-s- -triazine (TPTZ; 10 mM in 40 mM aq. hydrochloric acid) and FeCl3·6H2O (20  mM) were mixed in the ratio of 10:1:1 to obtain the working FRAP reagent. Test samples (500 µM) in methanol (10 mL) were mixed with 3 mL of working FRAP reagent and absorbance was mea- sured at 593 nm after vortexing. Methanolic solutions of FeSO4·7H2O ranging from 100 to 2000 μM were used for the preparation of the calibration curve of known Fe2+ concentration. The parameter equivalent concentration (EC) was defined as the concentration of antioxidant having a ferric–TPTZ reducing ability equivalent to that of 1 mM FeSO4·7H2O. BHA and curcumin were used as standards. β-Carotene bleaching assay. The inhibition of the oxidative bleaching of β-carotene in a β-carotene/linoleic acid emulsion is measured in the β-carotene bleaching assay. It was real- ised using the method of Hidalgo et al.21 by using an emulsion obtained by mixing β-carotene (0.2 mg), linoleic acid (20 mg) and Tween 20 (200 mg, 0.180 mL) in chloroform (0.5 mL), evaporating off the chloroform and suspending in distilled water (50 mL). The thus obtained emulsion (4 mL) was treated with the test samples in methanol (180 µL) at a concentration 10-3 M. BHA was used as the standard together with a control without sample and the absorbance was measured at 470 nm. Antioxidant activity was expressed as the percentage inhibition rel- ative to the control using the equation: AA = 100(DRC – DRS)/DRC where DRC is the degradation rate of the control (DRC = ln (a/b)/60, where a is initial absorb- ance of control and b is the final absorbance of control after 60 min) and DRS is the degrad- ation rate of the thiazole sample (DRS = ln (a/b)/60, where a is the initial absorbance of the sample and b is the final absorbance of sample after 60 min).22 RESULTS AND DISCUSSION Chemistry A retro-synthetic analysis indicated that a [4+1] heterocyclization of the type ((C4–N3–C2–S1)+C5), leading to the thiazole ring formation, could be adopted for the synthesis of the hitherto unreported 4-amino-2-(arylamino)-5-(3,5-di-t-butyl-4- -hydroxybenzoyl)thiazoles 5. The four ring atoms [(C4–N3–C2–S1) could be sourced from either N-aryl-N'-[imino(nitroamino)methyl]thioureas (1, method A; Scheme 1), obtainable from nitroguanidine and aryl isothiocyanates (2a–e), as reported earlier,15 or from N-aryl-N'-cyanothioureas (3a–e), accessible from ___________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. PHENOLIC AMINOTHIAZOLES 1091 cyanamide and aryl isothiocyanates (2a–e, method B; Scheme 2).23 The remain- ing C5 carbon required to assemble the thiazole core could arise from 2-bromo-1- (2,6-di-t-butyl-4-hydroxyphenyl)ethanone (4). It was found that both the above two methods afforded the target diaminothiazoles in good yields (see Supple- mentary material). Ar: NH2O2NHN NH Ar-N=C=S DMF; solid KOH Room Temp; 90 min H NO2NHN NH NHAr S 1a-e 2a-e N O2NHN HN NHAr SCH N S NHAr O2NHN H2N RCO R-CO-CH2Br 4 OH Bu-t Bu-t R = HH RCO 5a-e O HO t-Bu Bu-t S N NH2 NHAr [ - H2N-NO2] DMF; Et3N; 80-90 oC; 3hr 1; 2; 5 a: C6H5; b: 4-MeO-C6H4; c: 4-Cl-C6H4; d: 4-Me-C6H4; e: 4-EtO-C6H4 Et3N: Et3N: Scheme 1. Synthesis of [4-amino-2-(phenylamino)-5-thiazolyl](3,5-di-t-butyl-4-hydroxy- phenyl)methanone – Method A. Ar: C NN NHAr SCH N S NHAr HN RCO R-CO-CH2Br 4 OH Bu-t Bu-t R = HH RCO 5a-e O HO t-Bu Bu-t S N NH2 NHAr 1; 3; 5 a: C6H5; b: 4-MeO-C6H4; c: 4-Cl-C6H4; d: 4-Me-C6H4; e: 4-EtO-C6H4 Et3N: NC H N NHAr S H2N-CN 3a-e Ar-N=C=S DMF; solid KOH Room Temp; 95 min 2a-e DMF; Et3N Room Temp; 60 min Scheme 2. Synthesis of [4-amino-2-(phenylamino)-5-thiazolyl](3,5-di-t-butyl-4-hydroxy- phenyl)methanone – Method B. ___________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. 1092 SATHEESH et al. α-Glucosidase and α-amylase inhibitory activity determination The α-glucosidase enzyme inhibition activity was measured using the enzyme from Saccharomyces cerevisiae. The different concentrations of 4- amino-2-(arylamino)-5-(3,5-di-t-butyl-4-hydroxybenzoyl)thiazoles (5a–e) showed dose dependent inhibition compared with the standard acarbose. The results showed that [4-amino-2-(phenylamino)-5-thiazolyl](3,5-di-t-butyl-4-hydroxy- phenyl)methanone (5a) showed good α-glucosidase enzyme inhibition activity (IC50 = 117.02 µM), compared with the standard compound acarbose that showed an IC50 value of 48.26 µM (Table I). The study of inhibition of the α- amylase enzyme revealed that all the compounds showed good inhibition activity compared to that of acarbose. As a typical example, {4-amino-2-[(4-methylphe- nyl)amino]-5-thiazolyl}(3,5-di-t-butyl-4-hydroxyphenyl)methanone (5d) showed an IC50 value of 283.19 µM in comparison with acarbose which showed an IC50 value of 531.91 µM (Table I). The results indicated that the phenolic aminothiazole unit could be a potential structural platform for the development of compounds with antidiabetic activity. TABLE I. α-Glucosidase and α-amylase enzyme inhibition activity of compounds 5a–e Compound IC50 / µM α-Glucosidase α-Amylase 5a 117 350 5b 146 566 5c 180 293 5d 214 283 5e 239 325 Acarbose 48.3 532 Antioxidant activity The antioxidant activity of 4-amino-2-(arylamino)-5-(3,5-di-t-butyl-4-hydro- xybenzoyl)thiazoles (5a–e) were assessed based on the DPPH radical scavenging assay. These were selected as representative examples of aminothiazoles (5) with a 2-(arylamino) substituent bearing electron withdrawing, neutral or electron donating substituent on the phenyl ring. The 2-[(4-methoxyphenyl)amino] deri- vative (5b, EC50 = 250 µM) and 2-[(4-ethoxyphenyl)amino] derivative (5e, EC50 = 265 µM) showed better radical scavenging activities than the 2-phenylamino derivative (5a, EC50 = 340 µM), 2-[(4-methylphenyl)amino] derivative (5d, EC50 = 365 µM) and the 2-(4-chlorophenylamino) derivative (5c, EC50 590 µM), in comparison with the standards curcumin (EC50 = 200 µM) and BHA (EC50 = = 280 µM). The results of the DPPH assay showed that {4-amino-2-[(4-methyl- phenyl)amino]-5-thiazolyl}(3,5-di-t-butyl-4-hydroxyphenyl)methanone (5b) pos- sessed an antioxidant activity that was better than that of BHA, but lower than that of curcumin. ___________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. PHENOLIC AMINOTHIAZOLES 1093 In the case of FRAP assay, the 2-[(4-methoxyphenyl)amino]thiazole deri- vative (5b) showed a better activity, with a FeSO4 equivalence of 1700 µM, com- pared with those of the 2-[(4-ethoxyphenyl)amino]thiazole (5e, 1500 µM), 2- -(phenylamino)thiazole (5a, 1100 µM), 2-[(4-methylphenyl)amino]thiazole (5d, 900 µM) and the 2-[(4-chlorophenyl)amino)thiazole (5c, 800 µM) derivatives, in comparison with those of vitamin C (1400 µM) and of curcumin (1700 µM). The data of the β-carotene bleaching assay indicated that {4-amino-2-[(4- methylphenyl)amino]-5-thiazolyl}(3,5-di-t-butyl-4-hydroxyphenyl)methanone (5b) exhibited 56 % antioxidant activity whereas the 2-[(4-ethoxyphenyl)amino]- thiazole (5e), 2-(phenylamino)- (5a), 2-[(4-chlorophenyl)amino]- (5c) and 2-[(4- -methylphenyl)amino]thiazole (5d) derivatives showed 52, 30, 27 and 24 % antioxidant activity, respectively, in comparison with the 58 % activity of BHA (Table II). TABLE II. Antioxidant activity studies on compounds 5a–e Compound DPPH radical scavenging activity, µM FRAP µM β-carotene bleaching method, % 5a 340 1100 30 5b 250 1700 56 5c 590 800 27 5d 365 900 24 5e 265 1500 52 BHA 280 – 58 Curcumin 200 1700 – Vitamin C – 1400 – It appears that the presence of an electron donating substituent on the 2- arylamino group of 4-amino-2-(arylamino)-5-(3,5-di-t-butyl-4-hydroxybenzoyl)- thiazoles promotes antioxidant activity. The free radical scavenging activity largely depends on the hydrogen donating ability of phenolic compounds and the phenoxyl radicals thus formed are stabilized by resonance or intramolecular hyd- rogen bonding.24 The free radical scavenging activity was suggested to be enhanced by the presence of electron donating groups in the aromatic substi- tuents.25 In the present case, the presence of a hindered phenolic group and the aminothiazole unit together could be responsible for the observed antioxidant potential of the studied 4-amino-(2-arylamino)-5-(3,5-di-t-butyl-4-hydroxyben- zoyl)thiazoles. CONCLUSIONS In conclusion, hitherto unreported 4-amino-2-(arylamino)-5-(3,5-di-t-butyl-4- -hydroxybenzoyl)thiazoles (5a–e) were prepared as molecular hybrids of hindered phenol and 2-aminothiazole moieties, leading to new antioxidants. Among the compounds (5a–e), [4-amino-2-(phenylamino)-5-thiazolyl](3,5-di-t-butyl-4-hyd- ___________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. 1094 SATHEESH et al. roxyphenyl)methanone (5a) exhibited α-glucosidase inhibition activity (IC50 = = 117.02 µM) and {4-amino-2-[(4-methylphenyl)amino]-5-thiazolyl}(3,5-di-t- -butyl-4-hydroxyphenyl)methanone (5d) showed α-amylase inhibition activity (IC50 = 283.19 µM). It was further found that {4-amino-2-[(4-methoxyphe- nyl)amino]-5-thiazolyl}(3,5-di-t-butyl-4-hydroxyphenyl)methanone (5b) exhibited better antioxidant activity in comparison with the activity of BHA or vitamin C. The present results suggest that the antidiabetic potential of these newly synthesized hindered phenolic aminothiazoles, which exhibit a combination of α-glucosidase and α-amylase inhibition activities, as well as antioxidant properties, warrants further investigation. SUPPLEMENTARY MATERIAL Analytical and spectral data of the synthesised compounds are available electronically at the pages of the journal website: http://www.shd.org.rs/JSCS/, or from the corresponding author on request. Acknowledgements. MPR thanks UGC-DS Kothari Post Doctoral Fellowship Scheme for the postdoctoral fellowship. VRA, KGKP and KNR thank UGC, Govt. of India for junior research and emeritus fellowships. SVS thank KSCSTE, Govt. of Kerala for financial assist- ance and Prof. Dr. T. S. Anirudhan for mentorship. We also acknowledge Sophisticated Test and Instrumentation Centre (STIC), Cochin University, Cochin, Kerala and CSIR-NIIST, Trivandrum, Kerala for recording the NMR and mass spectra. И З В О Д СТЕРНО ЗАКЛОЊЕНИ АМИНОТИАЗОЛИ – СИНТЕЗА, ИНХИБИЦИЈА АКТИВНОСТИ α-ГЛУКОЗИДАЗЕ И α-АМИЛАЗЕ И АНТИОКСИДАТИВНА АКТИВНОСТ SANDHYA VYJAYANTHY SATHEESH, AKHILA VIJAYAN RADHA, KRISHNAPRIYA KRISHNAN NAIR GIRIJA, KALLIKAT NARAYANAN RAJASEKHARAN и PRIYA RANI MAHESWARI Department of Chemistry, University of Kerala, Kariavattom Campus, Trivandrum, Kerala, 695581, India У реакцији базно катализоване хетероциклизације N-арил-N'-[имино(нитроамино)- метил]тиоуреа са 2-бром-1-(2,6-ди-t-бутил-4-хидроксифенил)етаноном као производи су добијени 4-амино-2-(ариламино)-5-(3,5-ди-t-бутил-4-хидроксибензоил)тиазоли, једињења која су дизајнирана као хибридни молекули стерно захтевних фенола и 2-ами- нотиазола. Испитана је инхибиторна активност добијених једињења према хидроли- тичким ензимима угљених хидрата. Утврђено је да [4-амино-2-(фениламино)-5-тиазо- лил](3,5-ди-t-бутил-4-хидроксифенил)метанон показује инхибицију активности α-глу- козидазе са IC50 = 117,02 μM, док акарбоза као стандард показује IC50 од 48,26 μM, а дериват {4-амино-2-[(4-метилфенил)амино]-5-тиазолил}(3,5-ди-t-бутил-4-хидроксифе- нил)метанон показује добру инхибицију активности α-aмилазе са IC50 = 283,19 μM у поређењу са акарбозoм (IC50 = 531,91 μM). Такође, испитана је антиоксидативна активност стерно заклоњених фенолних тиазола, и 2-[(4-метоксифенил)амино] дериват показује бољу антиоксидативну активност од бутилованог хидроксианизола у тесту са 2,2-дифенил-1-пикрилхидразилом као хватачем радикала, затим од витамина це или куркумина у тесту са фери-јонима, и сличну активност као бутиловани хидроксианизол у тесту са β-каротеном. (Примљено 5. октобра 2016, ревидирано 1. јула, прихваћено 5. јула 2017) ___________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. PHENOLIC AMINOTHIAZOLES 1095 REFERENCES 1. R. Chakrabarti, R. Rajagopalan, Curr. Sci. 83 (2002) 1533 2. R. Subramanian, A. Z. Asmawi, A. Sadikun, Acta Biochim. Pol. 55 (2008) 391 3. J. L. Evans, B. A. Maddux, I. D. Goldfine, Antioxid. Redox Signaling 7 (2005) 1040 4. M. Y. Donath, S. E. Shoelson, Nat. Rev. Immunol. 11 (2011) 98 5. R. Rahimi, S. Nikfar, B. Larijani, M. Abdollahi, Biomed. Pharmacother. 59 (2005) 365 6. H. Babich, Environ. Res. 29 (1982) 1 7. H. Sun, Y. Li, X. Zhang, Y. Lei, W. Ding, X. Zhao, H. Wang, X. Song, Q. Yao, Y. Zhang, Y. Ma, R. Wang, T. Zhu, P. Yu, Bioorg. Med. Chem. Lett. 25 (2015) 4567 8. J. Lebeau, C. Furman, J. L. Bernier, P. Duriez, E. Teissier, N. Cotelle, Free Radical Biol. Med. 29 (2000) 900 9. A. Zhang, W. Xiong, J. E. Hilbert, E. K. DeVita, J. M. Bidlack, J. L. Neumeyer, J. Med. Chem. 47 (2004) 1886 10. N. E. Thomas, R. Thamkachy, K. C. Sivakumar, K. J. Sreedevi, X. L. Louis, S. A. Thomas, R. Kumar, K. N. Rajasekharan, L. Cassimeris, S. Sengupta, Mol. Cancer Ther. 13 (2014) 179 11. M. Juneja, U. Vanam, S. Paranthaman, A. Bharathan, V. S. Keerthi, J. K. Reena, R. Rajaram, K. N. Rajasekharan, D. Karunagaran, Eur. J. Med. Chem. 63 (2013) 474 12. M. Mayadevi, D. R. Sherin, V. S. Keerthi, K. N. Rajasekharan, R. V. Omkumar, Bioorg. Med. Chem. 20 (2012) 6040 13. O. Uchikawa, K. Fukatsu, M. Suno, T. Aono, T. Doi, Chem. Pharm. Bull. 44 (1996) 2070 14. K. B. Kalpana, M. Srinivasan, V. P. Menon, Mol. Cell. Biochem. 314 (2008) 95 15. R. Binu, K. K. Thomas, G. C. Jenardanan, K. N. Rajasekharan, Org. Prep. Proced. Int. 30 (1998) 93 16. N. V. Portnykh, A. A. Volod’kin, V. V. Ershov, Izv. Akad. Nauk SSSR, Ser. Khim. (1966) 2243 17. A. A. Volodd’kin, V. V. Ershov, N. V. Portnykh, Izv. Akad. Nauk SSSR, Ser. Khim. (1967) 215 18. E. Apostolidis, Y. I. Kwon, K. Shetty, Innovative Food Sci. Emerging Technol. 8 (2007) 46 19. W. Brand-Williams, M. E. Cuvelier, C. Berset, Lebensm.-Wiss. Technol. 28 (1995) 25 20. I. F. Benzie, J. J. Strain, Anal. Biochem. 239 (1996) 70 21. M. E. Hidalgo, E. Fernandez, W. Quilhot, E. Lissi, Phytochemistry 37 (1994) 1585 22. H. Y. Lai, Y. Y. Lim, Int. J. Environ. Sci. Dev. 2 (2011) 442 23. K. Gewald, P. Blauschmidt, R. Mayer, J. Prakt. Chem. 35 (1967) 97 24. E. Bendary, R. R. Francis, H. M. G. Ali, M. I. Sarwat, S. El Hady, Ann. Agric. Sci. 58 (2013) 173 25. X. Ma, H. Li, J. Dong, W. Qian, Food Chem. 126 (2011) 698. ___________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2017 SCS. << /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles true /AutoRotatePages /None /Binding /Left /CalGrayProfile (Dot Gain 20%) /CalRGBProfile (sRGB IEC61966-2.1) /CalCMYKProfile (U.S. Web Coated \050SWOP\051 v2) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Error /CompatibilityLevel 1.4 /CompressObjects /Tags /CompressPages true /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJobTicket false /DefaultRenderingIntent /Default /DetectBlends true /DetectCurves 0.0000 /ColorConversionStrategy /CMYK /DoThumbnails false /EmbedAllFonts true /EmbedOpenType false /ParseICCProfilesInComments true /EmbedJobOptions true /DSCReportingLevel 0 /EmitDSCWarnings false /EndPage -1 /ImageMemory 1048576 /LockDistillerParams false /MaxSubsetPct 100 /Optimize true /OPM 1 /ParseDSCComments true /ParseDSCCommentsForDocInfo true /PreserveCopyPage true /PreserveDICMYKValues true /PreserveEPSInfo true /PreserveFlatness true /PreserveHalftoneInfo false /PreserveOPIComments true /PreserveOverprintSettings true /StartPage 1 /SubsetFonts true /TransferFunctionInfo /Apply /UCRandBGInfo /Preserve /UsePrologue false /ColorSettingsFile () /AlwaysEmbed [ true ] /NeverEmbed [ true ] /AntiAliasColorImages false /CropColorImages true /ColorImageMinResolution 300 /ColorImageMinResolutionPolicy /OK /DownsampleColorImages true /ColorImageDownsampleType /Bicubic /ColorImageResolution 300 /ColorImageDepth -1 /ColorImageMinDownsampleDepth 1 /ColorImageDownsampleThreshold 1.50000 /EncodeColorImages true /ColorImageFilter /DCTEncode /AutoFilterColorImages true /ColorImageAutoFilterStrategy /JPEG /ColorACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /ColorImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000ColorACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000ColorImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /OK /DownsampleGrayImages true /GrayImageDownsampleType /Bicubic /GrayImageResolution 300 /GrayImageDepth -1 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /DCTEncode /AutoFilterGrayImages true /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /GrayImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000GrayACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000GrayImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1200 /MonoImageMinResolutionPolicy /OK /DownsampleMonoImages true /MonoImageDownsampleType /Bicubic /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict << /K -1 >> /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile () /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False /CreateJDFFile false /Description << /ARA /BGR /CHS /CHT /CZE /DAN /DEU /ESP /ETI /FRA /GRE /HEB /HRV (Za stvaranje Adobe PDF dokumenata najpogodnijih za visokokvalitetni ispis prije tiskanja koristite ove postavke. Stvoreni PDF dokumenti mogu se otvoriti Acrobat i Adobe Reader 5.0 i kasnijim verzijama.) /HUN /ITA /JPN /KOR /LTH /LVI /NLD (Gebruik deze instellingen om Adobe PDF-documenten te maken die zijn geoptimaliseerd voor prepress-afdrukken van hoge kwaliteit. De gemaakte PDF-documenten kunnen worden geopend met Acrobat en Adobe Reader 5.0 en hoger.) /NOR /POL /PTB /RUM /RUS /SKY /SLV /SUO /SVE /TUR /UKR /ENU (Use these settings to create Adobe PDF documents best suited for high-quality prepress printing. Created PDF documents can be opened with Acrobat and Adobe Reader 5.0 and later.) >> /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ << /AsReaderSpreads false /CropImagesToFrames true /ErrorControl /WarnAndContinue /FlattenerIgnoreSpreadOverrides false /IncludeGuidesGrids false /IncludeNonPrinting false /IncludeSlug false /Namespace [ (Adobe) (InDesign) (4.0) ] /OmitPlacedBitmaps false /OmitPlacedEPS false /OmitPlacedPDF false /SimulateOverprint /Legacy >> << /AddBleedMarks false /AddColorBars false /AddCropMarks false /AddPageInfo false /AddRegMarks false /ConvertColors /ConvertToCMYK /DestinationProfileName () /DestinationProfileSelector /DocumentCMYK /Downsample16BitImages true /FlattenerPreset << /PresetSelector /MediumResolution >> /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ] >> setdistillerparams << /HWResolution [2400 2400] /PageSize [612.000 792.000] >> setpagedevice