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European Journal of Medicinal Chemistry 71 (2014) 160e167

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European Journal of Medicinal Chemistry

journal homepage: http: / /www.elsevier .com/locate/ejmech

Original article

Rational design and synthesis of novel dibenzo[b,d]furan-1,2,3-triazole conjugates as potent inhibitors of Mycobacterium tuberculosis

Thirumal Yempala a, Jonnalagadda Padma Sridevi b, Perumal Yogeeswari b,Dharmarajan Sriramb, Srinivas Kantevari a,c,*aOrganic Chemistry Division-II (CPC Division), CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, IndiabMedicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus,Jawahar Nagar, Hyderabad 500078, IndiacAcademy of Scientific and Innovative Research, CSIR- Indian Institute of Chemical Technology, Hyderabad 500007, India

a r t i c l e i n f o

Article history:Received 27 August 2013Received in revised form10 October 2013Accepted 31 October 2013Available online 12 November 2013

Keywords:DibenzofuranMycobacterium tuberculosisClick chemistryCoreyeFuchs reactionCytotoxicity

* Corresponding author. Organic Chemistry DivisionInstitute of Chemical Technology, Hyderabad 500007,fax:þ91 4027198933.

E-mail addresses: kantevari@yahoo.com, kantevar

0223-5234/$ e see front matter � 2013 Elsevier Mashttp://dx.doi.org/10.1016/j.ejmech.2013.10.082

a b s t r a c t

A series of novel dibenzo[b,d]furan-1,2,3-triazole conjugates, rationally designed by reorientation ofdibenzo[b,d]furan pharmacophore and alkyl/aryl groups appended on 1,2,3-triazole core, were synthe-sized using click chemistry. The required key intermediate, 2-ethynyl dibenzo[b,d]furan 3 was preparedfrom dibenzofuran-2-carboxaldehyde using CoreyeFuchs reaction. Further reaction of 3 with variousalkyl/aryl azides in the presence of copper catalyst produced 1,2,3-triazole conjugates in excellent yields.Evaluation of all the new compounds for in vitro antimycobacterial activity against Mycobacteriumtuberculosis H37Rv (ATCC27294), resulted 5a (MIC: 1.56 mg/mL), 5d (MIC: 0.78 mg/mL) and 5f (MIC:0.78 mg/mL) as promising lead analogues. Among these three compounds, 1-(4-bromobenzyl)-4-(dibenzo[b,d]furan-2-yl)-1H-1,2,3-triazole (5f) emerged as the most promising antitubercular agent with lowestcytotoxicity (selectivity index: [25) against the HEK-293T cell line.

� 2013 Elsevier Masson SAS. All rights reserved.

1. Introduction

Tuberculosis (TB) is an ancient, contagious disease caused bypathogenMycobacterium tuberculosis (MTB) and is characterized bytubercle lesions in the lungs [1]. It is the second-leading cause inmortalities and is responsible for infecting one-third of the world’spopulation [2e4]. TheWorldHealth Organization (WHO) estimated1.4 million deaths in 2011 are due to TB, which included 350,000 TBassociated HIV infected deaths [5e7]. Additionally, the resurgenceof its new virulent forms like multi drug resistant (MDR-TB) andextremely drug resistant (XDR-TB) has become a major threat tohuman kind [8e11]. Theworsening situation necessitated an urgentneed for discovery of modern curative drugs active in all the formsof TB [12,13]. All these facts prompted re-engineering and reposi-tioning of old natural and synthetic bioactives for the developmentof fast acting new antitubercular drugs with novel mechanism ofaction to achieve effective TB control [14e16].

-II (CPC Division), CSIR-IndianIndia. Tel.: þ91 4027191438;

i@gmail.com (S. Kantevari).

son SAS. All rights reserved.

Natural products derived from plants or microbes play a majorrole in drug discovery as a source of original bioactive structuresand offer models for rational drug design [17e19]. In antitubercularagents, the lichen secondary metabolite usnic acid (I) derivedfrom dibenzofuran has shown to display an interesting anti-mycobacterial activity [20], but its weak potency did not permit itsfurther development as an antitubercular drug. Synthetic ana-logues, for example, benzofuro-benzopyran IV (Fig. 1) derived fromdibenzofuran have shown good inhibitory activity againstM. tuberculosisH37Rv but were found to bemore cytotoxic [21e23].On the other hand, 1,2,3-triazoles have gained enormous interest inrecent years due to their broad spectrum pharmaceutical andtherapeutic applications like antimicrobial activity against gram-positive bacteria, therapeutic fungicides of second generation,anti-inflammatory agents, inhibitors of tumour proliferation, in-vasion, metastasis, anti-HIV activity, etc. [24,25]. Triazole basedantitubercular agents (for example, VeVIII) may be regarded as anew class providing truly effective lead candidates [26e28] whichare reported to inhibit bacteria and among them VII is presently inpre-clinical trials [29e31].

Additionally, these 1,2,3-triazoles possess remarkable meta-bolic stability and prove to be amide surrogates in various bioac-tive compounds [32,33]. In our efforts to fight against tuberculosis,

O

NNN

R1

O

N NN

HN

NO

OHO

HO O

O

O

N

O

NN

N

O

IV

VIIVIII

O

OH

OO

HO

OH

OUsnic acid (I)

N

N

N NN

R R

R

O

O

HN

OR

II

VI

O

O

O O

O

III

V

F

Fig. 1. Representative antitubercular agents of dibenzofurans (IeIV), triazoles (VeVII) and their hybrid VIII.

T. Yempala et al. / European Journal of Medicinal Chemistry 71 (2014) 160e167 161

a series of dibenzofuran derived new molecules II and III (Fig. 1)designed and synthesized in our laboratory [34e37], exhibitedpromising antimycobacterial activity and are undergoing detailedinvestigations. Further, 1,2,3-triazole clubbed dibenzo[b,d]furansexhibited moderate activity with MICs ranging from 6.25 to25.0 mg/mL [38]. Continuing our work to attain potent antituber-cular agents by integrating dibenzo[b,d]furan and triazole units,we herein report an efficient synthesis and antitubercular evalu-ation of new variants of dibenzo[b,d]furan-1,2,3-triazole conju-gates in excellent yields via copper catalyzed click chemistry.Screening all ‘14’ new compounds for in vitro activity against M.tuberculosis H37Rv (MTB) resulted three compounds 5a, 5d and 5fas promising lead analogues with MIC ranging from 1.56 to0.78 mg/mL and has shown lower cytotoxicity with good selectivityindex (SI).

Fig. 2. Design strategy for new dibenzofuranetriazole hybrids.

2. Results and discussion

2.1. Chemistry

The design strategy adopted here is based on the structuralmodification of our recently reported hybrids IX (Fig. 2) [38]through re-alignment and positioning of pharmacophore dibenzo[b,d]furan and alkyl/aryl fragments of the 1,2,3-triazole nucleus toresult newer analogues for biological evaluation.

To begin with, dibenzo[b,d]furan-2-caraboxaldehyde (1),required was prepared by formylation of dibenzofuran followingthe literature procedure [39]. Aldehyde 1 was then reacted withCBr4 in the presence of triphenyl phosphine under standard re-action conditions [40e43] resulted 2-(2,2-dibromovinyl)dibenzo[b,d]furan 2 in excellent yield (Scheme 1). Compound 2 was usedas such without any further purification. Initial attempts toconvert 2-(2,2-dibromovinyl)dibenzo[b,d]furan 2 to 2-ethynyldibenzo[b,d]furan in the presence of a base under

standard CoreyeFuchs reaction conditions [44e46] were unsuc-cessful. After series experiments by varying reaction parameters,2-ethynyldibenzo[b,d]furan 3 (Scheme 1) was successfully ach-ieved in very good yields through the addition of n-butyl lithium(1.6 M) to a solution of 2 in THF at 0 �C followed by stirring thereaction mixture at room temperature for 3h. The alkyne 3 thusobtained was fully characterized by IR, 1H and 13C NMR, and massspectral data. Further the required azides 4aen depicted in Fig. 3was prepared by following the reported procedures and were fullycharacterized by correlating their spectral data with literature[38,47].

Having both alkyne 3 and azides 4aen in hand, we employedHuisgen’s (3 þ 2) cycloaddition in the presence of CuSO4 catalyst,sodium ascorbate in t-butanol and water (1:1, v/v) [48,49]. All theazides 4aen reacted well with 2-ethynyldibenzo[b,d]furan 3 togive triazole hybrids 5aen in excellent yields (Scheme 2). Here wenotice that coupling of alkyne 3 with azides bearing electronwithdrawing functional groups produced triazoles in slightlylower yields (for example, 5h) compared with the coupling ofalkyne 3 with azides bearing electron donating functional groups(for example, 5e). All the triazoles 5aen obtained was fully char-acterized by 1H, 13C NMR and mass (ESI and HR-MS) spectroscopic

O

CHO

1

O O

Br

Br

32

i ii

Reaction conditions: (i).CBr4, PPh3, DCM, 1h, 95 % (ii). nBu-Li, THF, 0°C to RT, 3h, 90%.

Scheme 1. Synthesis of 2-ethynyldibenzo[b,d]furan 3.

T. Yempala et al. / European Journal of Medicinal Chemistry 71 (2014) 160e167162

data. The purity of all the compounds (>95%) was determined byHPLC analysis.

2.2. Pharmacology

A total of “14” newly synthesized dibenzo[b,d]furan-1,2,3-triazole conjugates 5aen were screened for in vitro anti-mycobacterial activity against M. tuberculosis H37Rv (ATCC27294)by agar dilution method. The MIC is defined as the minimum con-centration of compound required to completely inhibit the bacterialgrowth. The MIC values (mg/mL) of all the compounds, 5aen andthree standard antitubercular drugs determined in triplicate at pH7.40 are presented in Fig. 4. All the new compounds 5aen screenedto have shown in vitro activity against MTB with MICs ranging from0.78 to 50.0 mg/mL. Among them seven triazole analogues 5a, 5degand 5jek displayed MIC values below 6.25 mg/mL, a value postu-lated by the global programme on the discovery of new antituber-cular drugs as an upper threshold for the evaluation of newM. tuberculosis therapies. Out of these seven triazole analogues, twocompounds 5d and 5f inhibited MTB with MIC 0.78 mg/mL; onecompound 5a inhibited MTB with MIC 1.56 mg/mL and three

O CH3

ON3 HO

N

BrBr

OCH3

NO2

N3 CH3CH3N3

OH3C

N

4e

4a 4b

4f 4g

4k 4l

N3 N3 N3N3

Fig. 3. Azides 4aen u

compounds 5e, 5j and 5k inhibited MTB with MIC of 3.12 mg/mL.When compared to first-line TB drug Ethambutol (MIC 3.13 mg/mL),six compounds 5a, 5def, 5j and 5k were found to be more potent,though all the compounds were less potent than other anti-TBdrug’s isoniazid (0.1 mg/mL) and Rifampicin (0.2 mg/mL).

Structureeactivity correlation of new compounds with respectto their antitubercular activity revealed that dibenzo[b,d]furan-1,2,3-triazole derivatives 5dee bearing electron donating methoxygroup on phenyl ring are found to be more potent than 5hei haveelectron withdrawing group (eNO2,COOMeeCOOMe) on phenylring. It was also observed that triazole 5f bearing 4-bromo phenyl ismost active (MIC 0.78 mg/mL) than triazole 5g bearing3-bromophenylgroup. Conversely, in 5d and 5e, 3-methoxyanalogue 5d is comparatively more active than respective4-methoxy analogue 5e. Compared with our previous work [38] onantitubercular dibenzo[b,d]furan clubbed triazoles, dibenzofuranunit linked through CeC bond to the 1,2,3-triazole core may bepharmacologically better positioned to exhibit improved antitu-bercular activity.

The in vitro cytotoxicity of all compounds evaluated for anti-TB activity was also assessed by 3-(4,5-dimethylthiazol-2-yl)-

3

NO2

O

3 CH3

S

N3CH3

CH3N3

CH3COOMe

4c 4d

4h 4i 4j

4m 4n

OH3C

N3

N3

N3

sed in the study.

O

3

5a-n

azides 4a-n,CuSO4,sodium ascorbate,

t-butanol and water (1:1,v/v)

1.0 - 2.0h, RT

O

N

N

N

O

N

N

N

O

N

N

N

CH3

O

N

N

N

CH3

X

5c: R=H; (91%)5d: R=3-OCH3; (90%)5e: R=4-OCH3; (92%)5f : R=4-Br; (85%)5g: R=3-Br; (86%)5h: R=4-NO2;( 80%)5i: R=4-COOMe; (91%)

5j: R=4-CH3; (90%)5k: R=4-OCH3; (91%)5l: R=4-NO2; (80%)

5m: X=O; (83%)5n: X=S; (84%)

R

R

O

O

O

N

N

NOH

5a (81%) 5b (83%)

Scheme 2. Synthesis of dibenzo[b,d]furan-1,2,3-triazoles 5aen.

T. Yempala et al. / European Journal of Medicinal Chemistry 71 (2014) 160e167 163

2,5-diphenyltetrazolium bromide assay (MTT) assay against HEK-293T cells at 50 mg/mL concentration. Percentage growth of cellswas reported in Table 1. Compounds that exhibited selectivityindex (SI) values greater than 10 in HEK-293T cells wereconsidered nontoxic. The most promising anti-TB compounds 5dand 5f exhibited 62.1% and 27.8% inhibition at 50 mg/mL with

Fig. 4. Antitubercular evaluation of new analo

selectivity index of >25. Compounds 5b, 5g and 5k were alsofound to be less cytotoxic at 50 mg/mL with favourable selectivityindex. The results obtained here demonstrated that compound 5fwith high inhibitory activity against M. tuberculosis (0.78 mg/mL)also exhibited lowest toxicity, i.e., high SI ([25) against HEK-293T cells.

gues 5aen against M. tuberculosis H37RV.

Table 1Percentage inhibition and selectivity index (SI) values of dibenzofuran analogues5aen against HEK-293Tcell line.

Entry Product % Cell inhibitionat 50 mg/mL

IC50 approximation(mg/mL)

SI index(IC50/MIC)

1 5a 38.8 >50 >252 5b 21.9 [50 w1e23 5c 36.1 >50 w1e24 5d 62.1 <50 w255 5e 52.7 w50 w166 5f 27.8 >50 [257 5g 12.0 [50 >108 5h 46.3 w50 w1e29 5i 58.1 <50 w1e210 5j 43.1 w50 w1611 5k 18.9 [50 [1612 5l 38.9 >50 w213 5m 52.6 w50 w1e214 5n 61.1 <50 w1e2

T. Yempala et al. / European Journal of Medicinal Chemistry 71 (2014) 160e167164

3. Conclusion

In conclusion, we have designed and synthesized a novel seriesof dibenzo[b,d]furan-1,2,3-triazoles 5aen through click chemistry.These new analogues were prepared by Huisgen’s (3 þ 2) cyclo-addition reaction of 2-ethynyldibenzo[b,d]furan 3 and differentazides 4aen in presence of copper sulphate and sodium ascorbate.All these products were obtained in excellent yields and were fullycharacterized by spectral data. Screening all these new derivativesagainst M. tuberculosis H37Rv (MTB) and cytotoxicity revealed that5a, 5d and 5f are best active antitubercular agents with therapeuticindex >25 compared to the other evaluated compounds. Amongthese three antitubercular agents, 5f is the most active (MIC0.78 mg/mL) and least cytotoxic (SI [ 25) compound. The resultsdescribed to here demonstrate the potential utility of dibenzo[b,d]furan-1,2,3-triazoles as antitubercular agents for furtheroptimization.

4. Experimental section

Melting points were measured with a Fischer-Johns meltingpoint apparatus and are uncorrected. IR spectra was recorded asneat liquids or KBr pellets and absorptions are reported in cm�1.NMR spectra was recorded on 300 (Bruker) and 500 MHz (Varian)spectrometers in appropriate solvents using TMS as internal stan-dard or the solvent signals as secondary standards and the chemicalshifts are shown in d scales. Multiplicities of NMR signals aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), br(broad), m (multiplet, for unresolved lines), etc. 13C NMR spectrawere recorded on 75 and 125 MHz spectrometers. High-resolutionmass spectra was obtained by using ESI-QTOF mass spectrometry.All the experiments were monitored by analytical thin layer chro-matography (TLC) performed on silica gel GF254 pre-coated plates.After elution, plate was visualized under UV illumination at 254 nmfor UV active materials. Further visualization was achieved bystaining with PMA and charring on a hot plate. Solvents wereremoved under vacuum and heated in a water bath at 35 �C. Silicagel finer than 200 mesh was used for column chromatography.Columns were packed as the slurry of silica gel in hexane andequilibrated with the appropriate solvent/solvent mixture prior touse. The compounds were loaded neat or as a concentrated solutionusing the appropriate solvent system. The elution was assisted byapplying pressure with an air pump. Yields refer to chromato-graphically and spectroscopically homogeneous materials unlessotherwise stated. Appropriate names (if possible) for all the newcompounds were given with the help of ChemBioOffice 12.0; 2010.

4.1. 2-(2,2-Dibromovinyl)dibenzo[b,d]furan 2

A solution of dibenzo[b,d]furan-2-carbaldehyde 1 (1.96 g,10 mmol), triphenyl phosphine (10.48 g, 40 mmol) and carbontetrabromide (6.62 g, 20 mmol) in dry dichloromethane at 0 �C wasstirred for 1 h at RT. Precipitation of triphenyl phosphine oxideusing pentane (50 mL) and filtration through a short column ofsilica gel, evaporation of dichloromethane resulted 2-(2,2-dibromovinyl)dibenzo[b,d]furan 2 (3.4 g, 95%) as yellow solid. Itwas directly used in the next step without any further purification.

4.2. Preparation of 2-ethynyldibenzo[b,d]furan 3

To a solution of dibromide 2 (3.52 g, 10 mmol) in dry THF(30 mL), n-BuLi (1. 6M, 25 mmol) was added with stirring at 0 �C.After completion (TLC), the reaction mixture was quenched withsaturated NH4Cl at 0 �C, extracted with ether (3 � 20 mL), driedover anhydrous sodium sulphate and concentrated under reducedpressure. The crude reaction mixture was purified over silica gelcolumn chromatography (n-pentane) to give 2-ethynyldibenzo[b,d]furan 3 (1.72 g, 90%) as white solid.

4.2.1. Analytical data of compound 3M.p. 86e88 �C; 1H NMR (300 MHz, CDCl3) d 8.07 (d, J ¼ 0.9 Hz,

1H, AreH), 7.89 (d, J ¼ 7.5 Hz, 1H, AreH), 7.59e7.39 (m, 4H, AreH),7.32 (dd, J ¼ 0.7 and 8.1 Hz, 1H, AreH), 3.00 (s, 1H, tbndCeH). 13CNMR (100 MHz, CDCl3) d 156.5, 155.9, 131.1, 127.6, 124.6, 124.4,123.4,123.0,120.7,116.6,111.7,111.7, 83.7 (eCtbndCe), 76.2 (tbndCeH). IR (KBr) 3268 (tbndCeH), 3046, 2925, 1775, 1445, 1279, 1197,888, 821, 745, 722 cm�1. MS-EI calcd for C14H8O: 192, found:[M]þ ¼ 192 (100%).

4.3. General procedure for the synthesis of 1,2,3-triazoles 5ae5n

Compound 3 (1.0 mmol), azides 4ae4n (1.0 mmol), coppersulphate pentahydrate (20 mol%) and sodium ascorbate (20 mol%)in tert-butanol and water (1:1, v/v, 4 mL) was stirred at RT forappropriate time. After completion (TLC), the reaction mixture wastreatedwith ethyl acetate (2�10mL) andwater (5 mL), the organiclayer was separated, washed with brine solution, dried overanhydrous sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatog-raphy over silica gel using ethyl acetate/hexane (1:2) to obtaincorresponding 1,2,3-triazoles 5aen.

4.3.1. Ethyl 2-(4-(dibenzo[b,d]furan-2-yl)-1H-1,2,3-triazol-1-yl)acetate 5a

White solid. M.p. 131e133 �C; 1H NMR (300 MHz, CDCl3) d 8.50(d, J¼ 1.5 Hz,1H, AreH), 8.02e7.85 (m, 3H, AreH), 7.59 (t, J¼ 7.5 Hz,2H, AreH), 7.48 (t, J ¼ 7.5 Hz, 1H, AreH), 7.36 (t, J ¼ 7.5 Hz, 1H, AreH), 5.24 (s, 2H, AreCH2e), 4.31 (q, J ¼ 6.7 Hz, 2H, eOCH2e), 1.33 (t,J ¼ 6.7 Hz, 3H, eCH3). 13C NMR(75 MHz, CDCl3) d 166.2 (CdbndO),156.5, 155.9, 148.2, 127.3, 125.2, 125.0, 124.7, 123.9, 122.8, 120.7,117.9, 111.8, 111.6, 62.4 (AreCH2), 50.9 (eOCH2), 14.0 (eCH3). IR(KBr) 3132, 3103, 2924, 2852, 1885, 1755 (CdbndO), 1459, 1373,1203, 841, 751 cm�1. MS (ESI) m/z 322 [M þ H]þ; HRMS (ESI) calcdfor C18H16 N3O3: 322.1186, found: 322.1186.

4.3.2. 4-(4-(Dibenzo[b,d]furan-2-yl)-1H-1,2,3-triazol-1-yl)butan-1-ol 5b

White solid. M.p. 127e129 �C; 1H NMR (500 MHz, CDCl3) d 8.45(s, 1H, AreH), 7.96 (d, J ¼ 6.8 Hz, 1H, AreH), 7.89e7.73 (m, 2H, AreH), 7.57 (t, J ¼ 8.3 Hz, 2H, AreH), 7.45 (t, J ¼ 7.5 Hz, 1H, AreH), 7.34(t, J ¼ 7.5 Hz, 1H, AreH), 4.47 (t, J ¼ 6.0 Hz, 2H, AreCH2e), 3.72 (t,J ¼ 5.3 Hz, 2H, eOCH2e), 2.18e2.00 (m, 2H, eCH2e), 1.74e1.55 (m,

T. Yempala et al. / European Journal of Medicinal Chemistry 71 (2014) 160e167 165

2H, eCH2e). 13C NMR (75 MHz, CDCl3) d 156.5, 155.9, 147.7, 127.3,125.4, 124.9, 123.9, 122.8, 120.7, 119.3, 117.8, 111.8, 111.6, 61.7 (AreCH2e), 50.1 (eOCH2e), 29.2 (eCH2e), 26.9 (eCH2e). IR (KBr) 3381(eOH), 3143, 2926, 2860, 1586, 1473, 1447, 1200, 1061, 842,745 cm�1. MS (ESI) m/z 308 [M þ H]þ; HRMS (ESI) calcd for C18H18N3O2: 308.1393, found: 308.1394.

4.3.3. 1-Benzyl-4-(dibenzo[b,d]furan-2-yl)-1H-1,2,3-triazole 5cWhite solid. M.p. 184e186 �C; 1H NMR (300 MHz, CDCl3) d 8.45

(d, J ¼ 1.5 Hz, 1H, AreH), 7.96 (d, J ¼ 7.7 Hz, 1H, AreH), 7.84 (dd,J¼ 1.6 and 8.3 Hz,1H, AreH), 7.72 (s,1H, AreH), 7.57 (dd, J¼ 2.2 and8.5 Hz, 2H, AreH), 7.47 (t, J ¼ 7.3 Hz, 2H, AreH), 7.43e7.31 (m, 5H,AreH), 5.57 (s, 2H, AreCH2e). 13C NMR (75 MHz, CDCl3) d 156.5,155.9, 148.2, 134.6, 129.1, 128.7, 128.0, 127.4, 125.4, 125.0, 124.7,123.9, 122.8, 120.8, 119.2, 117.9, 111.8, 111.7, 54.2 (AreCH2e). IR (KBr)3142, 2881, 1682, 1538, 1462, 1344, 1239, 1098, 1027, 856, 794 cm�1.MS (ESI) m/z 326 [M þ H]þ; HRMS (ESI) calcd for C21H16N3O:326.1287, found: 326.1291.

4.3.4. 4-(Dibenzo[b,d]furan-2-yl)-1-(3-methoxybenzyl)-1H-1,2,3-triazole 5d

White solid. M.p. 91e93 �C; 1H NMR (500 MHz, CDCl3) d 8.45 (s,1H, AreH), 7.97 (d, J ¼ 7.9 Hz, 1H, AreH), 7.84 (d, J ¼ 7.9 Hz, 1H, AreH), 7.73 (s, 1H, AreH), 7.57 (d, J ¼ 8.9 Hz, 2H, AreH), 7.46 (t,J ¼ 7.9 Hz, 1H, AreH), 7.38e7.28 (m, 2H, AreH), 6.95e6.82 (m, 3H,AreH), 5.57 (s, 2H, AreCH2e), 3.80 (s, 3H, eOCH3). 13C NMR(75MHz, CDCl3) d 160.1, 156.5,155.9,148.2, 136.0, 130.1, 127.3, 125.5,125.0, 124.7, 123.9, 122.8, 120.7, 120.2, 117.9, 114.1, 113.6, 111.8, 111.6,55.2 (AreCH2e), 54.1 (eOCH3). IR (KBr) 3418, 2927, 2095, 1583,1437, 1259, 1194, 1047, 846, 751 cm�1. MS (ESI) m/z 356 [M þ H]þ;HRMS (ESI) calcd for C22H18N3O2: 356.1393, found: 356.1397.

4.3.5. 4-(Dibenzo[b,d]furan-2-yl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole 5e

Pale white solid. M.p. 121e123 �C; 1H NMR (300 MHz, CDCl3)d 8.45 (d, J ¼ 1.5 Hz, 1H, AreH), 8.04e7.91 (m, 1H, AreH), 7.84 (dd,J ¼ 1.7 and 8.4 Hz, 1H, AreH), 7.68 (s, 1H, AreH), 7.57 (d, J ¼ 8.3 Hz,2H, AreH), 7.40e7.24 (m, 4H, AreH), 6.93 (d, J ¼ 8.4 Hz, 2H, AreH),5.54 (s, 2H, AreCH2e), 3.82 (s, 3H, eOCH3). 13C NMR (75 MHz,CDCl3) d 159.8, 156.5, 155.9, 148.1, 129.6, 127.3, 126.5, 125.5, 124.9,124.6, 123.7, 122.8, 120.7, 119.0, 117.8, 114.4, 111.8, 111.6, 55.2 (AreCH2e), 53.7 (eOCH3). IR (KBr) 3053, 2923, 2940, 1896, 1611, 1535,1446, 1201, 1181, 803, 741 cm�1. MS (ESI) m/z 356 [M þ H]þ; HRMS(ESI) calcd for C22H18 N3O2: 356.1393, found: 356.1398.

4.3.6. 1-(4-Bromobenzyl)-4-(dibenzo[b,d]furan-2-yl)-1H-1,2,3-triazole 5f

White solid. M.p. 125e127 �C; 1H NMR (300 MHz, CDCl3) d 8.45(s, 1H, AreH), 7.96 (d, J ¼ 8.3 Hz, 1H, AreH), 7.84 (dd, J ¼ 1.5 and8.3 Hz, 1H, AreH), 7.72 (s, 1H, AreH), 7.62e7.43 (m, 5H, AreH),7.40e7.32 (m, 1H, AreH), 7.20 (d, J ¼ 8.3 Hz, 2H, AreH), 5.50 (s, 2H,AreCH2e). 13C NMR (75 MHz, CDCl3) d 156.5, 156.0, 148.5, 133.6,132.3, 129.6, 127.4, 125.3, 124.9, 124.7, 123.9, 122.9, 122.8, 120.8,119.1, 117.9, 111.9, 111.7, 53.5 (AreCH2e). IR (KBr) 3082, 2925, 1916,1589, 1443, 1339, 1201, 1070, 1013, 843, 746 cm�1. MS (ESI) m/z 404[M þ H]þ; HRMS (ESI) Calcd for C21H15Br N3O: 404.0393, found:404.0398.

4.3.7. 1-(3-Bromobenzyl)-4-(dibenzo[b,d]furan-2-yl)-1H-1,2,3-triazole 5g

White solid. M.p. 143e145 �C; 1H NMR (300 MHz, CDCl3) d 8.45(d, J ¼ 1.5 Hz, 1H, AreH), 8.00e7.92 (m, 1H, AreH), 7.85 (dd, J ¼ 1.5and 8.3 Hz, 1H, AreH), 7.75 (s, 1H, AreH), 7.57 (dd, J ¼ 3.0 and8.3 Hz, 2H, AreH), 7.53e7.42 (m, 3H, AreH), 7.39e7.30 (m, 1H, AreH), 7.29e7.23 (m, 2H, AreH), 5.57 (s, 2H, AreCH2e). 13C NMR

(75 MHz, CDCl3) d 156.5, 156.0, 148.4, 136.8, 131.9, 130.9, 130.6,127.4, 126.5, 125.0, 124.7, 123.9, 123.0, 122.8,120.7, 119.2, 117.9, 111.8,111.6, 53.4 (AreCH2e). IR (KBr) 3056, 2923, 1775, 1594, 1474, 1440,1200, 1069, 841, 749 cm�1. MS (ESI) m/z 404 [M þ H]þ; HRMS (ESI)calcd for C21H15BrN3O: 404.0393, found: 404.0398.

4.3.8. 4-(Dibenzo[b,d]furan-2-yl)-1-(4-nitrobenzyl)-1H-1,2,3-triazole 5h

Light yellow solid. M.p. 156e158 �C; 1H NMR (300 MHz, CDCl3)d 8.47 (d, J ¼ 1.7 Hz, 1H, AreH), 8.26 (d, J ¼ 8.6 Hz, 2H, AreH), 7.98(d, J¼ 7.5 Hz,1H, AreH), 7.86 (dd, J¼ 1.7 and 8.4 Hz,1H, AreH), 7.81(s, 1H, AreH), 7.63e7.56 (m, 2H, AreH), 7.53e7.44 (m, 3H, AreH),7.37 (td, J ¼ 1.1 and 7.5 Hz, 1H, AreH), 5.73 (s, 2H, AreCH2e). 13CNMR (75 MHz, CDCl3) d 155.7, 155.0, 147.1, 146.8, 143.3, 128.9, 127.7,125.8, 124.9, 124.0, 123.8, 123.3, 123.1, 121.6, 121.2, 117.7, 112.0, 111.6,52.1 (AreCH2e). IR (KBr) 3130, 3088, 2924, 1603, 1515 (NeO), 1451,1346 (NeO),1195, 840, 750 cm�1. MS (ESI)m/z 371 [MþH]þ; HRMS(ESI) calcd for C21H15N4O3: 371.1138, found: 371.1149.

4.3.9. Methyl 4-((4-(dibenzo[b,d]furan-2-yl)-1H-1,2,3-triazol-1-yl)methyl)benzoate 5i

White solid. M.p. 177e179 �C; 1H NMR (300 MHz, CDCl3) d 8.47(s, 1H, AreH), 8.08 (d, J ¼ 7.5 Hz, 2H, AreH), 7.99 (d, J ¼ 7.5 Hz, 1H,AreH), 7.86 (d, J ¼ 8.3 Hz, 1H, AreH), 7.76 (s, 1H, AreH), 7.66e7.55(m, 2H, AreH), 7.53e7.32 (m, 4H, AreH), 5.68 (s, 2H, AreCH2e),3.93 (s, 3H, eOCH3). 13C NMR (75 MHz, CDCl3) d 166.3 (CdbndO),156.5, 156.0, 148.5, 139.4, 130.5, 130.3, 127.7, 127.4, 125.3, 125.0,124.7, 123.9, 122.8, 120.8, 119.3, 117.9, 111.9, 111.7, 53.7 (AreCH2e),52.2 (eOCH3). IR (KBr) 3077, 2923, 2852,1716 (CdbndO),1459,1277,1191, 840, 725 cm�1. MS (ESI) m/z 384 [M þ H]þ; HRMS (ESI) calcdfor C23H18 N3O3: 384.1342, found: 384.1351.

4.3.10. 4-(Dibenzo[b,d]furan-2-yl)-1-(1-p-tolylethyl)-1H-1,2,3-triazole 5j

White solid. M.p. 91e93 �C; 1H NMR (300 MHz, CDCl3) d 8.44(s, 1H, AreH), 7.97 (d, J ¼ 7.3 Hz, 1H, AreH), 7.84 (dd, J ¼ 1.5 and8.4 Hz, 1H, AreH), 7.68 (s, 1H, AreH), 7.56 (d, J ¼ 8.3 Hz, 2H, AreH), 7.47 (t, J ¼ 7.1 Hz, 1H, AreH), 7.36 (t, J ¼ 7.5 Hz, 1H, AreH),7.30e7.16 (m, 4H, AreH), 5.87 (q, J ¼ 6.9 Hz, 1H, AreCHe), 2.36 (s,3H, AreCH3), 2.04 (d, J ¼ 7.1 Hz, 3H, eCH3). 13C NMR (75 MHz,CDCl3) d 156.4, 155.8, 147.6, 138.3, 136.7, 129.6, 127.2, 126.4, 125.6,124.9, 124.6, 123.9, 122.7, 120.7, 120.4, 118.0, 117.8, 111.7, 111.6, 60.0(AreCHe), 21.2 (AreCH3), 21.0 (eCH3). IR (KBr) 3125, 2923, 2854,1892, 1589, 1514, 1447, 1359, 1202, 1125, 1019, 822, 745 cm�1. MS(ESI) m/z 354 [M þ H]þ; HRMS (ESI) calcd for C23H20 N3O:354.1600, found: 354.1603.

4.3.11. 4-(Dibenzo[b,d]furan-2-yl)-1-(1-(4-methoxyphenyl)ethyl)-1H-1,2,3-triazole 5k

White solid. M.p. 89e91 �C; 1H NMR (300 MHz, CDCl3) d 8.44 (d,J ¼ 1.3 Hz, 1H, AreH), 8.05e7.91 (m, 1H, AreH), 7.84 (dd, J ¼ 1.8 and8.6 Hz, 1H, AreH), 7.66 (s, 1H, AreH), 7.57 (d, J ¼ 8.3 Hz, 2H, AreH),7.51e7.42 (m, 1H, AreH), 7.40e7.28 (m, 3H, AreH), 6.92 (d,J¼ 8.6 Hz, 2H, AreH), 5.86 (q, J¼ 6.9 Hz,1H, AreCHe), 3.81 (s, 3H,eOCH3), 2.03 (d, J ¼ 6.9 Hz, 3H, eCH3). 13C NMR (75 MHz, CDCl3)d 156.4, 155.8, 147.5, 131.5, 127.8, 127.3, 125.3, 124.4, 124.6, 123.8,122.7, 120.7, 118.0, 117.8, 114.2, 111.7, 111.5, 59.7 (eOCH3), 21.1 (eCH3). IR(KBr) 3382, 3090, 2935, 2258, 1751, 1610, 1513, 1442, 1214,1030, 839, 727 cm�1. MS (ESI) m/z 370 [M þ H]þ; HRMS (ESI) calcdfor C23H20N3O2: 370.1550, found: 370.1557.

4.3.12. 4-(Dibenzo[b,d]furan-2-yl)-1-(1-(4-nitrophenyl)ethyl)-1H-1,2,3-triazole 5l

Light yellow syrup; 1H NMR (300 MHz, CDCl3) d 8.47 (s, 1H, AreH), 8.25 (d, J ¼ 8.3 Hz, 2H, AreH), 7.98 (d, J ¼ 7.5 Hz, 1H, AreH),

T. Yempala et al. / European Journal of Medicinal Chemistry 71 (2014) 160e167166

7.91e7.76 (m, 2H, AreH), 7.64e7.55 (m, 2H, AreH), 7.53e7.43 (m,3H, AreH), 7.36 (t, J ¼ 7.5 Hz, 1H, AreH), 5.99 (q, J ¼ 6.7 Hz, 1H, AreCHe), 2.11 (d, J ¼ 7.5 Hz, 3H, eCH3). 13C NMR (75 MHz, CDCl3)d 156.4, 155.9, 148.1, 147.6, 146.9, 127.4, 127.2, 126.0, 125.1, 124.9,124.7, 124.1, 122.8, 120.7, 118.7, 118.2, 117.8, 111.8, 111.6, 59.4 (AreCHe), 21.1 (eCH3).IR (Neat) 2924, 2853, 1605, 1519 (NeO), 1446,1346 (NeO), 1159, 1105, 856, 748, 716 cm�1. MS (ESI) m/z 385[M þ H]þ; HRMS (ESI) calcd for C22H17N4O3: 385.1295, found:385.1308.

4.3.13. 4-(Dibenzo[b,d]furan-2-yl)-1-(1-(dibenzo[b,d]furan-2-yl)ethyl)-1H-1,2,3-triazole 5m

White solid. M.p. 125e127 �C; 1H NMR (300 MHz, CDCl3) d 8.44(d, J ¼ 1.5 Hz, 1H, AreH), 8.01e7.91 (m, 3H, AreH), 7.85 (dd, J ¼ 1.5and 8.3 Hz, 1H, AreH), 7.72 (s, 1H, AreH), 7.63e7.54 (m, 4H, AreH),7.52e7.41 (m, 3H, AreH), 7.39e7.29 (m, 2H, AreH), 6.07 (q,J ¼ 7.5 Hz, 1H, AreCHe), 2.17 (d, J ¼ 6.7 Hz, 3H, eCH3). 13C NMR(75MHz, CDCl3) d 156.5,156.4,155.8,147.7, 134.3,127.5, 127.2, 125.6,124.9, 124.7, 124.5, 123.8, 123.5, 122.8, 122.7, 121.2, 121.0, 120.6,118.8, 118.1, 117.7, 112.0, 111.7, 111.6, 111.5, 60.2 (AreCHe), 21.5 (eCH3). IR (KBr) 3435, 2924, 1876, 1586, 1447, 1242, 1195, 1119, 1021,811, 743 cm�1. MS (ESI) m/z 430 [M þ H]þ; HRMS (ESI) calcd forC28H20N3O2: 430.15500, found: 430.15573.

4.3.14. 4-(Dibenzo[b,d]furan-2-yl)-1-(1-(dibenzo[b,d]thiophen-2-yl)ethyl)-1H-1,2,3-triazole 5n

White solid. M.p. 95e97 �C; 1H NMR (300 MHz, CDCl3) d 8.44(s, 1H, AreH), 8.23e8.09 (m, 2H, AreH), 8.00e7.82 (m, 4H, AreH), 7.73 (s, 1H, AreH), 7.62e7.40 (m, 6H, AreH), 7.33 (t,J ¼ 7.5 Hz, 1H, AreH), 6.06 (q, J ¼ 6.7 Hz, 1H, AreCHe), 2.18 (d,J ¼ 6.7 Hz, 3H, eCH3). 13C NMR (75 MHz, CDCl3) d 156.5, 155.9,147.8, 139.8, 139.6, 136.2, 134.8, 127.3, 125.6, 125.0, 125.0, 124.5,123.9, 122.8, 122.8, 121.6, 120.7, 119.6, 118.2, 117.8, 111.7, 111.6,60.3 (AreCHe), 21.4 (eCH3). IR(KBr) 3119, 2923, 1639, 1468,1440, 1323, 1192, 1021, 841, 813, 758 cm�1. MS (ESI) m/z 446[M þ H]þ; HRMS (ESI) calcd for C28H20 N3OS: 446.1321, found:446.1322.

4.4. Antitubercular evaluation

Two-fold serial dilutions (50.0, 25.0, 12.5, 6.25, 3.13, 1.56, 0.78and 0.4 mg/mL) of each test compounds 5aen and drugs wereprepared and incorporated into Middlebrook 7H11 agar mediumwith OADC Growth Supplement. Inoculum of M. tuberculosis H37RvATCC 27294was prepared from freshMiddlebrook 7H11 agar slantswith OADC (oleic acid, albumin, dextrose and catalase; Difco)growth supplement adjusted to 1 mg/mL (wet weight) in Tween 80(0.05%) saline diluted to 10�2 to give a concentration of w107 cfu/mL. A 5 mL amount of bacterial suspension was spotted into 7H11agar tubes containing 10-fold serial dilutions of drugs per mL. Thetubes were incubated at 37 �C, and final readings were recordedafter 28 days. This method is similar to that recommended by theNational Committee for Clinical Laboratory Standards for thedetermination of MIC in triplicate.

4.5. Cytotoxicity

All the new compounds synthesized were further examined forcytotoxicity against Human Embryonic Kidney Cell-line 293T (HEK-293T) cells at the concentration of 50 mg/mL (Table 1). After 72 h ofexposure, viability was assessed on the basis of cellular conversionof MTT into a formazan product using the Promega Cell Titer 96non-radioactive cell proliferation assay. The selectivity index (SI)values were determined based on the approximation of IC50values.

Acknowledgements

Authors are thankful to Dr. M. Lakshmi Kantham, Director andDr. V. Jayathirtha Rao, Head, Crop Protection Chemicals Division,CSIR-IICT, Hyderabad, INDIA for their continuous encouragement,support and financial assistance through CSIR-12th FYP (ORIGIN,CSC 0108; DENOVA, CSC0205 & INTELCOAT, CSC0114) and OSDD(HCP0001) projects. TY is thankful to CSIR for SRF.

Appendix A. Supplementary data

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejmech.2013.10.082.

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