Thiazole Based Carbohydrazide Derivatives as -Amylase ...downloads.hindawi.com/journals/htrc/2019/7502347.pdf · Thiazole Based Carbohydrazide Derivatives as -Amylase Inhibitor and

Research ArticleThiazole Based Carbohydrazide Derivatives as 120572-AmylaseInhibitor and Their Molecular Docking Study

Muhammad Taha 1 Maryam Irshad23 Syahrul Imran34 Fazal Rahim5

Manikandan Selvaraj6 Noor Barak Almandil1 Ashik Mosaddik1 Sridevi Chigurupati 7

Faisal Nawaz2 Nor Hadiani Ismail34 and Mohamed Ibrahim1

1Department of Clinical Pharmacy Institute for Research and Medical Consultations (IRMC)Imam Abdulrahman Bin Faisal University PO Box 1982 Dammam 31441 Saudi Arabia2Department of Chemistry University of Wah Quaid Avenue Wah Cantt 47000 Pakistan3Atta-ur-Rahman Institute for Natural Product Discovery Universiti Teknologi MARA (UiTM) Puncak Alam Campus42300 Bandar Puncak Alam Selangor Malaysia4Faculty of Applied Science UiTM Shah Alam 40450 Shah Alam Selangor DE Malaysia5Department of Chemistry Hazara University Mansehra-21300 Khyber Pakhtunkhwa Pakistan6School of Engineering Monash University (Malaysia Campus) Bandar Sunway 47500 Malaysia7Department of Medicinal Chemistry and Pharmacognosy College of Pharmacy Qassim University Buraidah 51452 Saudi Arabia

Correspondence should be addressed to Muhammad Taha mtahaiauedusa

Received 3 October 2018 Accepted 22 January 2019 Published 4 February 2019

Academic Editor Luke R Odell

Copyright copy 2019 Muhammad Taha et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

In this study we are going to present thiazole based carbohydrazide in search of potent antidiabetic agent as 120572-amylase inhibitorsThiazole based carbohydrazide derivatives 1-25 have been synthesized characterized by 1HNMR 13CNMR and EI-MS andevaluated for 120572-amylase inhibition Except compound 11 all analogs showed 120572-amylase inhibitory activity with IC

50values from

1709 plusmn 012 to 3049 plusmn 025 120583M against the standard acarbose (IC50= 1637 plusmn 0153 120583M) Compounds 1 10 14 and 20 exhibited

outstanding inhibitory potential with IC50value 1763 plusmn 003 1747 plusmn 020 1709 plusmn 012 and 1948 plusmn 023 120583M respectively compared

with the standard acarbose Structure activity relationships have been established for the active compounds To get an idea aboutthe binding interaction of the compounds molecular docking studies were done

1 Introduction

120572-Amylase is a protein enzyme EC3211 which helps inthe breakdown of starch to glucose and maltose Livingorganism used carbohydrates and sugars as the major energystorage molecules [1 2] The 120572-amylase enzyme is calciummetalloenzyme found in human saliva serum and urineAccording to clinical chemistry the presence of parotitis andpancreatitis can be determined by the activity of 120572-amylase inserum and urine respectively [3]120572-Amylase is one of themost critical endoamylases which

has ability to hydrolyze the inner 120572-14 glycosidic linkages toglucose dextrin and maltose while holding the 120572-anomeric

setup in the products [4] As an omnipresent enzyme 120572-amylase is delivered by numerous species including plantsanimals and microorganisms A huge number of microbialamylases of diverse origins have been broadly studied andwidely applied in various areas eg textile detergent foodpaper biofuel etc Besides very important clinical applica-tions have been carried out inmedicine and for the reductionof toxicity by the environmental pollutants [5 6]

Recently 120572-amylase has been isolated and characterizedfrom natural sources [7] Researchers have also studiedits effects on enzyme stability and analyzed the bindingproperties to develop new inhibitors [8 9] The thiazole andits derivatives are very much important in nature because

HindawiHeteroatom ChemistryVolume 2019 Article ID 7502347 8 pageshttpsdoiorg10115520197502347

2 Heteroatom Chemistry

OS

N NH

N ROS

N NH

OS

N O EtOHReflux 6 hr

RCHON（2N（2 （2O

N（2（

+

Scheme 1 Synthesis of thiazole based carbohydrazide

they keep versatile biological properties Thiazole containingmolecules are used as an antimicrobial drug abafungin asantifungal drug ritonavir as antiretroviral drug thiazofurinand bleomycine as antineoplastic [10] antihistaminic nirida-zole as schistosomicidal and nitazoxanide as antiprotozoal[11] Our group has already reported thiazole analogs asacetylcholinesterase and butyrylcholinesterase inhibitor [12]with hopes to further explore their potential as alpha-amylaseinhibitor In this regard here in the present study we are goingto report thiazole analogs as potent alpha-amylase inhibiter

2 Results and Discussion

21 Chemistry Methyl 2-(25-dimethylthiazol-4-yl) acetateand excess amount of hydrazine hydrate were refluxedin ethanol for six hrs to obtaine pure methyl 2-(25-dimethylthiazol-4-yl) hydrazide Intermediate 2-(25-dimethylthiazol-4-yl) hydrazide was further treated withdifferent substituted aromatic aldehydes in ethanol as solventthe reaction mixture was acidified by 3-4 drops glacial aceticto achieve the target compounds (Scheme 1) (1-25) (Table 1)Here in this study each step was monitored by TLC throughethyl acetatehexane system (ratio 37)

22 120572-Amylase Inhibitory Potential To carry on our researchwork on enzyme inhibition [13 14] we have synthesizedthiazole based carbohydrazide analogs (1-25) (Table 1) andthey were evaluated for 120572-amylase inhibitory activity Allanalogs except 11 have 120572-amylase inhibition with IC

50values

from 1709 plusmn 012 to 3049 plusmn 025 120583M against the standardacarbose (IC

50= 1637 plusmn 0153 120583M) (Table 2) The structure

activity relationship has been also studied and it is mainlybased upon the difference of substituents on phenyl ringattached to the carbohydrazide part

The analog 14 a para nitro-substituted analog was foundto be the most active analog among allThemore noteworthypotential of the compound might be due to the presence ofnitro group which is a strong electron withdrawing groupWhen comparing compound 14 (IC

50value 1709 plusmn 012 120583M)

with analog 12 an ortho nitro-substituted analog (IC50value

2416 plusmn 004 120583M) and 13 a meta nitro-substituted analog(IC50

value 2544 plusmn 006 120583M) analog 14 showed greaterpotential than analogs 12 and 13 which seems to be due todifferent positioning of nitro group on phenyl ring

Compound 10 a para hydroxy analog was found to bethe second most dynamic analog within this series with IC

50

value 1747 plusmn 020 120583M The greater potential shown by thiscompound seems to be due to the hydroxyl group whichmight be involved in hydrogen bonding with the active siteof enzyme By comparing analog 10 with other hydroxylanalogs like 9 a meta hydroxyl analog (IC

50= 2594 plusmn 005

120583M) 5 a 25-dihydroxyl analog (IC50= 2752 plusmn 008 120583M) 6

a 23-dihydroxyl analog (IC50= 2479 plusmn 0104 120583M) 7 a 24-

dihydroxyl analog (IC50= 2481 plusmn 004 120583M) and 8 a 34-

dihydroxyl analog (IC50= 2613 plusmn 005 120583M) the compound

is superior The slight activity difference seems to be mainlygoverned by the position of substituent Analog 17 a 246-trihydroxyl analog (IC

50=2649plusmn 008120583M) showedpotential

but analog 11 a 234-trihydroxyl analog was found to becompletely inactive This might be due to position differenceof hydroxyl group

Compound 1 a para methyl analog was the third mostactive analog among the series with IC

50value 1763 plusmn 003

120583M when compared to 2 an ortho methyl analog (IC50=

2608 plusmn 023 120583M) The reason for the greater potential isagainmight be due to position difference Similar pattern wasobserved for other substituted analogs like chloro analogsfluoro analogs and pyridine analogs

It was concluded from this study that either EWGor EDGon phenyl portion appeared to have potential while the slightchanges in potential was basically due to the position of thesubstituent as well as the number of substituents which isalso a vital factor In additionmolecular docking analysis wasdone to get an idea about the binding interaction of the activeanalogs

23 Molecular Docking Docking simulation was performedto determine the bindingmodes of synthesized thiazole basedanalogs (1-25) targeting the crystal structure of amylase (PDBID 4W93) [15] Earlier to docking the crystal structure of theamylase was arranged utilizing protein preparation techniquedescribed in Schrodinger Maestro [15] Crystal structurewas recovered from the protein data bank (PDB) and wasadditionally optimized through eliminating the cofactorshetero atoms water molecules missing atoms hydrogenbonds and chargeswere computed [16]Docking calculationswere fulfilled utilizing additional Precision (XP) mode Thedocking results came out by advanced analyze method withthe help of the XPGS score and each derivative bindingmodewas visually assessed utilizing PyMOL system [17]

All the 25 compounds of the Schiff bases were dockedusing glide to show the binding mode of the active amylaseinhibitors Analysis of the docking results based on the GlideXP G Score and binding mode in the active site were doneAmong them only the top four compounds binding modeson the amylase active site are reported

Figure 1(a) shows the binding mode of compound 14 theside chain imidazole ring of His201 establishes 120587-120587 stackingwith the nitrophenyl ring of the compound and in additionthe same ring forms hydrophobic interaction with Tyr151Leu162 Leu165 Ala198 and Ile235 The dimethyl groupattached to the thiazole ring forms hydrophobic interactionwith Trp59 and Tyr62

Heteroatom Chemistry 3

Table 1 Thiazole based carbohydrazide analogs (1-25)

NO R NO R

1（3C

142N

2（3

15OH

MeO

3MeO

OH

16

BrF

4OHMeO

17

OHHO

OH

5OH

HO18

Cl

6OH

OH

19N

7HO OH

20N

8HO

OH

21F

9HO

22

F

10HO

23F

11HO OH

OH

24Cl

122

25Cl

132N


Table 2 120572-Amylase inhibitory potential of thiazole based carbohydrazides

No IC50 plusmn SEMa No IC50 plusmn SEMa No IC50 plusmn SEMa

1 1763 plusmn 003 10 1747 plusmn 020 19 2133 plusmn 0122 2608 plusmn 023 11 NA 20 1948 plusmn 0233 2713 plusmn 003 12 2416 plusmn 004 21 240 plusmn 024 3049 plusmn 025 13 2544 plusmn 006 22 2385 plusmn 0095 2752 plusmn 008 14 1709 plusmn 012 23 2797 plusmn 0146 2479 plusmn 0104 15 2338 plusmn 007 24 2909 plusmn 0087 2481 plusmn 004 16 2581 plusmn 003 25 2703 plusmn 0068 2613 plusmn 005 17 2649 plusmn 008 Acarbose 1637 plusmn 01539 2594 plusmn 005 18 2525 plusmn 005SEMa= standard mean error

(a) (b)

(c) (d)

Figure 1 Binding modes on the amylase active site of top four compounds (14 10 1 and 20) by molecular docking study

On the other hand the binding mode of compound 10(Figure 1(a)) shows that the hydroxyl group in the phenolforms hydrogen bond with side chain oxygen of Glu233Furthermore 120587-120587 stacking between thiazole ring and Trp59

was established despite the fact that there is also hydrophobicinteraction between the benzothiophenyl ring and Y159L229 M273 and L319 In addition the phenyl ring of thecompound and aliphatic chain of residues Tyr62 Ala198


and Ile235 form hydrophobic contact Similarly the dimethylgroup attached to the thiazole ring forms hydrophobic inter-action with Trp59 Tyr62 Leu162 and Leu165 (Figure 1(b))

The preferred binding poses of compound 1 (Fig-ure 1(c)) showed that the compound was totally stabilizedby hydrophobic moieties such as toluene and dimethylgroups establishing contact with residues such as Leu162Leu165 Trp59 Tyr62 and Tyr151 Ala198 Ile235 respectivelySimilarly the binding mode of compound 20 shows thepresence of hydrogen bond between the pyridine with themain chain oxygen and the ring also forms120587-120587 stacking withHis201 Next the dimethyl group attached to the thiazole ringforms hydrophobic interaction with Trp59 Tyr62 Leu162andLeu165 Finally pyridinewas also found to be establishinghydrophobic contact with Tyr151 Ala198 and Ile235 as inFigure 1(d)

3 Conclusion

Thiazole based carbohydrazide derivatives (1-25) have beensynthesized and evaluated for 120572-amylase inhibitory potential24 out of 25 derivatives displayed significant 120572-amylaseinhibitory activity from 1709 to 3049 120583M The bindinginteraction of analogs with active site of protein ligandswas confirmed through molecular docking study where theactive molecules form stable hydrogen bond network withthe key residues in the active site Consistently the activityprofile of the compounds directly depends on magnitude ofhydrogen bonding and hydrophobic contact enhancing thecomplex stabilization SAR study was established to know theeffect of substitution on aromatic residues of aldehyde towardinhibitions

4 Experimental

Avance Bruker 600MHz was used for nuclear magneticresonance experiments Carlo Erba Strumentazion-Mod-1106 Italy was used for Elemental analysis Precoated silicagel aluminum plates (Kieselgel 60 254 E Merck Germany)were utilized for thin layer chromatography Chromatogramswere visualized by UV at 254 and 365 nm Finnigan MAT-311A Germany was utilized for electron impact mass spectra(EI-MS)

41 Synthesis of 2-(25-Dimethylthiazol-4-yl) AcetohydrazideEquimolar amount of methyl 2-(25-dimethylthiazol-4-yl)acetate (1mmol) and hydrazine hydrate (1mmol) wererefluxed for 6 hours in ethanol (25ml) as a solvent After6 hours TLC was done to observe reaction completionAfter first step completion the intermediate and differentbenzaldehydes were refluxed and methanol was used as asolvent

Yield 83 m p 86∘C yellow crystals 1H NMR(600MHz DMSO) 120575 913 (s 1H) 369 (s 2H NH

2) 350 (s

2H CH2) 281 (s 3H) 234 (s 3H) HR-EI-MS mz calcd

for C7H11N3OS [M]+ 1852450 Found 1852462 13C NMR

(150MHz DMSO) 120575 1681 1594 1504 1225 361 196 10Anal Calcd for C

7H11N3OS C 4539 H 599 N 2268

Found C 4537 H 601 N 2267

42 General Procedure for the Synthesis of (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(arylidene) Acetohydrazide Synthe-sis of the series of acetohyrazide was done on basis ofpreviously described reaction procedure in published paperby our group [13] All the derivatives were subjected to 1HNMR for structural elucidation and confirmation

421 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(4-methylbenzylid-ene) Acetohydrazide (1) Yield 1706 m p 86∘C whitepowder 1H NMR (600MHz DMSO) 120575 1010 (s 1H) 837(s 1H) 794ndash788 (m 2H) 743ndash737 (m 2H) 383 (s 2H)283 (s 3H) 256 (s 3H) 232 (s 3H) HR-ESI-MS mz calcdfor C15H17N3OS [M]+ 3601508 Found 3601517 13C NMR

(150MHz DMSO) 120575 1594 1504 1441 1407 1307 12911291 1261 1261 1225 1710 364 213 196 106 Anal Calcdfor C15H17N3OS C 6269 H 596 N 1462 Found C 6260

H 588 N 1454

422 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(2-methylbenzylid-ene) Acetohydrazide (2) Yield 83 m p 2062∘C whitepowder 1H NMR (600MHz DMSO) 120575 1020 (s 1H) 835(s 1H) 775ndash768 (m 2H) 723 (d J = 40Hz 3H) 383 (s2H) 283 (s 3H) 243 (s 3H) 232 (s 3H) HR-EI-MS mzcalcd for C

15H17N3OS [M]+ 2873810 Found 2873801 13C

NMR (150MHz DMSO) 120575 1710 1594 1504 1433 13531311 1309 1290 1265 1258 1225 364 196 189 106 AnalCalcd for C

15H17N3OS C 6269 H 596 N 1462 Found C

6261 H 587 N 1452

423 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(3-hydroxy-4-meth-oxybenzylidene) Acetohydrazide (3) Yield 82 m p1875∘C white powder 1H NMR (600MHz DMSO) 120575 1130(s 1H) 931 (s 1H) 835 (s 1H) 740 (dd J = 21 11 Hz 1H)711 (ddd J = 75 21 11 Hz 1H) 707-702 (m 2H) 374 (s2H) 284 (s 3H) 232 (s 3H) HR-EI-MS mz calcd forC15H17N3O3S [M]+ 3193790 Found 3193779 13C NMR

(150MHz DMSO) 120575 1710 1594 1524 1504 1473 14681311 1228 1225 1159 1123 561 364 196 106 Anal Calcdfor C15H17N3O3S C 5641 H 537 N 1316 Found C 5632

H 531 N 1309

424 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(2-hydroxy-4-meth-oxybenzylidene) Acetohydrazide (4) Yield 84 m p 201∘Cyellow 1H NMR (600MHz DMSO) 120575 1030 (s 1H) 940 (s1H) 878 (d J = 60Hz 1H) 775 (dd J = 75 20Hz 1H) 653(dd J = 75 20Hz 1H) 647 (d J = 21Hz 1H) 386 (m 3H)350 (s 2H) 283 (s 3H) 233 (s 3H) HR-EI-MS mz calcdfor C15H17N3O3S [M]+ 3193790 Found 3193782 13C NMR

(150MHz DMSO) 120575 1710 1643 1621 1594 1504 14601334 1225 1108 1070 1034 558 364 196 106 AnalCalcd for C

15H17N3O3S C 5641 H 537 N 1316 Found C

5631 H 532 N 1311

425 (E)-N1015840-(25-Dihydroxybenzylidene)-2-(25-dimethylthi-azol-4-yl) Acetohydrazide (5) Yield 87m p 180∘C brown1H NMR (600MHz DMSO) 120575 1120 (s 1H) 1030 (s1H) 910 (s 1H) 839 (s 1H) 878 (d J = 60Hz 1H)


678 (d J = 60 20Hz 1H) 677-669 (m 1H) 385 (s2H) 286 (s 3H) 233 (s 3H) HR-EI-MS mz calcd forC14H15N3O3S [M]+ 3053520 Found 3053512 13C NMR

(150MHz DMSO) 120575 1710 1594 1537 1512 1504 14601225 1204 119911961163 364 196 106 Anal Calcd forC14H15N3O3S C 5507 H 495 N 1376 Found C 5501 H

490 N 1368

426 (E)-N1015840-(23-Dihydroxybenzylidene)-2-(25-dimethylthi-azol-4-yl) Acetohydrazide (6) Yield 83m p 163∘C brown1H NMR (600MHz DMSO) 120575 1040 (s 1H) 1010 (s 1H)940 (s 1H) 840 (s 1H) 878 (d J = 60Hz 1H) 701 (d J= 70Hz 1H) 683-676 (m 1H) 383 (s 2H) 284 (s 3H)232 (s 3H) HR-EI-MS mz calcd for C

14H15N3O3S [M]+

3053520 Found 3053508 13C NMR (150MHz DMSO) 1205751710 1594 1517 1504 1461 1460 1247 1225 1228 11991196 364 196 106 Anal Calcd for C

14H15N3O3S C 5507

H 495 N 1376 Found C 5501 H 490 N 1371

427 (E)-N1015840-(24-Dihydroxybenzylidene)-2-(25-dimethylthi-azol-4-yl) Acetohydrazide (7) Yield 80 m p 207∘C paleyellow 1H NMR (600MHz DMSO) 120575 1060 (s 2H) 1020(s1H) 880 (s 1H) 860 (d J = 20Hz 1H) 770 (dd J= 80 20Hz 1H) 640 (dd J = 80 20Hz 1H) 340 (s2H) 280 (s 3H) 235 (s 3H) HR-EI-MS mz calcd forC14H15N3O3S [M]+ 3053520 Found 3053505 13C NMR

(150MHz DMSO) 120575 1700 1584 1534 1510 1502 14621221 1202 1196 11931160 366 198 109 Anal Calcd forC14H15N3O3S C 5507 H 495 N 1376 Found C 5500 H

485 N 1365

428 (E)-N1015840-(34-Dihydroxybenzylidene)-2-(25-dimethylthi-azol-4-yl) Acetohydrazide (8) Yield 79m p 216∘C browncystals 1H NMR (600MHz DMSO) 120575 1110 (s 1H) 962 (s1H) 917 (s 1H) 837 (s 1H) 693 (d J = 75Hz 1H) 688 (dd J= 20Hz 1H) 682 (d J = 74Hz 1H) 361 (s 2H) 264 (s 3H)230 (s 3H) HR-EI-MS mz calcd for C

14H15N3O3S [M]+


14H15N3O3S C 5507

H 495 N 1376 Found C 5500 H 487 N 1369

429 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(3-hydroxybenzyl-idene) Acetohydrazide (9) Yield 81 m p 157∘C whitepowder 1H NMR (600MHz DMSO) 120575 1040 (s 1H) 1010(s 1H) 837 (s 1H) 720 (t J = 75Hz 1H) 709-702 (m1H) 692 (dt J = 75 18Hz 1H) 687 (d J = 20Hz 1H)384 (s 2H) 286 (s 3H) 232 (s 3H) HR-EI-MS mz calcdfor C14H15N3O2S [M]+ 2893530 Found 2893516 13CNMR


511 N 1443

4210 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(4-hydroxybenzyl-idene) Acetohydrazide (10) Yield 85 m p 213∘C whitepowder 1H NMR (600MHz DMSO) 120575 1110 (s 1H) 989

(s 1H) 837 (s 1H) 737-731 (s J = 75Hz 2H) 685-684(s J = 75Hz 2H) 383 (s 2H) 283 (s 3H) 232 (s 3H)HR-EI-MS mz calcd for C

14H15N3O2S [M]+ 2893530

Found 2893520 13C NMR (150MHz DMSO) 1205751710 16081594 1504 1441 1306 1306 1263 1225 1160 1160 364196 106 Anal Calcd for C

14H15N3O2S C 5811 H 523 N

1452 Found C 5806 H 518 N 1444

4211 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(234-trihydroxy-benzylidene) Acetohydrazide (11) Yield 95 m p 213∘Cyellow crystals 1H NMR (600MHz DMSO) 120575 1140 (s 1H)1120 (s 1H) 1040 (s 1H) 950 (s 1H) 1110 (s 1H) 642(s 2H) 383 (s 2H) 282 (s 3H) 233 (s 3H) HR-EI-MSmz calcd for C

14H15N3O4S [M]+ 3213510 Found 3213502

13CNMR (150MHz DMSO) 1205751710 1594 1531 1524 15041468 1361 1264 1225 1125 1100 364 196 106 AnalCalcd for C

14H15N3O4S C 5233 H 471 N 1308 Found C

5224 H 460 N 1301

4212 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(2-nitrobenzylid-ene) Acetohydrazide (12) Yield 76 m p 167∘C yellowcrystals 1H NMR (600MHz DMSO) 120575 1130 (s 1H) 1050(s 1H) 835 (d J = 10Hz 1H) 810 (ddd J = 75Hz 1H)793 (d J = 75Hz 1H) 769 (d J = 75Hz 1H) 351 (s2H) 284 (s 3H) 233 (s 3H) HR-EI-MS mz calcd forC14H14N4O3S [M]+ 3183510 Found 3183502 13C NMR

(150MHzDMSO)1205751710 1594 1504 1478 1433 1349 13191301 1284 1240 1225 364 196 106 Anal Calcd forC14H14N4O3S C 5282 H 443 N 1760 Found C 5274 H

436 N 1751

4213 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(3-nitrobenzylid-ene) Acetohydrazide (13) Yield 86 m p 221∘C brown 1HNMR (600MHzDMSO) 120575 1040 (s 1H) 940 (s 1H) 848 (dJ = 20Hz 1H) 837 (d J = 20Hz 1H) 809 (dd J = 75Hz1H) 772 (t J = 75Hz 1H) 384 (s 2H) 283 (s 3H) 233 (s3H) HR-EI-MS mz calcd for C

14H14N4O3S [M]+ 3183510

Found 3183502 13C NMR (150MHz DMSO) 120575 1710 15941504 1480 1428 1346 1325 1297 1262 1216 1225 364196 106 Anal Calcd for C

14H14N4O3S C 5282 H 443 N

1760 Found C 5274 H 436 N 1753

4214 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(4-nitrobenzylid-ene) Acetohydrazide (14) Yield 99 m p 167∘C yellowpowder 1H NMR (600MHz DMSO) 120575 1040 (s 1H) 837(s 1H) 790 (d J = 80Hz 2H) 696 (d J = 80Hz 2H)353 (s 2H) 286 (s 3H) 233 (s 3H) HR-EI-MS mz calcdfor C14H14N4O3S [M]+ 3183510 Found 3183501 13C NMR

(150MHz DMS) 120575 1720 1595 1505 1502 1441 1398 12421242 1240 1240 1225 364 196 106 Anal Calcd forC14H14N4O3S C 5282 H 443 N 1760 Found C 5276 H

436 N 1753

4215 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(2-hydroxy-5-meth-oxybenzylidene) Acetohydrazide (15) Yield 83 m p 89∘Cwhite powder 1H NMR (600MHz DMSO) 120575 1020 (s1H) 930 (s 1H) 840 (s 1H) 780 (d J = 60Hz 1H)


724-720 (m 1H) 683 (d J = 10Hz 1H) 385 (s 3H) 353(s 2H) 243 (s 3H) 232 (s 3H) HR-EI-MS mz calcd forC15H17N3O3S [M]+ 3193790 Found 3193782 13C NMR


H 530 N 1310

4216 (E)-N1015840-(3-Bromo-4-fluorobenzylidene)-2-(25-dimeth-ylthiazol-4-yl) Acetohydrazide (16) Yield 97 m p 255∘Cyellow powder 1HNMR (600MHz DMSO) 120575 1060 (s 1H)837 (s 1H) 758 (s 1H) 727 (dd J = 60 75Hz 1H) 697(dd J = 60 75Hz 1H) 351 (s 2H) 284 (s 3H) 233 (s 3H)HR-EI-MS mz calcd for C

14H13BrFN3OS [M]+ 3702404


14H13BrFN3OS C 4542 H 354

N 1135 Found C 4533 H 349 N 1131

4217 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(246-trihydroxy-benzylidene) Acetohydrazide (17) Yield 96 m p 141∘Cyellow powder 1H NMR (600MHz DMSO) 120575 1170 (s 1H)1085 (s 1H) 1040 (s 1H) 9650 (s 1H) 835 (s 1H) 654(s 2H) 383 (s 2H) 284 (s 3H) 233 (s 3H) HR-EI-MSmz calcd for C

14H15N3O4S [M]+ 3213510 Found 3213523

13CNMR (150MHz DMSO) 120575 1710 1639 1639 1636 15941504 1433 1225 1062 963 963 364 196 106 Anal Calcdfor C14H15N3O4S C 5233 H 471 N 1308 Found C 5225

H 466 N 1302

4218 (E)-N1015840-(3-Chlorobenzylidene)-2-(25-dimethylthiazol-4-yl) Acetohydrazide (18) Yield 77 m p 141∘C whitepowder 1HNMR (600MHz DMSO) 120575 1080 (s 1H) 835 (s1H) 792 (d J = 20Hz 1H) 765 (d J = 20Hz 1H) 720 (d J= 75Hz 1H) 772 (d J = 75Hz 1H) 353 (s 2H) 286 (s 3H)233 (s 3H) HR-EI-MS mz calcd for C

14H14ClN3OS [M]+


14H14ClN3OS C

5463 H 458 N 1365 Found C 5456 H 449 N 1358

4219 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(pyridin-3-ylmeth-ylene) Acetohydrazide (19) Yield 87 m p 88∘C yellowpowder 1H NMR (600MHz DMSO) 120575 1040 (s 1H) 908(d J = 20Hz 1H) 871 (dd J = 50 20Hz 1H) 842 (dtJ = 80 20Hz 1H) 834 (s 1H) 742 (dd J = 80 50Hz1H) 382 (s 2H) 283 (s 3H) 232 (s 3H) HR-EI-MS mzcalcd for C

13H14N4OS [M]+ 2743420 Found 2743411 13C

NMR (150MHz DMSO) 120575 1710 1594 1519 1504 14901433 1337 1304 1239 1225 364 196 106 Anal Calcd forC13H14N4OS C 5692 H 514 N 2042 Found C 5684 H

519 N 2034

4220 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(pyridin-4-ylmeth-ylene) Acetohydrazide (20) Yield 87 m p 98∘C whitepowder 1H NMR (600MHz DMSO) 120575 1030 (s 1H) 862(s 1H) 822 (d J = 60Hz 2H) 757 (d J = 60Hz 2H) 353

(s 2H) 284 (s 3H) 232 (s 3H) HR-EI-MS mz calcd forC13H14N4OS [M]+ 2743420 Found 2743412 13C NMR

(150MHz DMSO) 120575 1710 1594 1504 1494 1494 14681443 1204 1204 1225 364 196 106 Anal Calcd forC13H14N4OS C 5692 H 514 N 2042 Found C 5684 H

510 N 2036

4221 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(2-fluorobenzylid-ene) Acetohydrazide (21) Yield 83 m p 105∘C whitemilky 1H NMR (600MHz DMSO) 120575 1040 (s 1H) 840 (s1H) 820 (d J = 70Hz 1H) 753-746 (m 1H) 728 (d J =70Hz 1H) 722 (td J =75 2Hz 1H) 381 (s 2H) 286 (s 3H)233 (s 3H) HR-EI-MS mz calcd for C

14H14FN3OS [M]+


14H14FN3OS C 5772

H 484 N 1442 Found C 5765 H 480 N 1436

4222 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(4-fluorobenzyl-idene) Acetohydrazide (22) Yield 85 m p 97∘C whitecrystals 1H NMR (600MHz DMSO) 120575 1036 (s 1H) 835(s 1H) 790 (t J = 70Hz 2H) 708 (d J = 70Hz 2H) 352(s 2H) 245 (s 3H) 233 (s 3H) HR-EI-MS mz calcd forC14H14FN3OS [M]+ 2913444 Found 2913431 13C NMR

(150MHz DMSO) 120575 1710 1652 1594 1504 1441 13081308 1293 1156 1156 1225 364 196 106 Anal Calcd forC14H14FN3OS C 5772 H 484 N 1442 Found C 5766 H

480 N 1438

4223 (E)-2-(25-Dimethylthiazol-4-yl)-N1015840-(3-fluorobenzyl-idene) Acetohydrazide (23) Yield 84 m p 97∘C whitecrystals 1H NMR (600MHz DMSO) 120575 1020 (s 1H) 838(s 1H) 759 (td J = 76 57Hz 1H) 748-739 (m 2H)719-713 (m 1H) 354 (s 2H) 252 (s 3H) 230 (s 3H)HR-EI-MS mz calcd for C

14H14FN3OS [M]+ 2913444


14H14FN3OS C 5772 H 484

N 1442 Found C 5767 H 481 N 1446

4224 (E)-N1015840-(2-Chlorobenzylidene)-2-(25-dimethylthiazol-4-yl) Acetohydrazide (24) Yield 75 m p 127∘C whitecrystals 1H NMR (600MHz DMSO) 120575 1020 (s 1H) 835(s 1H) 820 (d J = 20Hz 1H) 752-744 (m 2H) 735 (td J= 75 20Hz 1H) 355 (s 2H) 284 (s 3H) 233 (s 3H) HR-EI-MS mz calcd for C

14H14ClN3OS [M]+ 3077960 Found

3077952 13C NMR (150MHz DMSO) 120575 1710 1594 15041387 1347 1339 1324 1301 1272 1269 1225 364 196 106Anal Calcd for C

14H14ClN3OS C 5463 H 458 N 1365

Found C 5454 H 454 N 1360

4225 (E)-N1015840-(4-Chlorobenzylidene)-2-(25-dimethylthiazol-4-yl) Acetohydrazide (25) Yield 95 m p 120∘C yellowcrystals 1HNMR (600MHz DMSO) 120575 1175 (s 1H) 837 (s1H) 785 (d J = 75Hz 2H)) 750 (d J = 75Hz 2H) 346(s 2H) 286 (s 3H) 233 (s 3H) HR-EI-MS mz calcd forC14H14ClN3OS [M]+ 3077960 Found 3077972 13C NMR


(150MHz DMSO) 120575 1710 1594 1504 1441 1366 13181306 1306 1289 1289 1225 364 196 106 Anal Calcd forC14H14ClN3OS C 5463 H 458 N 1365 Found C 5458

H 454 N 1360

43 120572-Amlyase Inhibition Assay The 120572-amylase inhibitionwas estimated by an assay modified from Kwon Apostolidisamp Shetty [18 19]

Data Availability

The data used to support the findings of this study areavailable from the corresponding author upon request

Conflicts of Interest

The authors report that there are no conflicts of interest

Acknowledgments

The authors are thankful to AIMST University Malaysiafor providing the facilities for this project and the Ministryof Higher Education (MOHE) Malaysia for funding thecomputational part (Software and Workstation) through theldquoTRGSrdquo (Grant No 600-RMITRGS 53 (12014)-3)

References

[1] N Ramasubbu V Paloth Y Luo G D Brayer andM J LevineldquoStructure of human salivary 120572-amylase at 16 A resolutionimplications for its role in the oral cavityrdquoActaCrystallographicaSection D Biological Crystallography vol 52 no 3 pp 435ndash4461996

[2] B P Maureen Stedmanrsquos Medical Dictionary Baltimore MDUSA 27th edition p 65 2000

[3] M S Attia andN S Al-Radadi ldquoProgress of pancreatitis diseasebiomarker alpha amylase enzyme by new nano optical sensorrdquoBiosensors and Bioelectronics vol 86 pp 413ndash419 2016

[4] R Gupta P Gigras H Mohapatra V K Goswami and BChauhan ldquoMicrobial 120572-amylases a biotechnological perspec-tiverdquo Process Biochemistry vol 38 p 1599 2003

[5] M Mobini-dehkordi and F A Javan ldquoApplication of alpha-amylase in biotechnologyrdquo Journal of Biology and TodayrsquosWorldvol 1 p 39 2012

[6] W J Quax Bacterial enzymes in The Prokaryotes Springer2006

[7] Y Narita and K Inouye ldquoKinetic analysis and mechanism onthe inhibition of chlorogenic acid and its components againstporcine pancreas 120572-amylase isozymes I and IIrdquo Journal ofAgricultural and Food Chemistry vol 57 no 19 pp 9218ndash92252009

[8] B Najafian E Svarstad L Bostad et al ldquoProgressive podocyteinjury and globotriaosylceramide (GL-3) accumulation inyoung patients with Fabry diseaserdquo Kidney International vol79 no 6 pp 663ndash670 2011

[9] A A Adegboye K M Khan U Salar et al ldquo2-Aryl benz-imidazoles Synthesis In vitro 120572-amylase inhibitory activityand molecular docking studyrdquo European Journal of MedicinalChemistry vol 150 pp 248ndash260 2018

[10] J Quiroga P Hernandez B Insuasty et al ldquoControl ofthe reaction between 2-aminobenzothiazoles and Mannichbases Synthesis of pyrido[21-b][13]benzothiazoles versus[13]benzothiazolo[23-b]quinazolinesrdquo Journal of the ChemicalSociety Perkin Transactions 1 vol 4 p 555 2002

[11] I Hutchinson S A Jennings B R Vishnuvajjala A DWestwell and M F G Stevens ldquoAntitumor benzothiazoles16 Synthesis and pharmaceutical properties of antitumor 2-(4-aminophenyl)benzothiazole amino acid prodrugsrdquo Journal ofMedicinal Chemistry vol 45 p 744 2002

[12] F Rahim M T Javed H Ullah et al ldquoSynthesis molec-ular docking acetylcholinesterase and butyrylcholinesteraseinhibitory potential of thiazole analogs as new inhibitors forAlzheimer diseaserdquo Bioorganic Chemistry vol 62 pp 106ndash1162015

[13] S Imran M Taha N H Ismail et al ldquoSynthesis in vitroand docking studies of new flavone ethers as 120572-glucosidaseinhibitorsrdquoChemical BiologyampDrugDesign vol 87 p 361 2016

[14] U Salar M Taha N H Ismail et al ldquoThiadiazole derivativesas New Class of 120573-glucuronidase inhibitorsrdquo Bioorganic ampMedicinal Chemistry vol 24 no 8 pp 1909ndash1918 2016

[15] Schrodinger Release Maestro version 101 Schrodinger LLCNew York NY USA 2015 Maestro Schrodinger LLC NewYork NY USA version 101 2015

[16] M Taha S Imran N H Ismail et al ldquoBiology-orienteddrug synthesis (BIODS) of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl aryl ether derivatives in vitro 120572-amylase inhibitoryactivity and in silico studiesrdquo Bioorganic Chemistry vol 74 pp1ndash9 2017

[17] PyMOL Molecular Graphics System Schrodinger LCC NewYork NY USA 2010

[18] Y I Kwon E Apostolidis and K Shetty ldquoIn vitro studiesof eggplant (Solanum melongena) phenolics as inhibitors ofkey enzymes relevant for type 2 diabetes and hypertensionrdquoBioresource Technology vol 99 no 8 pp 2981ndash2988 2008

[19] S P Loh and O Hadira ldquoIn vitro inhibitory potential ofselected malaysian plants against key enzymes involved inhyperglycemia and hypertensionrdquo Malaysian Journal of Nutri-tion vol 17 no 1 pp 77ndash86 2011

TribologyAdvances in

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Advances inPhysical Chemistry

Hindawiwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2018

Bioinorganic Chemistry and ApplicationsHindawiwwwhindawicom Volume 2018

SpectroscopyInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Medicinal ChemistryInternational Journal of


NanotechnologyHindawiwwwhindawicom Volume 2018

Journal of

Applied ChemistryJournal of



Biochemistry Research International


Enzyme Research


Journal of

SpectroscopyAnalytical ChemistryInternational Journal of


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International Journal of


Na

nom

ate

ria

ls


Journal ofNanomaterials

Submit your manuscripts atwwwhindawicom


OS

N NH

N ROS

N NH

OS

N O EtOHReflux 6 hr

RCHON（2N（2 （2O

N（2（

+

Scheme 1 Synthesis of thiazole based carbohydrazide

they keep versatile biological properties Thiazole containingmolecules are used as an antimicrobial drug abafungin asantifungal drug ritonavir as antiretroviral drug thiazofurinand bleomycine as antineoplastic [10] antihistaminic nirida-zole as schistosomicidal and nitazoxanide as antiprotozoal[11] Our group has already reported thiazole analogs asacetylcholinesterase and butyrylcholinesterase inhibitor [12]with hopes to further explore their potential as alpha-amylaseinhibitor In this regard here in the present study we are goingto report thiazole analogs as potent alpha-amylase inhibiter

2 Results and Discussion

21 Chemistry Methyl 2-(25-dimethylthiazol-4-yl) acetateand excess amount of hydrazine hydrate were refluxedin ethanol for six hrs to obtaine pure methyl 2-(25-dimethylthiazol-4-yl) hydrazide Intermediate 2-(25-dimethylthiazol-4-yl) hydrazide was further treated withdifferent substituted aromatic aldehydes in ethanol as solventthe reaction mixture was acidified by 3-4 drops glacial aceticto achieve the target compounds (Scheme 1) (1-25) (Table 1)Here in this study each step was monitored by TLC throughethyl acetatehexane system (ratio 37)

22 120572-Amylase Inhibitory Potential To carry on our researchwork on enzyme inhibition [13 14] we have synthesizedthiazole based carbohydrazide analogs (1-25) (Table 1) andthey were evaluated for 120572-amylase inhibitory activity Allanalogs except 11 have 120572-amylase inhibition with IC

50values

from 1709 plusmn 012 to 3049 plusmn 025 120583M against the standardacarbose (IC

50= 1637 plusmn 0153 120583M) (Table 2) The structure

activity relationship has been also studied and it is mainlybased upon the difference of substituents on phenyl ringattached to the carbohydrazide part

The analog 14 a para nitro-substituted analog was foundto be the most active analog among allThemore noteworthypotential of the compound might be due to the presence ofnitro group which is a strong electron withdrawing groupWhen comparing compound 14 (IC

50value 1709 plusmn 012 120583M)

with analog 12 an ortho nitro-substituted analog (IC50value

2416 plusmn 004 120583M) and 13 a meta nitro-substituted analog(IC50

value 2544 plusmn 006 120583M) analog 14 showed greaterpotential than analogs 12 and 13 which seems to be due todifferent positioning of nitro group on phenyl ring

Compound 10 a para hydroxy analog was found to bethe second most dynamic analog within this series with IC

50

value 1747 plusmn 020 120583M The greater potential shown by thiscompound seems to be due to the hydroxyl group whichmight be involved in hydrogen bonding with the active siteof enzyme By comparing analog 10 with other hydroxylanalogs like 9 a meta hydroxyl analog (IC

50= 2594 plusmn 005

120583M) 5 a 25-dihydroxyl analog (IC50= 2752 plusmn 008 120583M) 6

a 23-dihydroxyl analog (IC50= 2479 plusmn 0104 120583M) 7 a 24-

dihydroxyl analog (IC50= 2481 plusmn 004 120583M) and 8 a 34-

dihydroxyl analog (IC50= 2613 plusmn 005 120583M) the compound

is superior The slight activity difference seems to be mainlygoverned by the position of substituent Analog 17 a 246-trihydroxyl analog (IC

50=2649plusmn 008120583M) showedpotential

but analog 11 a 234-trihydroxyl analog was found to becompletely inactive This might be due to position differenceof hydroxyl group

Compound 1 a para methyl analog was the third mostactive analog among the series with IC

50value 1763 plusmn 003

120583M when compared to 2 an ortho methyl analog (IC50=

2608 plusmn 023 120583M) The reason for the greater potential isagainmight be due to position difference Similar pattern wasobserved for other substituted analogs like chloro analogsfluoro analogs and pyridine analogs

It was concluded from this study that either EWGor EDGon phenyl portion appeared to have potential while the slightchanges in potential was basically due to the position of thesubstituent as well as the number of substituents which isalso a vital factor In additionmolecular docking analysis wasdone to get an idea about the binding interaction of the activeanalogs

23 Molecular Docking Docking simulation was performedto determine the bindingmodes of synthesized thiazole basedanalogs (1-25) targeting the crystal structure of amylase (PDBID 4W93) [15] Earlier to docking the crystal structure of theamylase was arranged utilizing protein preparation techniquedescribed in Schrodinger Maestro [15] Crystal structurewas recovered from the protein data bank (PDB) and wasadditionally optimized through eliminating the cofactorshetero atoms water molecules missing atoms hydrogenbonds and chargeswere computed [16]Docking calculationswere fulfilled utilizing additional Precision (XP) mode Thedocking results came out by advanced analyze method withthe help of the XPGS score and each derivative bindingmodewas visually assessed utilizing PyMOL system [17]

All the 25 compounds of the Schiff bases were dockedusing glide to show the binding mode of the active amylaseinhibitors Analysis of the docking results based on the GlideXP G Score and binding mode in the active site were doneAmong them only the top four compounds binding modeson the amylase active site are reported

Figure 1(a) shows the binding mode of compound 14 theside chain imidazole ring of His201 establishes 120587-120587 stackingwith the nitrophenyl ring of the compound and in additionthe same ring forms hydrophobic interaction with Tyr151Leu162 Leu165 Ala198 and Ile235 The dimethyl groupattached to the thiazole ring forms hydrophobic interactionwith Trp59 and Tyr62



NO R NO R

1（3C

142N

2（3

15OH

MeO

3MeO

OH

16

BrF

4OHMeO

17

OHHO

OH

5OH

HO18

Cl

6OH

OH

19N

7HO OH

20N

8HO

OH

21F

9HO

22

F

10HO

23F

11HO OH

OH

24Cl

122

25Cl

132N





(a) (b)

(c) (d)







3 Conclusion


4 Experimental




2) 350 (s




7H11N3OS C 4539 H 599 N 2268

Found C 4537 H 601 N 2267




H 588 N 1454


15H17N3OS [M]+ 2873810 Found 2873801 13C


15H17N3OS C 6269 H 596 N 1462 Found C

6261 H 587 N 1452



H 531 N 1309



15H17N3O3S C 5641 H 537 N 1316 Found C

5631 H 532 N 1311





490 N 1368


14H15N3O3S [M]+


14H15N3O3S C 5507

H 495 N 1376 Found C 5501 H 490 N 1371



485 N 1365


14H15N3O3S [M]+


14H15N3O3S C 5507

H 495 N 1376 Found C 5500 H 487 N 1369



511 N 1443



14H15N3O2S [M]+ 2893530


14H15N3O2S C 5811 H 523 N

1452 Found C 5806 H 518 N 1444


14H15N3O4S [M]+ 3213510 Found 3213502


14H15N3O4S C 5233 H 471 N 1308 Found C

5224 H 460 N 1301



436 N 1751


14H14N4O3S [M]+ 3183510


14H14N4O3S C 5282 H 443 N

1760 Found C 5274 H 436 N 1753



436 N 1753





H 530 N 1310


14H13BrFN3OS [M]+ 3702404


14H13BrFN3OS C 4542 H 354

N 1135 Found C 4533 H 349 N 1131


14H15N3O4S [M]+ 3213510 Found 3213523


H 466 N 1302


14H14ClN3OS [M]+


14H14ClN3OS C

5463 H 458 N 1365 Found C 5456 H 449 N 1358


13H14N4OS [M]+ 2743420 Found 2743411 13C


519 N 2034




510 N 2036


14H14FN3OS [M]+


14H14FN3OS C 5772

H 484 N 1442 Found C 5765 H 480 N 1436



480 N 1438


14H14FN3OS [M]+ 2913444


14H14FN3OS C 5772 H 484

N 1442 Found C 5767 H 481 N 1446




14H14ClN3OS C 5463 H 458 N 1365

Found C 5454 H 454 N 1360




H 454 N 1360


Data Availability




Acknowledgments


References

























Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls






NO R NO R

1（3C

142N

2（3

15OH

MeO

3MeO

OH

16

BrF

4OHMeO

17

OHHO

OH

5OH

HO18

Cl

6OH

OH

19N

7HO OH

20N

8HO

OH

21F

9HO

22

F

10HO

23F

11HO OH

OH

24Cl

122

25Cl

132N





(a) (b)

(c) (d)







3 Conclusion


4 Experimental




2) 350 (s




7H11N3OS C 4539 H 599 N 2268

Found C 4537 H 601 N 2267




H 588 N 1454


15H17N3OS [M]+ 2873810 Found 2873801 13C


15H17N3OS C 6269 H 596 N 1462 Found C

6261 H 587 N 1452



H 531 N 1309



15H17N3O3S C 5641 H 537 N 1316 Found C

5631 H 532 N 1311





490 N 1368


14H15N3O3S [M]+


14H15N3O3S C 5507

H 495 N 1376 Found C 5501 H 490 N 1371



485 N 1365


14H15N3O3S [M]+


14H15N3O3S C 5507

H 495 N 1376 Found C 5500 H 487 N 1369



511 N 1443



14H15N3O2S [M]+ 2893530


14H15N3O2S C 5811 H 523 N

1452 Found C 5806 H 518 N 1444


14H15N3O4S [M]+ 3213510 Found 3213502


14H15N3O4S C 5233 H 471 N 1308 Found C

5224 H 460 N 1301



436 N 1751


14H14N4O3S [M]+ 3183510


14H14N4O3S C 5282 H 443 N

1760 Found C 5274 H 436 N 1753



436 N 1753





H 530 N 1310


14H13BrFN3OS [M]+ 3702404


14H13BrFN3OS C 4542 H 354

N 1135 Found C 4533 H 349 N 1131


14H15N3O4S [M]+ 3213510 Found 3213523


H 466 N 1302


14H14ClN3OS [M]+


14H14ClN3OS C

5463 H 458 N 1365 Found C 5456 H 449 N 1358


13H14N4OS [M]+ 2743420 Found 2743411 13C


519 N 2034




510 N 2036


14H14FN3OS [M]+


14H14FN3OS C 5772

H 484 N 1442 Found C 5765 H 480 N 1436



480 N 1438


14H14FN3OS [M]+ 2913444


14H14FN3OS C 5772 H 484

N 1442 Found C 5767 H 481 N 1446




14H14ClN3OS C 5463 H 458 N 1365

Found C 5454 H 454 N 1360




H 454 N 1360


Data Availability




Acknowledgments


References

























Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls








(a) (b)

(c) (d)







3 Conclusion


4 Experimental




2) 350 (s




7H11N3OS C 4539 H 599 N 2268

Found C 4537 H 601 N 2267




H 588 N 1454


15H17N3OS [M]+ 2873810 Found 2873801 13C


15H17N3OS C 6269 H 596 N 1462 Found C

6261 H 587 N 1452



H 531 N 1309



15H17N3O3S C 5641 H 537 N 1316 Found C

5631 H 532 N 1311





490 N 1368


14H15N3O3S [M]+


14H15N3O3S C 5507

H 495 N 1376 Found C 5501 H 490 N 1371



485 N 1365


14H15N3O3S [M]+


14H15N3O3S C 5507

H 495 N 1376 Found C 5500 H 487 N 1369



511 N 1443



14H15N3O2S [M]+ 2893530


14H15N3O2S C 5811 H 523 N

1452 Found C 5806 H 518 N 1444


14H15N3O4S [M]+ 3213510 Found 3213502


14H15N3O4S C 5233 H 471 N 1308 Found C

5224 H 460 N 1301



436 N 1751


14H14N4O3S [M]+ 3183510


14H14N4O3S C 5282 H 443 N

1760 Found C 5274 H 436 N 1753



436 N 1753





H 530 N 1310


14H13BrFN3OS [M]+ 3702404


14H13BrFN3OS C 4542 H 354

N 1135 Found C 4533 H 349 N 1131


14H15N3O4S [M]+ 3213510 Found 3213523


H 466 N 1302


14H14ClN3OS [M]+


14H14ClN3OS C

5463 H 458 N 1365 Found C 5456 H 449 N 1358


13H14N4OS [M]+ 2743420 Found 2743411 13C


519 N 2034




510 N 2036


14H14FN3OS [M]+


14H14FN3OS C 5772

H 484 N 1442 Found C 5765 H 480 N 1436



480 N 1438


14H14FN3OS [M]+ 2913444


14H14FN3OS C 5772 H 484

N 1442 Found C 5767 H 481 N 1446




14H14ClN3OS C 5463 H 458 N 1365

Found C 5454 H 454 N 1360




H 454 N 1360


Data Availability




Acknowledgments


References

























Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls







3 Conclusion


4 Experimental




2) 350 (s




7H11N3OS C 4539 H 599 N 2268

Found C 4537 H 601 N 2267




H 588 N 1454


15H17N3OS [M]+ 2873810 Found 2873801 13C


15H17N3OS C 6269 H 596 N 1462 Found C

6261 H 587 N 1452



H 531 N 1309



15H17N3O3S C 5641 H 537 N 1316 Found C

5631 H 532 N 1311





490 N 1368


14H15N3O3S [M]+


14H15N3O3S C 5507

H 495 N 1376 Found C 5501 H 490 N 1371



485 N 1365


14H15N3O3S [M]+


14H15N3O3S C 5507

H 495 N 1376 Found C 5500 H 487 N 1369



511 N 1443



14H15N3O2S [M]+ 2893530


14H15N3O2S C 5811 H 523 N

1452 Found C 5806 H 518 N 1444


14H15N3O4S [M]+ 3213510 Found 3213502


14H15N3O4S C 5233 H 471 N 1308 Found C

5224 H 460 N 1301



436 N 1751


14H14N4O3S [M]+ 3183510


14H14N4O3S C 5282 H 443 N

1760 Found C 5274 H 436 N 1753



436 N 1753





H 530 N 1310


14H13BrFN3OS [M]+ 3702404


14H13BrFN3OS C 4542 H 354

N 1135 Found C 4533 H 349 N 1131


14H15N3O4S [M]+ 3213510 Found 3213523


H 466 N 1302


14H14ClN3OS [M]+


14H14ClN3OS C

5463 H 458 N 1365 Found C 5456 H 449 N 1358


13H14N4OS [M]+ 2743420 Found 2743411 13C


519 N 2034




510 N 2036


14H14FN3OS [M]+


14H14FN3OS C 5772

H 484 N 1442 Found C 5765 H 480 N 1436



480 N 1438


14H14FN3OS [M]+ 2913444


14H14FN3OS C 5772 H 484

N 1442 Found C 5767 H 481 N 1446




14H14ClN3OS C 5463 H 458 N 1365

Found C 5454 H 454 N 1360




H 454 N 1360


Data Availability




Acknowledgments


References

























Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls







490 N 1368


14H15N3O3S [M]+


14H15N3O3S C 5507

H 495 N 1376 Found C 5501 H 490 N 1371



485 N 1365


14H15N3O3S [M]+


14H15N3O3S C 5507

H 495 N 1376 Found C 5500 H 487 N 1369



511 N 1443



14H15N3O2S [M]+ 2893530


14H15N3O2S C 5811 H 523 N

1452 Found C 5806 H 518 N 1444


14H15N3O4S [M]+ 3213510 Found 3213502


14H15N3O4S C 5233 H 471 N 1308 Found C

5224 H 460 N 1301



436 N 1751


14H14N4O3S [M]+ 3183510


14H14N4O3S C 5282 H 443 N

1760 Found C 5274 H 436 N 1753



436 N 1753





H 530 N 1310


14H13BrFN3OS [M]+ 3702404


14H13BrFN3OS C 4542 H 354

N 1135 Found C 4533 H 349 N 1131


14H15N3O4S [M]+ 3213510 Found 3213523


H 466 N 1302


14H14ClN3OS [M]+


14H14ClN3OS C

5463 H 458 N 1365 Found C 5456 H 449 N 1358


13H14N4OS [M]+ 2743420 Found 2743411 13C


519 N 2034




510 N 2036


14H14FN3OS [M]+


14H14FN3OS C 5772

H 484 N 1442 Found C 5765 H 480 N 1436



480 N 1438


14H14FN3OS [M]+ 2913444


14H14FN3OS C 5772 H 484

N 1442 Found C 5767 H 481 N 1446




14H14ClN3OS C 5463 H 458 N 1365

Found C 5454 H 454 N 1360




H 454 N 1360


Data Availability




Acknowledgments


References

























Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls







H 530 N 1310


14H13BrFN3OS [M]+ 3702404


14H13BrFN3OS C 4542 H 354

N 1135 Found C 4533 H 349 N 1131


14H15N3O4S [M]+ 3213510 Found 3213523


H 466 N 1302


14H14ClN3OS [M]+


14H14ClN3OS C

5463 H 458 N 1365 Found C 5456 H 449 N 1358


13H14N4OS [M]+ 2743420 Found 2743411 13C


519 N 2034




510 N 2036


14H14FN3OS [M]+


14H14FN3OS C 5772

H 484 N 1442 Found C 5765 H 480 N 1436



480 N 1438


14H14FN3OS [M]+ 2913444


14H14FN3OS C 5772 H 484

N 1442 Found C 5767 H 481 N 1446




14H14ClN3OS C 5463 H 458 N 1365

Found C 5454 H 454 N 1360




H 454 N 1360


Data Availability




Acknowledgments


References

























Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls






H 454 N 1360


Data Availability




Acknowledgments


References

























Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls









Journal of

Chemistry





Journal of

Volume 2018






Volume 2018




Journal of






Enzyme Research


Journal of



MaterialsJournal of






Na

nom

ate

ria

ls




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