Research Article Synthesis and Antiproliferative Activity of Some … · 2019. 7. 30. · cervix cancer cell line) and MDA-MB- (melanoma) cell lines [, , ]. Hence we selected HeLa

Research ArticleSynthesis and Antiproliferative Activity of Some Quinoline andOxadiazole Derivatives

Mohamed Jawed Ahsan1 Sunil Shastri1 Rita Yadav1 Mohd Zaheen Hassan2

Mohammed Afroz Bakht3 Surender Singh Jadav4 and Sabina Yasmin4

1Department of Pharmaceutical ChemistryMaharishi Arvind College of Pharmacy Ambabari Circle Jaipur Rajasthan 302 039 India2School of Chemical Science University Sains Malaysia Penang 118 00 Malaysia3Department of Pharmaceutical Chemistry College of Pharmacy Prince Sattam Bin Abdulaziz UniversityPO Box 11323 Al-Kharj Saudi Arabia4Department of Pharmaceutical Chemistry Birla Institute of Technology Mesra Ranchi Jharkhand 835 215 India

Correspondence should be addressed to Mohamed Jawed Ahsan jawedpharmagmailcom

Received 21 July 2016 Revised 20 October 2016 Accepted 31 October 2016

Academic Editor Kirpal Bisht

Copyright copy 2016 Mohamed Jawed Ahsan et alThis 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 continuance of our search for newer antiproliferative agents we report herein the synthesis and antiproliferative studies of twoseries (5andashj and 10andashc) of heterocyclic compounds All the new compounds were characterized by IR NMR and mass spectraldata The antiproliferative activity of 10 compounds (5andashj) was carried out on HeLa (cervix cancer cell line) and MDA-MB-435(melanoma) and LC50 TGI and GI50 were calculated while the antiproliferative activity of 3 compounds (10andashc) was carried outagainst nine different panels of nearly 60 cell lines (NCI-60) according to the National Cancer Institute (NCI US) Protocol at 10 120583M1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-(4-methoxylphenyl)urea (5j) was found to have antiproliferative activity withGI50 of 351 120583MagainstHeLa (cervix cancer cell line) and 604 120583MagainstMDA-MB-435 (melanoma) respectivelyThe compounds10a 10b and 10c showed antiproliferative activity with comparatively higher selectivity towards HOP-92 (Non-Small Cell LungCancer) with percent growth inhibitions (GIs) of 3414 3529 and 3159 respectively

1 Introduction

Cancer is a genetic disease that is caused by changes to genethat control the way our cell functions In all types of cancerssome of the bodyrsquos cells begin to divide without stopping andspread into the surrounding tissues There are more than 100types of cancer [1] A total of 1658370 new cancer cases and589430 cancer deaths are projected to occur in the UnitedStates in 2015 [2] Despite the availability of improved drugsand targeted cancer therapies it is expected that the new casesof cancer will jump to 193 million worldwide by 2025 [3]The types of cancer treatment include surgery chemotherapyradiation therapy immunotherapy targeted therapy andhormonal therapy The cancer patients are treated eitherwith single therapy or with combinations of more than onetherapy depending on the type of cancerrsquos advancement[1] The therapeutic applications of antiproliferative drugs

are restricted due to their toxic potentials resistance andgenotoxicity [4]The demand for relativelymore effective andsafer agents for the treatment of cancer is todayrsquos need

Heterocyclic quinoline nucleus occurs in nature andbiologically active substances displaying broad therapeuticapplications [5] Several quinoline analogues were reportedas anticancer agents [6ndash13] The structure of some of thequinoline anticancer drug is shown in Figure 1 [6] Thebiological potential of quinoline inspired us to explore furtherthe quinoline derivatives The quinoline derivatives showedpromising antiproliferative activity against HeLa (humancervix cancer cell line) and MDA-MB-435 (melanoma) celllines [6 7 14] Hence we selected HeLa and MDA-MB-435 to test the in vitro antiproliferative activity of quinolinederivatives (5andashj) reported here in the present investigationThree-dose response parameters (GI50 TGI and LC50) werecalculated for each of the experimental agents Similarly the

Hindawi Publishing CorporationOrganic Chemistry InternationalVolume 2016 Article ID 9589517 10 pageshttpdxdoiorg10115520169589517

2 Organic Chemistry International

Camptothecin Topotecan Irinotecan

O

O

O

O

O

O

O

O

O

O

OHO

HO

HOHO

N

N

NN

N

N

NNN

Figure 1 Some of the quinoline containing anticancer drugs

biological prospects of fivemember oxadiazoles as anticancer[15 16] antitubercular [17] anticonvulsant [18] antimicrobial[19] anti-HIV [20] and anti-inflammatory [21] inspired us togo on further with the exploration of this moiety Zibotentanan endothelin receptor A (ETA) antagonist is an anticanceragent which contains 134-oxadiazole ring [22] A series ofoxadiazoles (10andashc) were synthesized and evaluated for theirantiproliferative activity against 60 cell lines according tothe National Cancer Institute (NCI US) Protocol at 10 120583Mdrug concentration and percent growth inhibition (GI) wasreported

2 Materials and Methods

21 General The chemicals were procured from MerckMumbai and S D Fine Chemicals Mumbai (India) Meltingpoints were determined by open tube capillary methodand are uncorrected The completion of reaction was mon-itored throughout by thin layer chromatography (TLC)using mobile phase benzenemethanol (1 4) and cyclohex-aneacetone (1 4) and the spots were located under iodinevapours or UV light IR spectra were obtained on a Shimadzu8201 PC FT-IR spectrometer (KBr pellets) 1H NMR spectrawere recorded on a Bruker AC 400MHz spectrometer usingTMS as internal standard in DMSOd6 Mass spectra wererecorded on a Bruker Esquire LCMS using ESI and elementalanalyses were performed on Perkin-Elmer 2400 ElementalAnalyzer

22 Procedure for the Synthesis of 7-Hydroxy-4-methyl-2H-chromen-2-one (3) A solution of resorcinol (1) (01mol1101 g) in ethyl acetoacetate (2) (01mol 1301 g sim13mL) wasadded slowly into the concentratedH2SO4 (previously cooledto 5∘C) and stirred and the temperature was maintainedbelow 10∘C for 05 h The reaction mixture was then pouredinto the crushed ice filtered washed and dried to obtain7-hydroxy-4-methyl-2H-chromen-2-one (3) Yield 78 Mp192-193∘C (reported) [23] 194ndash196∘C (found)

23 Procedure for the Synthesis of 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)ureathiourea (5a-b) Equimolar quan-tity of 7-hydroxy-4-methyl-2H-chromen-2-one (3) (0005mol088 g) and semicarbazidethiosemicarbazide (0005mol)was dissolved in ethanol and was refluxed for 4ndash8 h at 200∘C

and the reaction mixture was then kept overnight The reac-tionwasmonitored throughout by thin layer chromatography(TLC) using benzeneacetone (1 4) as mobile phase Finallythe product was separated dried and recrystallized withmethylated spirit

231 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)urea (5a)Yield 70 Mp 142ndash144∘C IR (KBr) cmminus1 3404 (OH) 3202(NH) 1685 (C=O) 1HNMR (400MHz DMSO-d6) ppm 211(3H s CH3) 542 (2H s NH2) 631 (1H s CH) 618 (1H sArH) 638 (1H d J = 61Hz ArH) 708 (1H d J = 60HzArH) 902 (1H s CONH) 1046 (1H s OH) Mass (119898119911) 233(M+) CacldAnal [C (5665) 5659 H (475) 478 N (1802)1805]

232 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)thiourea(5b) Yield 68 Mp 112ndash114∘C IR (KBr) cmminus1 3414 (OH)3201 (NH) 1286 (C=S) 1HNMR(400MHzDMSO-d6) ppm212 (3H s CH3) 540 (2H s NH2) 631 (1H s CH) 628 (1Hs ArH) 629 (1H d J = 61Hz ArH) 705 (1H d J = 60HzArH) 832 (1H s CSNH) 1041 (1H s OH) Mass (119898119911) 249(M+) CacldAnal [C (5300) 5305 H (445) 442 N (1686)1685]

24 Procedure for the Synthesis of 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-substituted Phenyl Urea (5cndashj) Eq-uimolar quantity of 7-hydroxy-4-methyl-2H-chromen-2-one (3) (0005mol 088 g) and substituted phenyl sem-icarbazide (0005mol) was dissolved in ethanol and wasrefluxed for 4ndash8 h at 200∘C and the reaction mixture wasthen kept overnight Finally the product was separated driedand recrystallized with methylated spirit The reaction wasmonitored throughout by thin layer chromatography (TLC)using benzeneacetone (1 4) asmobile phaseThe substitutedphenyl semicarbazide was synthesized as per the reportedmethod [24]

241 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-phe-nylurea (5c) Yield 80 Mp 150ndash152∘C IR (KBr) cmminus1 3424(OH) 3018 (NH) 1675 (C=O) 1H NMR (400MHz DMSO-d6) ppm 211 (3H s CH3) 590 (1H s NH) 631 (1H s CH)638ndash705 (8H m ArH) 839 (1H s CONH) 1049 (1H s

Organic Chemistry International 3

OH) Mass (119898119911) 3091 (M+) CacldAnal [C (6601) 6604H (489) 490 N (1358) 1349]

242 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-(24-dimethylphenyl)urea (5d) Yield 70 Mp 130ndash132∘C IR(KBr) cmminus1 3434 (OH) 3010 (NH) 1670 (C=O) 1H NMR(400MHz DMSO-d6) ppm 211 (3H s CH3) 219 (3H sCH3) 234 (3H s CH3) 591 (1H s NH) 610 (1H s CH)668ndash695 (6H m ArH) 829 (1H s CONH) 1051 (1H sOH) Mass (119898119911) 3381 (M+) CacldAnal [C (6764) 6759 H(568) 570 N (1246) 1247]

2431-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-(2-chlo-rophenyl)urea (5e) Yield 65Mp 118ndash120∘C IR (KBr) cmminus13421 (OH) 3110 (NH) 1679 (C=O) 695 (C-Cl) 1H NMR(400MHz DMSO-d6) ppm 213 (3H s CH3) 592 (1H sNH) 633 (1H s CH) 628ndash745 (7H m ArH) 872 (1H sCONH) 1049 (1H s OH) 13C NMR (100MHz DMSO-d6)ppm 1607 1583 1537 1488 1415 1349 1307 1291 12891281 1273 1259 1235 1207 1138 1066 975 156 Mass(119898119911) 3430 (M+)3451 (M+2)+ CacldAnal [C (5940) 5945H (410) 408 N (1222) 1225]

244 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-(4-methylphenyl)urea (5f) Yield 59 Mp 134ndash136∘C IR(KBr) cmminus1 3409 (OH) 3112 (NH) 1682 (C=O) 1H NMR(400MHz DMSO-d6) ppm 211 (3H s CH3) 233 (3Hs CH3) 591 (1H s NH) 634 (1H s CH) 618ndash709 (7Hm ArH) 891 (1H s CONH) 1052 (1H s OH) 13C NMR(100MHz DMSO-d6) ppm 1599 1581 1563 1530 14791416 1289 1281 1225 1201 1149 1129 1053 979 182155 Mass (119898119911) 3232 (M+) CacldAnal [C (6686) 6682H (530) 535 N (1300) 1304]

245 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-(2-methylphenyl)urea (5g) Yield 73 Mp 140ndash142∘C IR(KBr) cmminus1 3410 (OH) 3108 (NH) 1680 (C=O) 1H NMR(400MHz DMSO-d6) ppm 214 (3H s CH3) 234 (3H sCH3) 590 (1H s NH) 631 (1H s CH) 619ndash708 (7H mArH) 896 (1H s CONH) 1048 (1H s OH) Mass (119898119911)3232 (M+) CacldAnal [C (6686) 6683 H (530) 534 N(1300) 1303]

246 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-(4-fluorophenyl)urea (5 h) Yield 64 Mp 136ndash138∘C IR (KBr)cmminus1 3411 (OH) 3108 (NH) 1678 (C=O) 785 (C-F) 1HNMR (400MHz DMSO-d6) ppm 233 (3H s CH3) 590(1H s NH) 635 (1H s CH) 624ndash707 (7H m ArH) 892(1H s CONH) 1059 (1H s OH) 13C NMR (100MHzDMSO-d6) ppm 1589 1561 1539 1487 1479 1413 12891271 1223 1201 1149 1129 1063 979 155 Mass (119898119911)3273 (M+) 3291 (M+2)+ CacldAnal [C (6238) 6235 H(431) 434 N (1284) 1285]

247 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-(4-bromophenyl)urea (5i) Yield 66 Mp 126-126∘C IR (KBr)cmminus1 3411 (OH) 3102 (NH) 1672 (C=O) 694 (C-Br) 1H

NMR (400MHz DMSO-d6) ppm 231 (3H s CH3) 591(1H s NH) 635 (1H s CH) 628ndash725 (7H m ArH) 882(1H s CONH) 1054 (1H s OH) Mass (119898119911) 3871 (M+)3893 (M+2)+ CacldAnal [C (5260) 5263 H (363) 364 N(1082) 1084]

248 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-(4-methoxylphenyl)urea (5j) Yield 72 Mp 166ndash168∘C IR(KBr) cmminus1 3401 (OH) 3099 (NH) 1678 (C=O) 1H NMR(400MHz DMSO-d6) ppm 233 (3H s CH3) 381 (3H sOCH3) 590 (1H s NH) 634 (1H s CH) 625ndash709 (7Hm ArH) 888 (1H s CONH) 1055 (1H s OH) 13C NMR(100MHz DMSO-d6) ppm 1609 1582 1564 1539 14871417 1283 1281 1226 1209 1145 1139 1063 979 562158 Mass (119898119911) 3393 (M+) CacldAnal [C (6371) 6373 H(505) 508 N (1238) 1235]

25 Procedure for the Synthesis of Ethyl(pyridine-2-ylami-no)acetate (8) 2-Aminopyridine (6) (01mol 941 g) andethylchloroacetate (7) (02mol sim24mL) were taken in around bottom flask and suspended in 80ndash100mL acetoneand 10 g anhydrous potassium carbonate was added to themixture The mixture was refluxed for 24 h on sand bathwith vigorous stirring and then cooled and the excess solventremoved under reduced pressure The residual mass wastriturated with ice water to remove potassium carbonate andextracted with ethylacetate (3 times 50mL) and the ethylacetatelayer was washed with 10 sodium hydroxide solution (3 times30mL) followed by water (3 times 30mL) and then dried overanhydrous sodium sulphate and evaporated to dryness toobtain ethyl(pyridin-2-ylamino)acetate (8) as brown solidYield 81 Mp 94ndash96∘C (reported) [25] 90ndash92∘C (found)

26 Procedure for the Synthesis of 2-(Pyridin-2-ylami-no)acetohydrazide (9) Ethyl(pyridine-2-ylamino)acetate (8)(0075mol 1246 g) and hydrazine hydrate (015molsim75mL) were refluxed in ethanol for 16 h on water bath Thetwo-third volume of reaction mixture was removed underreduced pressure and then poured into crushed ice to obtain2-(pyridin-2-ylamino)acetohydrazide (9) as brown solidYield 85 Mp 100ndash102∘C (reported) [25] 104∘C (found)

27 General Procedure for the Synthesis of N-[5-Aryl-134-oxadiazol-2-yl]methyl Pyridin-2-amine Analogues (10andashc)2-(Pyridin-2-ylamino)acetohydrazide (9) (0001mol 0166 g)and aromatic aldehydes (0001mol) were refluxed 10ndash12 husing 20mol NaHSO3 and ethanol-water system (1 2vv) solvent [26] After completion of reaction the excesssolvent was removed and the concentrate was poured into thecrushed ice filter washed with water dried and recrystallizedwith absolute ethanol to obtain the final product N-[5-arylalkyl-134-oxadiazol-2-yl]methyl pyridin-2-amine an-alogues (10andashc) The completion of reaction was moni-tored throughout by thin layer chromatography (TLC)using mobile phase benzenemethanol (1 4) and cyclohex-aneacetone (1 4) and the spots were located under iodinevapours or UV light


N O

X

N O

OR

O

OO

+

O O

321

ArNHCONH

EtOH

EtOH

HO HO

HO

HO

OHConc H2SO4

NH2

NH2

NH

HN

HN

X = OS

NHC(=X)NHNH2

4a-b

5a-b

4cndashj 5cndashj

Scheme 1 Protocol for the synthesis of quinoline analogues (5andashj)

271 N-[5-(4-Chlorophenyl)-134-oxadiazol-2-yl]methylpyr-idin-2-amine (10a) Yield 79 Mp 198ndash200∘C IR (KBr)cmminus1 3192 (NH) 1531 (C=N) 1153 (C-O-C) 764 (C-Cl) 1HNMR (400MHz DMSO-d6) ppm 332 (2H s CH2) 754ndash756 (2H d J = 57Hz ArH) 756ndash758 (2H d J = 63HzArH) 787ndash793 (4H m pyridine) 870 (1H s NH) Mass(119898119911) 286 (M+) 288 (M+2)+ CacldAnal [C (5862) 5865H (389) 387 N (1951) 1954]

272 N-[5-(4-Methoxyphenyl)-134-oxadiazol-2-yl]meth-ylpyridin-2-amine (10b) Yield 80 Mp 150ndash152∘C IR(KBr) cmminus1 3199 (NH) 1541 (C=N) 1165 (C-O-C) 1H NMR(400MHz DMSO-d6) ppm 332 (2H s CH2) 380 (3H sOCH3) 702ndash704 (2H d J = 66Hz ArH) 732ndash734 (2Hd J = 61Hz ArH) 778ndash783 (4H m pyridine) 862 (1Hs NH) 13C NMR (100MHz DMSO-d6) ppm 1621 16071523 1489 1383 1345 1285 1186 1148 1136 1097 562515 Mass (119898119911) 282 (M+) CacldAnal [C (6378) 6382 H(503) 500 N (1987) 1985]

273 N-[5-(34-Dimethoxyphenyl)-134-oxadiazol-2-yl]meth-ylpyridin-2-amine (10c) Yield 82Mp 160ndash162∘C IR (KBr)cmminus1 3194 (NH) 1537 (C=N) 1166 (C-O-C) 1H NMR(400MHz DMSO-d6) ppm 332 (2H s CH2) 380 (6H sOCH3) 704ndash706 (2H d J = 63Hz ArH) 734ndash736 (2H d J= 63Hz ArH) 746ndash757 (4H m pyridine) 862 (1H s NH)Mass (119898119911) 312 (M+) CacldAnal [C (6156) 6153 H (513)516 N (1791) 1794]

28 In Vitro Antiproliferative Activity Antiproliferative activ-ity of the ten compounds (5andashj) was evaluated in twodifferent human cell lines (HeLa and MDA-MB-435) usingthe sulforhodamine B (SRB) protocol [27 28] while theantiproliferative screening compounds (10andashc) were carriedout on leukemiamelanoma lung colon CNS ovarian renalprostate and breast cancers cell lines nearly 60 in numberaccording to the reported NCI US protocol [29ndash32]

Three-dose response parameters (GI50 TGI and LC50)were calculated for each of the experimental agents Growthinhibition of 50 (GI50) was calculated from 100 times [(119879119894 minus119879119911)(119862 minus 119879119911)] = 50 which was the drug concentration re-sulting in a 50 reduction in the net protein increase (asmeasured by sulforhodamine B SRB staining) in controlcells during the drug incubation The total growth inhibition(TGI) was calculated from 119879119894 = 119879119911 which was the drug con-centration resulting in total growth inhibition and signifiedthe cytostatic effectThe LC50 was calculated from 100times[(119879119894minus119879119911)(119862 minus 119879119911)] = minus50 which was the drug concentrationresulting in a net loss of cells following treatment whichindicated the concentration of drug resulting in a 50reduction in the measured protein at the end of the drugtreatment as compared to that at the beginning

3 Results and Discussion

31 Chemistry The synthetic protocol of quinoline analogues(5andashj) is summarized in Scheme 1 In the initial step solutionof resorcinol (1) (01mol 1101 g) in ethyl acetoacetate(2) (01mol 1301 g sim13mL) was added slowly into theconcentrated H2SO4 (previously cooled to 5∘C) and stirredand the temperature was maintained below 10∘C for 05 h toobtain the intermediate 7-hydroxy-4-methyl-2H-chromen-2-one (3) In the subsequent step an equimolar quantityof 7-hydroxy-4-methyl-2H-chromen-2-one (3) (0005mol088 g) and semicarbazidethiosemicarbazidesubstitutedphenyl semicarbazide (0005mol) in ethanol (20mL) wasrefluxed for 4ndash8 h at 200∘C to obtain 1-(7-hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)ureathiourea (5a-b) and 1-(7-hy-droxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-substituted phe-nyl urea (5cndashj) The reaction was monitored throughout bythin layer chromatography (TLC) using benzeneacetone(1 4) as mobile phase The substituted phenyl semicarbazideused in the final step was synthesized as per the reportedmethod [21] The yields of the final compounds (5andashj) wereranging from 59 to 80 after recrystallization with methy-lated spirit 25-Disubstituted-134-oxadiazole analogues


N + ClO

O

N

NH

O

O

6 7 8

N

NH

O

NH

N

NH N

O

N

ArR

Acetone EtOH

EtOH

9

ArCHO

NH2 NH2

K2CO3

NaHSO3

NH2NH2middotH2O

10andashc

Scheme 2 Protocol for the synthesis of N-[5-aryl-134-oxadiazol-2-yl]methylpyridin-2-amine analogues (10andashc)

00

500

1000

1500

minus500

minus1000

01 120583M 1120583M 10120583M

5a5b5c5d5e5f

5g5h5i5jADR

Molar drug concentrations

100120583M

(a)

01120583M 1120583M 10120583M 100120583M

5a5b5c5d5e5f

5g5h5i5jADR

minus1000

minus500

00

500

1000

1500


(b)

Figure 2 (a) Growth curve of quinoline analogues (5andashj) HeLa (human cervix cancer cell line) at molar concentrations (b) Growth curveof quinoline analogues (5andashj) MDA-MB-435 (melanoma) at molar concentrations

(10andashc) described in this study were synthesized as per thesynthetic protocol summarized in Scheme 2 In the initial step2-aminopyridine (6) (01mol 941 g) and ethylchloroacetate(7) (02mol sim24mL) were taken in a round bottom flaskand suspended in 80ndash100mL acetone and 10 g anhydrouspotassium carbonate was added to the mixture Themixture was refluxed for 24 h on sand bath with vigorousstirring to obtain intermediate semisolid ethyl(pyridine-2-ylamino)acetate (8) In the subsequent step compound 8was refluxed with hydrazine hydrate in ethanol for 8ndash12 h toobtain 2-(pyridine-2-ylamino)acetohydrazide (9) as brownsemisolid In the final step compound 9 was refluxed witharomatic aldehydes for 12ndash14 h using 20mol NaHSO3 andethanol-water system (1 2 vv) solvent to obtain N-[5-aryl-134-oxadiazol-2-yl]methylpyridin-2-amine analogues(10andashc)Theoxadiazole analogueswere synthesized as per thereportedmethod [23]The yields of the title compounds were

ranging between 79 and 82 after recrystallization withabsolute ethanol The completion of reaction was monitoredthroughout by thin layer chromatography (TLC) usingmobile phase benzeneacetone (1 4) benzenemethanol(1 4) and cyclohexaneacetone (1 4) The purity of thesynthesized compounds was checked by elemental analysisBoth the analytical and spectral data of the compounds werein full agreement with the proposed structure

32 In Vitro Antiproliferative Activity 10 compounds (5andashj)were evaluated for antiproliferative activity on HeLa (humancervix cancer cell line) and MDA-MB-435 (melanoma) atfour different molar drug concentrations (10minus7 10minus6 10minus5and 10minus4M) and the growth percent was recorded Thecytotoxic result was less at first three concentrations but10minus4M concentration produced strong cytotoxicity rangingbetween minus669 and 612 percent growth against HeLa and


Table 1 LC50 TGI and GI50 of quinoline analogues (5andashj) against HeLa and MDA-MB-435 cancer cell lines

CompoundDrug concentrations calculated from graph (120583M)

Human cervix cancer cell line HeLa Melanoma MDA-MB-435LC50 TGI GI50 LC50 TGI GI50

5a gt100 gt100 870 gt100 gt100 gt1005b gt100 gt100 806 gt100 gt100 gt1005c gt100 gt100 7320 gt100 gt100 gt1005d gt100 9728 589 gt100 9728 gt1005e gt100 8817 506 gt100 8817 gt1005f gt100 gt100 599 gt100 gt100 gt1005g gt100 gt100 930 gt100 gt100 gt1005 h gt100 gt100 627 gt100 gt100 gt1005i gt100 gt100 gt100 gt100 gt100 gt1005j 9133 6319 351 gt100 gt100 604ADR 5442 lt01 lt01 706 17 lt01ADR = adriamycin positive control compoundGI50 value of le10

minus6M (ie 1120583molar) is considered to demonstrate activity

between 06 and 878 percent growth against MDA-MB-435(Figures 2(a) and 2(b)) The compound 5j showed maximumcytotoxicity with minus669 and 06 percent growths againstHeLa and MDA-MB-435 respectively The cytotoxicity ofcompound 5jwas found to be higher than the standard drugadriamycin at 10minus4M concentration against HeLa Furtherthree parameters (GI50 TGI and LC50) were calculated forall the quinoline derivatives The GI50 recorded were rangingbetween 351 and gt100 120583M against HeLa while only thecompound 5j registered GI50 of 604 120583M against MDA-MB-435 and rest of the compounds showed GI50 of gt100 120583MThe LC50 recorded was found to be gt100 120583M for both thecell lines except for the compound 5j which showed LC50of 9133 120583M against HeLa The compounds 5j 5e and 5dshowed TGI of 6319 8817 and 9728120583M respectively againstHeLa while compounds 5e and 5d showed TGI of 6319 and8817 120583M respectively against MDA-MB-435The GI50 TGIand LC50 were recorded for the quinoline derivatives (5andashj)and are shown in Table 1 The value of GI50 was taken intoconsideration to establish the structure activity relationship(SAR) of the synthesized compounds The quinoline having24-dimethyl substitution in phenyl ring was found to bemore favorable than 4-methyl and 2-methyl substitutionwhile 2-chloro substitution was found to be more favorablethan 4-fluoro and 4-bromo substitutions The 4-methoxysubstitution on phenyl ring showed significant antiprolifer-ative activity The order of antiproliferative activity followedwith substitution on phenyl ring as 4-OCH3 gt 2-Cl gt 24-(CH3)2 gt 4-CH3 gt 2-CH3 The images of growth controlof MDA-MB-435 and HeLa cancer cell lines by some of thequinoline analogues (5andashj) and adriamycin are shown inFigures 3(a) and 3(b)

Further since quinoline derivatives were found to inhibitepidermal growth factor receptor tyrosine kinase (EGFR-TK)[33] A molecular docking study implying epidermal growthfactor receptor tyrosine kinase (EGFR-TK) was carried out

to observe the binding mode of new quinoline analogues(5andashj) on the active site of EGFR-TKThe molecular dockingprotocol is the same as reported earlier by our research group[34] Three different binding modes (green yellow and grey)were observed by ligands (5andashj) as shown in the Figure 4The binding mode of compounds 5c 5d 5f 5 h 5i and5j (green ligands) with the active site of EGFR-TK showedinteractionwith backboneH-bonding of hydroxyl groupwithMet793 and side chain H-bonding of NH with Asp855 (5f5i and 5j) The binding mode of compounds 5b (yellowligands) with the active site of EGFR-TK showed backboneH-bonding of hydroxy group with Met793 and side chain H-bonding of terminal amine with Thr854 The binding modeof compounds 5a 5e and 5g (grey ligands) with the active siteof EGFR-TK showed backbone H-bonding of NH group withArg841 and side chain H-bonding of hydroxyl and aryl NHgroup with Asp855 and Asn842 respectively while showing120587-120587 stacking with Phe723 (compound 5e) 120587-cationic inter-action of substituted phenyl ring with Arg841 (compound5g) The compound 5j showed hydrophobic interaction withMet793 Leu792 Ala743 Gly796 Met766 Leu788 Leu777and Lys745 backbone H-bonding of hydroxyl group withMet793 and side chain H-bonding of NH with Asp855The binding mode of interaction with EGFR-TK is given inFigure 5

Three compounds (10andashc) were tested for antiprolifer-ative activity on leukemia melanoma lung colon CNSovarian prostate and breast cancer cell lines (nearly 60 celllines) as per the NCI US protocol and carried out at NationCancer Institute USAThe compound 10b showedmaximumactivity with growth percent (GP) of 9433 followed bycompound 10c (GP = 9512) and 10a (GP = 9637) Thecompound 10a showed maximum selectivity towards HOP-92 MCF7 SNB-75 T-47D PC-3 and UO-31 with percentGI of 3414 2122 2052 1539 1497 and 1357 respectivelyThe compound 10b showed maximum selectivity towards


Control

Compound 5d (GI50 = 589 120583M) Compound 5e (GI50 = 506 120583M)

Compound 5f (GI50 = 599 120583M) Compound 5j (GI50 = 351 120583M) Andriamycin (GI50 le 01 120583M)

(a)

Control Compound 5j (GI50 = 604 120583M) Andriamycin (GI50 le 01 120583M)

(b)

Figure 3 (a) Images of growth control of MDA-MB-435 cancer cell line by quinoline (5andashj) and adriamycin (b) Images of growth controlof HeLa cancer cell line by quinoline (5andashj) and adriamycin

HOP-92 CCRF-CEMHOP-62 PC-3 T-47DA498 andUO-31 with percent GI of 3529 2442 2338 2227 2200 1953and 1953 respectively while compound 10c showed maxi-mum selectivity towards HOP-92 PC-3 HOP-62 SNB-75 T-47D and UO-31 with percent GI of 3159 2576 2361 23042147 and 1948 respectively The antiproliferative activity isgiven in Figure 6 The compounds 10a 10b and 10c showedmaximum selectivity towards HOP-92 (Non-Small Cell LungCancer)Themaximum percent GI was recorded on HOP-92by compound 10b No clear cut structure activity relationship(SAR) was observed with antiproliferative data however4-methoxyphenyl substitution on position 5 of oxadiazolering showed significant result than 34-dimethoxyphenyl and4-chlorophenyl substitution Earlier we have reported thesynthesis of oxadiazole derivatives from pyrimidine-2-aminethat showed efficiently binding to the active site of EGFR-TK [35] We can conclude here that EGFR-TK could also be

target of the oxadiazoles (10andashc) reported here in the presentinvestigation

4 Conclusion

All the quinoline (5andashj) and oxadiazole (10andashc) derivativeswere synthesized in satisfactory yields The compound 5jshowed antiproliferative activity among quinoline derivativeswithGI50 of 351 120583MagainstHeLa (cervix cancer cell line) and604 120583M against MDA-MB-435 (melanoma) respectivelyThe structure activity relationship established showed that4-methoxy substitution was found to be more favorablethan 2-chloro and 24-dimethyl substitution in the phenylring Similarly the compound 10b expressed maximum an-tiproliferative activity on human cancer cell lines at 10 120583Mconcentration EGFR-TK could be the potential target of thequinoline and oxadiazole derivatives reported here


Figure 4 The binding modes of quinoline derivatives (5andashj) with the active site of EGFR-TK

N

N

H

HN

OH

O

O

O

VAL726

MET766

LEU788

THR790

LEU777

ILE789

LYS745

GLU762 LEU

844 ASP855

THR854

GLN791

MET793 LEU

792

ALA743

GLY796

LEU718

ASP800

CYS797

Charged (negative)Charged (positive)PolarHydrophobicGlycine

MetalWaterHydration siteDisplaced hydration site

H-bond (backbone)H-bond (side chain)Metal coordinationSolvent exposure

120587-cation

120587-120587 stacking

H2O

Figure 5 The binding modes of quinoline derivative 5j with the active site of EGFR-TK


020406080

100

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

T-47

D (b

reas

t can

cer)

MCF

7 (b

reas

t can

cer)

SNB-

75 (C

NS

canc

er)

PC-3

(pro

stat

eca

ncer

)

UO

-31

(ren

alca

ncer

)

CCRF

-CEM

(leuk

emia

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

PC-3

(pro

stat

eca

ncer

)

T-47

D (b

reas

tcan

cer)

A49

8 (r

enal

canc

er)

UO

-31

(ren

alca

ncer

)

PC-3

(pro

stat

eca

ncer

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

SNB-

75 (C

NSc

ance

r)

T-47

D (b

reas

t can

cer)

UO

-31

(ren

alca

ncer

)

10a 10b 10cGP GI

Figure 6 In vitro antiproliferative activity of N-[5-aryl-134-oxadiazol-2-yl]methylpyridin-2-amine analogues (10andashc) at 10120583M drugconcentration

Disclosure

Part of the work was presented at 1st International Elec-tronic Conference on Medicinal Chemistry 2015 (doi103390ecmc-1-A033 and doi 103390ecmc-1-A029)

Competing Interests

The authors confirm that this articlersquos content has no conflictof interests

Acknowledgments

Antiproliferative data were provided by Anticancer DrugScreening Facility (ACTREC) Navi Mumbai India andNational Cancer Institute (NCI US) Bethesda MD USAThe authors are grateful for all help provided by Dr JyotiKode ACTREC India Professor Doug Smallwood and MrMohammed Nayel NCI USA The people holding the man-agement of Maharishi Arvind College of Pharmacy JaipurRajasthan India are acknowledged for providing researchfacilities They are also grateful to Dr Reddy Institute of LifeScience Hyderabad Andhra Pradesh India for providingspectral data of synthesized compounds One of the authorsis thankful to DST Jaipur for partial financial support(11562015)

References

[1] httpwwwcancergov[2] R L Siegel K D Miller and A Jemal ldquoCancer statistics 2015rdquo

CA A Cancer Journal for Clinicians vol 65 no 1 pp 5ndash29 2015[3] WHO World Cancer Report 2014 httpwwwnydailynews

comlife-stylehealth14-million-people-cancer-2012-article-11545738

[4] N Aydemir and R Bilaloglu ldquoGenotoxicity of two anticancerdrugs gemcitabine and topotecan in mouse bone marrow invivordquoMutation Research vol 537 no 1 pp 43ndash51 2003

[5] BHeiniger GGakhar K Prasain DHHua andTANguyenldquoSecond-generation substituted quinolines as anticancer drugsfor breast cancerrdquo Anticancer Research vol 30 no 10 pp 3927ndash3932 2010

[6] O Afzal S Kumar M R Haider et al ldquoA review on anticancerpotential of bioactive heterocycles quinolinerdquo European Journalof Medicinal Chemistry vol 97 pp 871ndash910 2015

[7] S B Marganakop R R Kamble T Taj and M Y Karidura-ganvar ldquoAn efficient one-pot cyclization of quinoline thiosemi-carbazones to quinolines derivatized with 134-thiadiazole asanticancer and anti-tubercular agentsrdquo Medicinal ChemistryResearch vol 21 no 2 pp 185ndash191 2012

[8] S B Marganakop R R Kamble J Hoskeri D J Prasad andG Y Meti ldquoFacile synthesis of novel quinoline derivatives asanticancer agentsrdquoMedicinal Chemistry Research vol 23 no 6pp 2727ndash2735 2014

[9] E I Aly ldquoDesign synthesis and in vitro cytotoxic activity ofnew 4-anilino-7-chloro quinoline derivatives targeting EGFRtyrosine kinaserdquo Journal of American Science vol 6 pp 73ndash832010

[10] K Kubo T Shimizu S I Ohyama et al ldquoNovel potent orallyactive selective VEGFR-2 tyrosine kinase inhibitors synthesisstructure-activity relationships and antitumor activities of N-phenyl-N1015840-(4-(4-quinolyloxy)phenyl)ureasrdquo Journal of Medici-nal Chemistry vol 48 no 5 pp 1359ndash1366 2005

[11] C-H Tseng Y-L ChenC-YHsu et al ldquoSynthesis and antipro-liferative evaluation of 3-phenylquinolinylchalcone derivativesagainst non-small cell lung cancers and breast cancersrdquo Euro-pean Journal of Medicinal Chemistry vol 59 pp 274ndash282 2013

[12] M I El-Gamal M A Khan M S Abdel-Maksoud M M GEl-Din and C-H Oh ldquoA new series of diarylamides possessingquinoline nucleus synthesis in vitro anticancer activitiesand kinase inhibitory effectrdquo European Journal of MedicinalChemistry vol 87 pp 484ndash492 2014


[13] S Chakrabarty M S Croft M G Marko and G MoynaldquoSynthesis and evaluation as potential anticancer agents ofnovel tetracyclic indenoquinoline derivativesrdquo Bioorganic ampMedicinal Chemistry vol 21 no 5 pp 1143ndash1149 2013

[14] C-T Chen M-H Hsu Y-Y Cheng et al ldquoSynthesis and invitro anticancer activity of 67-methylenedioxy (or 5-hydroxy-6-methoxy)-2-(substituted selenophenyl)quinolin-4-one ana-logsrdquo European Journal of Medicinal Chemistry vol 46 no 12pp 6046ndash6056 2011

[15] M Abdel-Aziz K A Metwally A M Gamal-Eldeen and OM Aly ldquo134-oxadiazole-2-thione derivatives novel approachfor anticancer and tubulin polymerization inhibitory activitiesrdquoAnti-Cancer Agents Medicinal Chemistry vol 16 no 2 pp 269ndash277 2016

[16] Salahuddin M Shaharyar A Majumdar and M J AhsanldquoSynthesis characterization and anticancer evaluation of 2-(naphthalen-1-ylmethylnaphthalen-2-yloxymethyl)-1-[5-(sub-stitutedpheny)-[1 3 4]oxadiazol-2-ylmethyl]-1H-benzimida-zolerdquo Arabian Journal of Chemistry vol 7 no 4 pp 418ndash4242014

[17] G Karabanovich J Zemanova T Smutny et al ldquoDevelopmentof 35-dinitrobenzylsulfanyl-134-oxadiazoles and thiadiazolesas selective antitubercular agents active against replicating andnonreplicating Mycobacterium tuberculosisrdquo Journal of Medici-nal Chemistry vol 59 no 6 pp 2362ndash2380 2016

[18] HRajak B SThakurA Singh et al ldquoNovel limonene and citralbased 25-disubstituted-134-oxadiazoles a natural productcoupled approach to semicarbazones for antiepileptic activityrdquoBioorganic amp Medicinal Chemistry Letters vol 23 no 3 pp864ndash868 2013

[19] M A Bakht M S Yar S G Abdel-Hamid S I Al Qasoumiand A Samad ldquoMolecular properties prediction synthesis andantimicrobial activity of some newer oxadiazole derivativesrdquoEuropean Journal of Medicinal Chemistry vol 45 no 12 pp5862ndash5869 2010

[20] M U Khan T Akhtar N A Al-Masoudi H Stoeckli-Evans and S Hameed ldquoSynthesis crystal structure and anti-HIV activity of 2-adamantyladamantylmethyl-5-aryl-134-oxadiazolesrdquo Medicinal Chemistry vol 8 no 6 pp 1190ndash11972012

[21] G C Ramaprasad B Kalluraya B Sunil Kumar and S MallyaldquoSynthesis of new oxadiazole derivatives as anti-inflammato-ry analgesic and antimicrobial agentsrdquo Medicinal ChemistryResearch vol 22 no 11 pp 5381ndash5389 2013

[22] httpsncatsnihgovfilesZD4054pdf[23] A Kar Advanced Practical Medicinal Chemistry New Age

International Publishers New Delhi India 2004[24] M J Ahsan and J P Stables ldquoPsychomotor seizure test neu-

rotoxicity and in vitro neuroprotection assay of some semicar-bazone analoguesrdquo Central Nervous System Agents in MedicinalChemistry vol 13 no 2 pp 141ndash147 2013

[25] F W Askar N K Abood and N A Jinzell ldquoSynthesis andcharacterization of new 2-aminopyridine derivativesrdquo IraqiNational Journal of Chemistry vol 52 pp 453ndash465 2013

[26] J N Sangshetti A R Chabukswar and D B Shinde ldquoMicro-wave assisted one pot synthesis of some novel 25-disubstituted134-oxadiazoles as antifungal agentsrdquo Bioorganic amp MedicinalChemistry Letters vol 21 no 1 pp 444ndash448 2011

[27] V Vichai and K Kirtikara ldquoSulforhodamine B colorimetricassay for cytotoxicity screeningrdquo Nature Protocols vol 1 no 3pp 1112ndash1116 2006

[28] V Prabhakar R Balasubramanium P Sathe C M Krishnaand A Juvekar ldquoIn vitro anticancer activity of monosubstitutedchalcone derivativesrdquo International Journal of Tumor Therapyvol 3 pp 1ndash9 2014

[29] Development therapeutic program NCINIH 2014 httpdtpncinihgov

[30] A Monks D Scudiero P Skehan et al ldquoFeasibility of a high-flux anticancer drug screen using a diverse panel of culturedhuman tumor cell linesrdquo Journal of theNational Cancer Institutevol 83 no 11 pp 757ndash766 1991

[31] M R Body and K D Paull ldquoSome practical considerations andapplications of the national cancer institute in vitro anticancerdrug discovery screenrdquoDrug Development Research vol 34 no2 pp 91ndash109 1995

[32] R H Shoemaker ldquoThe NCI60 human tumour cell line anti-cancer drug screenrdquo Nature Reviews Cancer vol 6 no 10 pp813ndash823 2006

[33] M Chauhan G Joshi H Kler et al ldquoDual inhibitor of epider-mal growth factor receptor and topoisomerase II120572 derived froma quinoline scaffoldrdquo RSC Advances vol 6 pp 77717ndash777342016

[34] M J Ahsan H Khalilullah S Yasmin S S Jadav and J Govin-dasamy ldquoSynthesis characterisation and in vitro anticanceractivity of curcumin analogues bearing pyrazolepyrimidinering targeting EGFR tyrosine kinaserdquo BioMed Research Interna-tional vol 2013 Article ID 239354 14 pages 2013

[35] M J Ahsan J Sharma S Bhatia P K Goyal K Shankhalaand M Didel ldquoSynthesis of 25-disubstituted-134-oxadiazoleanalogs as novel anticancer and antimicrobial agentsrdquo Letters inDrug Design amp Discovery vol 11 no 4 pp 413ndash419 2014

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


Camptothecin Topotecan Irinotecan

O

O

O

O

O

O

O

O

O

O

OHO

HO

HOHO

N

N

NN

N

N

NNN

Figure 1 Some of the quinoline containing anticancer drugs

biological prospects of fivemember oxadiazoles as anticancer[15 16] antitubercular [17] anticonvulsant [18] antimicrobial[19] anti-HIV [20] and anti-inflammatory [21] inspired us togo on further with the exploration of this moiety Zibotentanan endothelin receptor A (ETA) antagonist is an anticanceragent which contains 134-oxadiazole ring [22] A series ofoxadiazoles (10andashc) were synthesized and evaluated for theirantiproliferative activity against 60 cell lines according tothe National Cancer Institute (NCI US) Protocol at 10 120583Mdrug concentration and percent growth inhibition (GI) wasreported

2 Materials and Methods

21 General The chemicals were procured from MerckMumbai and S D Fine Chemicals Mumbai (India) Meltingpoints were determined by open tube capillary methodand are uncorrected The completion of reaction was mon-itored throughout by thin layer chromatography (TLC)using mobile phase benzenemethanol (1 4) and cyclohex-aneacetone (1 4) and the spots were located under iodinevapours or UV light IR spectra were obtained on a Shimadzu8201 PC FT-IR spectrometer (KBr pellets) 1H NMR spectrawere recorded on a Bruker AC 400MHz spectrometer usingTMS as internal standard in DMSOd6 Mass spectra wererecorded on a Bruker Esquire LCMS using ESI and elementalanalyses were performed on Perkin-Elmer 2400 ElementalAnalyzer

22 Procedure for the Synthesis of 7-Hydroxy-4-methyl-2H-chromen-2-one (3) A solution of resorcinol (1) (01mol1101 g) in ethyl acetoacetate (2) (01mol 1301 g sim13mL) wasadded slowly into the concentratedH2SO4 (previously cooledto 5∘C) and stirred and the temperature was maintainedbelow 10∘C for 05 h The reaction mixture was then pouredinto the crushed ice filtered washed and dried to obtain7-hydroxy-4-methyl-2H-chromen-2-one (3) Yield 78 Mp192-193∘C (reported) [23] 194ndash196∘C (found)

23 Procedure for the Synthesis of 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)ureathiourea (5a-b) Equimolar quan-tity of 7-hydroxy-4-methyl-2H-chromen-2-one (3) (0005mol088 g) and semicarbazidethiosemicarbazide (0005mol)was dissolved in ethanol and was refluxed for 4ndash8 h at 200∘C

and the reaction mixture was then kept overnight The reac-tionwasmonitored throughout by thin layer chromatography(TLC) using benzeneacetone (1 4) as mobile phase Finallythe product was separated dried and recrystallized withmethylated spirit

231 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)urea (5a)Yield 70 Mp 142ndash144∘C IR (KBr) cmminus1 3404 (OH) 3202(NH) 1685 (C=O) 1HNMR (400MHz DMSO-d6) ppm 211(3H s CH3) 542 (2H s NH2) 631 (1H s CH) 618 (1H sArH) 638 (1H d J = 61Hz ArH) 708 (1H d J = 60HzArH) 902 (1H s CONH) 1046 (1H s OH) Mass (119898119911) 233(M+) CacldAnal [C (5665) 5659 H (475) 478 N (1802)1805]

232 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)thiourea(5b) Yield 68 Mp 112ndash114∘C IR (KBr) cmminus1 3414 (OH)3201 (NH) 1286 (C=S) 1HNMR(400MHzDMSO-d6) ppm212 (3H s CH3) 540 (2H s NH2) 631 (1H s CH) 628 (1Hs ArH) 629 (1H d J = 61Hz ArH) 705 (1H d J = 60HzArH) 832 (1H s CSNH) 1041 (1H s OH) Mass (119898119911) 249(M+) CacldAnal [C (5300) 5305 H (445) 442 N (1686)1685]

24 Procedure for the Synthesis of 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-substituted Phenyl Urea (5cndashj) Eq-uimolar quantity of 7-hydroxy-4-methyl-2H-chromen-2-one (3) (0005mol 088 g) and substituted phenyl sem-icarbazide (0005mol) was dissolved in ethanol and wasrefluxed for 4ndash8 h at 200∘C and the reaction mixture wasthen kept overnight Finally the product was separated driedand recrystallized with methylated spirit The reaction wasmonitored throughout by thin layer chromatography (TLC)using benzeneacetone (1 4) asmobile phaseThe substitutedphenyl semicarbazide was synthesized as per the reportedmethod [24]

241 1-(7-Hydroxy-4-methyl-2-oxoquinolin-1(2H)-yl)-3-phe-nylurea (5c) Yield 80 Mp 150ndash152∘C IR (KBr) cmminus1 3424(OH) 3018 (NH) 1675 (C=O) 1H NMR (400MHz DMSO-d6) ppm 211 (3H s CH3) 590 (1H s NH) 631 (1H s CH)638ndash705 (8H m ArH) 839 (1H s CONH) 1049 (1H s















N O

X

N O

OR

O

OO

+

O O

321

ArNHCONH

EtOH

EtOH

HO HO

HO

HO

OHConc H2SO4

NH2

NH2

NH

HN

HN

X = OS

NHC(=X)NHNH2

4a-b

5a-b

4cndashj 5cndashj










N + ClO

O

N

NH

O

O

6 7 8

N

NH

O

NH

N

NH N

O

N

ArR

Acetone EtOH

EtOH

9

ArCHO

NH2 NH2

K2CO3

NaHSO3

NH2NH2middotH2O

10andashc


00

500

1000

1500

minus500

minus1000

01 120583M 1120583M 10120583M

5a5b5c5d5e5f

5g5h5i5jADR


100120583M

(a)

01120583M 1120583M 10120583M 100120583M

5a5b5c5d5e5f

5g5h5i5jADR

minus1000

minus500

00

500

1000

1500


(b)
















Control



(a)


(b)




4 Conclusion




N

N

H

HN

OH

O

O

O

VAL726

MET766

LEU788

THR790

LEU777

ILE789

LYS745

GLU762 LEU

844 ASP855

THR854

GLN791

MET793 LEU

792

ALA743

GLY796

LEU718

ASP800

CYS797




120587-cation

120587-120587 stacking

H2O



020406080

100

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

T-47

D (b

reas

t can

cer)

MCF

7 (b

reas

t can

cer)

SNB-

75 (C

NS

canc

er)

PC-3

(pro

stat

eca

ncer

)

UO

-31

(ren

alca

ncer

)

CCRF

-CEM

(leuk

emia

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

PC-3

(pro

stat

eca

ncer

)

T-47

D (b

reas

tcan

cer)

A49

8 (r

enal

canc

er)

UO

-31

(ren

alca

ncer

)

PC-3

(pro

stat

eca

ncer

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

SNB-

75 (C

NSc

ance

r)

T-47

D (b

reas

t can

cer)

UO

-31

(ren

alca

ncer

)

10a 10b 10cGP GI


Disclosure


Competing Interests


Acknowledgments


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of















N O

X

N O

OR

O

OO

+

O O

321

ArNHCONH

EtOH

EtOH

HO HO

HO

HO

OHConc H2SO4

NH2

NH2

NH

HN

HN

X = OS

NHC(=X)NHNH2

4a-b

5a-b

4cndashj 5cndashj










N + ClO

O

N

NH

O

O

6 7 8

N

NH

O

NH

N

NH N

O

N

ArR

Acetone EtOH

EtOH

9

ArCHO

NH2 NH2

K2CO3

NaHSO3

NH2NH2middotH2O

10andashc


00

500

1000

1500

minus500

minus1000

01 120583M 1120583M 10120583M

5a5b5c5d5e5f

5g5h5i5jADR


100120583M

(a)

01120583M 1120583M 10120583M 100120583M

5a5b5c5d5e5f

5g5h5i5jADR

minus1000

minus500

00

500

1000

1500


(b)
















Control



(a)


(b)




4 Conclusion




N

N

H

HN

OH

O

O

O

VAL726

MET766

LEU788

THR790

LEU777

ILE789

LYS745

GLU762 LEU

844 ASP855

THR854

GLN791

MET793 LEU

792

ALA743

GLY796

LEU718

ASP800

CYS797




120587-cation

120587-120587 stacking

H2O



020406080

100

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

T-47

D (b

reas

t can

cer)

MCF

7 (b

reas

t can

cer)

SNB-

75 (C

NS

canc

er)

PC-3

(pro

stat

eca

ncer

)

UO

-31

(ren

alca

ncer

)

CCRF

-CEM

(leuk

emia

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

PC-3

(pro

stat

eca

ncer

)

T-47

D (b

reas

tcan

cer)

A49

8 (r

enal

canc

er)

UO

-31

(ren

alca

ncer

)

PC-3

(pro

stat

eca

ncer

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

SNB-

75 (C

NSc

ance

r)

T-47

D (b

reas

t can

cer)

UO

-31

(ren

alca

ncer

)

10a 10b 10cGP GI


Disclosure


Competing Interests


Acknowledgments


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N O

X

N O

OR

O

OO

+

O O

321

ArNHCONH

EtOH

EtOH

HO HO

HO

HO

OHConc H2SO4

NH2

NH2

NH

HN

HN

X = OS

NHC(=X)NHNH2

4a-b

5a-b

4cndashj 5cndashj










N + ClO

O

N

NH

O

O

6 7 8

N

NH

O

NH

N

NH N

O

N

ArR

Acetone EtOH

EtOH

9

ArCHO

NH2 NH2

K2CO3

NaHSO3

NH2NH2middotH2O

10andashc


00

500

1000

1500

minus500

minus1000

01 120583M 1120583M 10120583M

5a5b5c5d5e5f

5g5h5i5jADR


100120583M

(a)

01120583M 1120583M 10120583M 100120583M

5a5b5c5d5e5f

5g5h5i5jADR

minus1000

minus500

00

500

1000

1500


(b)
















Control



(a)


(b)




4 Conclusion




N

N

H

HN

OH

O

O

O

VAL726

MET766

LEU788

THR790

LEU777

ILE789

LYS745

GLU762 LEU

844 ASP855

THR854

GLN791

MET793 LEU

792

ALA743

GLY796

LEU718

ASP800

CYS797




120587-cation

120587-120587 stacking

H2O



020406080

100

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

T-47

D (b

reas

t can

cer)

MCF

7 (b

reas

t can

cer)

SNB-

75 (C

NS

canc

er)

PC-3

(pro

stat

eca

ncer

)

UO

-31

(ren

alca

ncer

)

CCRF

-CEM

(leuk

emia

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

PC-3

(pro

stat

eca

ncer

)

T-47

D (b

reas

tcan

cer)

A49

8 (r

enal

canc

er)

UO

-31

(ren

alca

ncer

)

PC-3

(pro

stat

eca

ncer

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

SNB-

75 (C

NSc

ance

r)

T-47

D (b

reas

t can

cer)

UO

-31

(ren

alca

ncer

)

10a 10b 10cGP GI


Disclosure


Competing Interests


Acknowledgments


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N + ClO

O

N

NH

O

O

6 7 8

N

NH

O

NH

N

NH N

O

N

ArR

Acetone EtOH

EtOH

9

ArCHO

NH2 NH2

K2CO3

NaHSO3

NH2NH2middotH2O

10andashc


00

500

1000

1500

minus500

minus1000

01 120583M 1120583M 10120583M

5a5b5c5d5e5f

5g5h5i5jADR


100120583M

(a)

01120583M 1120583M 10120583M 100120583M

5a5b5c5d5e5f

5g5h5i5jADR

minus1000

minus500

00

500

1000

1500


(b)
















Control



(a)


(b)




4 Conclusion




N

N

H

HN

OH

O

O

O

VAL726

MET766

LEU788

THR790

LEU777

ILE789

LYS745

GLU762 LEU

844 ASP855

THR854

GLN791

MET793 LEU

792

ALA743

GLY796

LEU718

ASP800

CYS797




120587-cation

120587-120587 stacking

H2O



020406080

100

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

T-47

D (b

reas

t can

cer)

MCF

7 (b

reas

t can

cer)

SNB-

75 (C

NS

canc

er)

PC-3

(pro

stat

eca

ncer

)

UO

-31

(ren

alca

ncer

)

CCRF

-CEM

(leuk

emia

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

PC-3

(pro

stat

eca

ncer

)

T-47

D (b

reas

tcan

cer)

A49

8 (r

enal

canc

er)

UO

-31

(ren

alca

ncer

)

PC-3

(pro

stat

eca

ncer

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

SNB-

75 (C

NSc

ance

r)

T-47

D (b

reas

t can

cer)

UO

-31

(ren

alca

ncer

)

10a 10b 10cGP GI


Disclosure


Competing Interests


Acknowledgments


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of












Control



(a)


(b)




4 Conclusion




N

N

H

HN

OH

O

O

O

VAL726

MET766

LEU788

THR790

LEU777

ILE789

LYS745

GLU762 LEU

844 ASP855

THR854

GLN791

MET793 LEU

792

ALA743

GLY796

LEU718

ASP800

CYS797




120587-cation

120587-120587 stacking

H2O



020406080

100

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

T-47

D (b

reas

t can

cer)

MCF

7 (b

reas

t can

cer)

SNB-

75 (C

NS

canc

er)

PC-3

(pro

stat

eca

ncer

)

UO

-31

(ren

alca

ncer

)

CCRF

-CEM

(leuk

emia

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

PC-3

(pro

stat

eca

ncer

)

T-47

D (b

reas

tcan

cer)

A49

8 (r

enal

canc

er)

UO

-31

(ren

alca

ncer

)

PC-3

(pro

stat

eca

ncer

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

SNB-

75 (C

NSc

ance

r)

T-47

D (b

reas

t can

cer)

UO

-31

(ren

alca

ncer

)

10a 10b 10cGP GI


Disclosure


Competing Interests


Acknowledgments


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Control



(a)


(b)




4 Conclusion




N

N

H

HN

OH

O

O

O

VAL726

MET766

LEU788

THR790

LEU777

ILE789

LYS745

GLU762 LEU

844 ASP855

THR854

GLN791

MET793 LEU

792

ALA743

GLY796

LEU718

ASP800

CYS797




120587-cation

120587-120587 stacking

H2O



020406080

100

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

T-47

D (b

reas

t can

cer)

MCF

7 (b

reas

t can

cer)

SNB-

75 (C

NS

canc

er)

PC-3

(pro

stat

eca

ncer

)

UO

-31

(ren

alca

ncer

)

CCRF

-CEM

(leuk

emia

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

PC-3

(pro

stat

eca

ncer

)

T-47

D (b

reas

tcan

cer)

A49

8 (r

enal

canc

er)

UO

-31

(ren

alca

ncer

)

PC-3

(pro

stat

eca

ncer

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

SNB-

75 (C

NSc

ance

r)

T-47

D (b

reas

t can

cer)

UO

-31

(ren

alca

ncer

)

10a 10b 10cGP GI


Disclosure


Competing Interests


Acknowledgments


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



N

N

H

HN

OH

O

O

O

VAL726

MET766

LEU788

THR790

LEU777

ILE789

LYS745

GLU762 LEU

844 ASP855

THR854

GLN791

MET793 LEU

792

ALA743

GLY796

LEU718

ASP800

CYS797




120587-cation

120587-120587 stacking

H2O



020406080

100

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

T-47

D (b

reas

t can

cer)

MCF

7 (b

reas

t can

cer)

SNB-

75 (C

NS

canc

er)

PC-3

(pro

stat

eca

ncer

)

UO

-31

(ren

alca

ncer

)

CCRF

-CEM

(leuk

emia

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

PC-3

(pro

stat

eca

ncer

)

T-47

D (b

reas

tcan

cer)

A49

8 (r

enal

canc

er)

UO

-31

(ren

alca

ncer

)

PC-3

(pro

stat

eca

ncer

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

SNB-

75 (C

NSc

ance

r)

T-47

D (b

reas

t can

cer)

UO

-31

(ren

alca

ncer

)

10a 10b 10cGP GI


Disclosure


Competing Interests


Acknowledgments


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


020406080

100

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

HO

P-92

(Non

-Sm

all C

ell L

ung

Canc

er)

T-47

D (b

reas

t can

cer)

MCF

7 (b

reas

t can

cer)

SNB-

75 (C

NS

canc

er)

PC-3

(pro

stat

eca

ncer

)

UO

-31

(ren

alca

ncer

)

CCRF

-CEM

(leuk

emia

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

PC-3

(pro

stat

eca

ncer

)

T-47

D (b

reas

tcan

cer)

A49

8 (r

enal

canc

er)

UO

-31

(ren

alca

ncer

)

PC-3

(pro

stat

eca

ncer

)

HO

P-62

(Non

-Sm

all C

ell L

ung

Canc

er)

SNB-

75 (C

NSc

ance

r)

T-47

D (b

reas

t can

cer)

UO

-31

(ren

alca

ncer

)

10a 10b 10cGP GI


Disclosure


Competing Interests


Acknowledgments


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Documents

Research Article Synthesis and Antiproliferative Activity of Some … · 2019. 7. 30. · cervix cancer cell line) and MDA-MB- (melanoma) cell lines [, , ]. Hence we selected HeLa