Introduction

Tuberculosis (TB) is a life-threatening syndrome that emerges as a global health issue, due to this second most important reason of death among the infectious diseases after HIV [1]. World Health Organization (WHO) report, expected 2 million deaths occur per year and 10 million latest cases of TB [2]. Additional > 30 million lives will be claimed by tubercular between 2000 and 2020 [3]. Mycobacterium tuberculosis (MTB) strains together with co-infection with HIV is another disadvantage of tuberculosis [4]. The M. BovisBacille Calmette-Guerin (M. Bovis BCG) injection has been among the most frequently administrated worldwide [5] and the only attenuated live vaccine [6]. In addition to this, totally drug-resistant TB (TDR-TB) has recently arisen which is resistant to all clinical drugs [7]. Delamanid (OPC-67683) and bedaquiline (TMC207) are the two drugs agreed with by the US FDA for the multi-drug-resistant tuberculosis (MDR-TB) treatment [8, 9]; however there are no present medicinal drugs under clinical trials. Due to this, there is an insistent need for novel, safe and effective anti-mycobacterial drugs which will efficiently treat XDR and MDR tuberculosis.

1,2,3-Triazole, a five-membered N-heterocyclic compounds, is a very well-known bioactive molecules constructed by the copper-catalyzed azide-alkyne by cycloaddition(CuAAC) reaction, which is popular as a click chemistry reaction [10]. Among the various 1,2,3- triazoles, 1,4-disubstituted-1,2,3-triazole derivatives have been found to have broad spectrum applications and is used in numerous fields including material science [11], polymer chemistry [12], and drug discovery [13]. Literature survey revealed that, 1,2,3-triazole-based molecules display various therapeutic activities such as anti-inflammatory [14], antibacterial [15], anti-fungal [16], anti-convulsant [17], antiproliferative [18], antitubercular [19,20,21,22], anti-HIV [23] and anticancer [24]. Some molecular structures of antitubercular agents bearing 1,2,3-triazolyl scaffolds are shown in Fig. 1.

Fig. 1
figure 1

1,2,3-triazole-incorporated bioactive molecules

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Thiazolidinediones is a privileged five-membered heteroatomic compound containing sulfur, oxygen and nitrogen as heteroatoms. Thiazolidinediones and its derivatives offer high degree of structural diversity that has proven their usefulness for searching new therapeutic leads. Thiazolidinediones are well-known class of biological active substances that became basic for the whole number of innovative medicinal agents, such as anticancer activity [25], anti-inflammatory [26], antimicrobial [27], anti-mycobacterial agents [28], antitrypanosomal/antiviral [29], inhibitors of protein tyrosine phosphatase 1B (PTP1B) [30], estrogen-related receptor 1 [31], cyclooxygenase-2 (COX-2) [32], pim kinase 1 [33], aldose reductase (ALR2) [34], hypoglycemic [35], murD ligase [36], DNA sensors [37], pim-1 and pim-2 protein kinases [38], leishmania pteridine reductase 1 [39] and PI3Ka/MEK1 [40].

The copper-catalyzed 1,3-dipolar cycloaddition of organic azides and terminal alkynes has been reported by using various methods [41, 42] and environmentally benign catalyst such as Fe3O4/silicalite-1/PVA/Cu(I) nanocomposites [43], Cu2O/Agar@Fe3O4 [44], [bmim][BF4] [45, 46], [Bmim]OH [47], (SNILCu(II)) [48], ([Hmim]TFA) [49] and [C8dabco][N(CN)2] [50] and DBU based ionic liquids [51]. The design of 1,2,3-triazoles-incorporated 2,4 thiazolidinedione conjugates are mainly divided into three different sections as depicted in Fig. 2. The first one is the main backbone of the design strategy that is 2,4-thiazolidinediones bioactive unit. It helps to enhance the pharmacophoric properties as they exhibits drug-like properties. The second backbone is showing 1,2,3-triazoles with amide and ethereal linkages which is responsible for biological activity. Last of all, the aryl group part with diverse substitutional unit is responsible for the lipophilicity control while contributing highly potent pharmacological part due to existence of various functional groups.

Fig. 2
figure 2

Molecular design approach for the preparation of 1,2,3-triazoles bearing 2,4 thiazolidinedione moiety

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Considering the therapeutic significance of the above, herein, we have planned and synthesized 1,2,3-triazolesbearing 2,4 thiazolidinedione by accumulating amide linked substituted variant unit, 1,2,3-triazoles and 2,4 thiazolidinedione moiety in a single molecular framework with hope to obtain better antitubercular agents with reduced side effects.

Results and discussion

Chemistry

There are numerous reports on the synthesis of 1,4-disubstituted- 1,2,3-triazoles bearing amide functionality and displaying broad spectrum of biological activities [52] recently, Ferroni et al. developed triazoles as nonsteroidal anti-androgens for prostate cancer treatment [53]. On the basis of these findings, we designed small 1,2,3-triazoles with amide linkage in their structures.

Initially, the starting materials, 4-(prop-2-yn-1-yloxy)benzaldehyde2 were prepared from commercially available 4-hydroxybenzaldehyde 1 and propargyl bromide in the presence of K2CO3 as a base in N,N-dimethylformamide (DMF) afforded 4-(prop-2-yn-1-yloxy)benzaldehyde in excellent yield (93%). In the next step cyclocondensation reaction of 4-(prop-2-yn-1-yloxy)benzaldehyde 2 with 2,4-thiazolidinedione 3 using sodium acetate as a base in acetic acid to give 88% yield of 5-(4-(ethynyloxy)benzylidene)thiazolidine-2,4-dione 4. The synthesis of 2-Azido-N-phenylacetamides [54] 7a–l from their corresponding anilines via chloroacetylation using chloroacetyl chloride, followed by nucleophilic substitution with sodium azide in good to excellent yields (84–95%) (Scheme 1).

Scheme 1
scheme 1

Synthesis of alkynes 2 and 2-azido-N-phenylacetamides 5a–l

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The Huisgen CuAAC reaction has been performed on 5-(4(ethynyloxy)benzylidene)thiazolidine-2,4-dione 4with 2-Azido-N-phenylacetamides 7a-l in the presence of Cu(OAc)2 in t-BuOH–H2O (3:1) at room temperature for 20 h affording 2-(4-((4-((2,4-dioxothiazolidin-5 ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-phenylacetamide derivatives 8a-l in good to excellent (72–89%) yield (Scheme 2).The synthetic sequence is depicted in Scheme 2.

Scheme 2
scheme 2

Synthesis of 1,2,3-triazoles-incorporated 2,4 thiazolidinedione conjugates 8a–l

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Comparison of Cu(OAc)2 catalyst with previous reported protocol

We have also compare the Cu(OAc)2 catalyst with other reported catalysts for the preparation of 1,2,3-triazoles-incorporated 2,4 thiazolidinedione derivative (Table 1, entry 9).

Table 1 Comparative catalytic performance of the Cu(OAc)2 with other previously reported catalysts
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All the newly synthesized compounds were characterized by 1H NMR, 13C NMR and HRMS techniques. In the 1H NMR spectra of representative compound 8a displays two sharp singlet at δ 5.30 and 5.36 ppm as a methylene protons of –CH2–CO– and –CH2–O–, respectively. The singlet peak appeared at 7.97 due to the –CH = C proton. The singlet observed at δ 8.30 ppm due to proton present on the triazole ring and singlet at 10.49 and 9.41 ppm assigned for the –CO–NH– of amide and -CO–NH–CO of 2,4 thiazolidinedione ring. In 13CNMR spectra, the peaks appears at δ 48.91 ppm shows the methylene carbon connected to the nitrogen of triazole ring and peak at 56.93 ppm assigned for methylene carbon near to oxygen, peak at 143.31 ppm for the triazole quaternary carbon and peak at 161.25, 166.90, 169.55 ppm indicating carbonyl carbon for the –CO–NH- of amide and –CO–NH–CO of 2,4 thiazolidinedione ring in compound 8a. In addition the formation of compound 8a was confirmed by the HRMS spectrum and the calculated [M + H]+ was 436.3442 and in HRMS, the [M + H]+ observed peak at 436.3420.

In the first step reaction of alkyne to the Cu(I) metal to form a Cu(I)-alkyne π-complex (A). The generation of the Cu(I)-acetylide species permits the subsequent displacement of the ligand with azide and results in a dimeric copper species (B). Azide complexation induces the nucleophile attack at the N-3 with the C-4 acetylide. The resulting metallocycle (C) give the copper-triazole complex (D). Finally, protonation of the copper-triazole complex by water and disassociation of the labile copper complex gives the 1,4-disubstituted 1,2,3-trazole (E) and regeneration of catalyst (Fig. 3).

Fig. 3
figure 3

Plausible mechanisms for the CuAAC reaction

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Biological evaluation

In vitro Anti-mycobacterial activity evaluation

The novel synthesized 1,2,3-triazoles-incorporated 2,4 thiazolidinedione conjugates (8a–l) were evaluated for in vitro anti-mycobacterial activity against M. bovis BCG (ATCC 35743) and MTB H37Ra (ATCC 25177) in liquid medium [63]. We have explored the eminent XTT Reduction Menadione assay (XRMA) of anti-mycobacterial screening protocol employing first-line anti-mycobacterial rifampicin drug as a standard reference and the IC50 and IC90 values are presented in Table 2.

Table 2 Anti-mycobacterial activity of the 1,2,3-triazoles-incorporated 2,4 thiazolidinedione conjugates
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The 1,2,3-triazoles-incorporated 2,4 thiazolidinedione conjugates 8g, 8h, 8j and 8l shows promising anti-mycobacterial activity against M. bovis BCG and MTB strain with IC90 range 1.20–2.70 and 1.24–2.65 µg/mL, respectively. However, the remaining 1,2,3-triazoles-incorporated 2,4-thiazolidinedione derivatives 8a, 8b, 8c, 8d, 8e, 8f, 8i and 8 k exhibit lower anti-mycobacterial activity against M. bovis BCG and MTB strain with IC90 = > 30 µg/mL with reference to rifampicin as a standard reference.

Structure activity relationship (SAR)

According to the data, the 1,2,3-triazoles-incorporated 2,4 thiazolidinedione conjugates exhibits promising anti-mycobacterial activity and the outcomes are presented in Table 1. In compounds (8a–l), the 2,4 thiazolidinedione moiety attached to aryl ring is constant and modifications in the amides aryl unit shows difference in the anti-mycobacterial activity against the M. bovis BCG and MTB strain. Firstly, we will discuss the anti-mycobacterial activity of synthesized 1,2,3-triazoles-incorporated 2,4 thiazolidinedione conjugates against M. bovis BCG strain. From the series (8a–l), compound 8a without any substituent on aryl ring displays lesser antitubercular activity with IC90 value > 30 µg/mL against M. bovis BCG strain in comparison with rifampicin as a standard and results are displayed in Table 1. Compounds 8b in which (R1 = -methyl), 8c (R2 = -methyl) and8c in which (R3 = -methyl) exhibit less antitubercular activity as compared rifampicin against M. bovis BCG strain with IC90 values 30 > µg/mL. Introduction of methoxy group in aryl ring compound 8e (R1 = -methoxy) and 8f (R2 = -methoxy) displays less active against M. bovis BCG strain with IC90 value > 30 μg/mL as compared to standard rifampicin drug. Surprisingly, methoxy group at para position in compound 8g (R3 = -methoxy) exhibit excellent anti-mycobacterial activity against M. bovis BCG strain with IC90 value 2.70 μg/mL compared to rifampicin drug. Introduction of chloro group in aryl ring compound 8h (R1 = -chloro) and 8j (R3 = -chloro) displays promising antitubercular activity against M. bovis BCG strain with IC90 value 2.05 and 1.20 μg/mL, respectively.

When chloro group R2 position in compound 8i (R2 = -chloro) are less active against M. bovis BCG strain with IC90 value > 30 μg/mL. When nitro group present at ortho position 8k (R2 = -NO2) does not show any antitubercular activity against the M. bovis BCG strain. In compounds 8l (R3 = -NO2) is highly potent against the M. bovis BCG strain with 1.24 μg/mL compared with rifampicin as a standard. Hence, among all the synthesized compounds (8a–l), compounds 8g, 8, 8j and 8 l, displays promising anti-mycobacterial activity against M. bovis BCG and the results are summarized in Table 2.

Further, we screened the antitubercular activity against the MTB strain. From the 1,2,3-triazoles-incorporated 2,4 thiazolidinedione conjugates series (8a–l), compound 8a without any substituent on aryl ring showed lower anti-mycobacterial activity with IC90 value > 30 µg/mL against MTB strain as compared to rifampicin as a reference and the results are shown in Table 2. Compounds 8b in which (R1 = -methyl), 8c (R2 = -methyl) and 8d in which (R3 =-methyl) exhibits less active against MTB strain with IC90 values 30 > µg/mL. It is observed that methoxy group in compound 8e (R1 = -methoxy) and 8f (R2 = -methoxy) exhibit lesser activity against MTB strain with IC90 value that is > 30 μg/mL as compared with rifampicin drug. In compound 8g (R3 = -methoxy) exhibit promising tubercular activity against MTB strain with IC90 value that is 2.65 μg/mL as compared with rifampicin drug.

Introduction of chloro group in aryl ring compound 8h (R1 = -chloro) and 8j (R3 = -chloro) are highly potent against MTB strain with IC90 value 2.35 and 2.04 μg/mL, respectively. When chloro group R2 position in compound 8i (R3 = -chloro) decreasing in antitubercular activity against MTB strain with IC90 value > 30 μg/mL compared to rifampicin drug. Replacing the chloro group by nitro group 8k (R2 = -nitro) exhibits lower activity with IC90 value > 30 µg/mL against MTB strain. Introduction of nitro group at para position 8l (R3 = -nitro) exhibits promising anti-mycobacterial activity with IC90 value 2.41 µg/mL against MTB strain. Hence, among all the synthesized compounds 8a–l, compounds 8 g, 8h, 8j and 8l showed excellent antitubercular activity against MTB and the results are disclosed in Table 2.

Cytotoxicity

Highly active 1,2,3-triazoles-incorporated 2,4 thiazolidinedione conjugates 8g, 8h, 8j and 8l were further screened against different human cancer cells (MCF-7, HCT 116 and A549) to determine their toxicity (Table 3) [64]. The cytotoxicity results of these compounds indicate they are highly potent and specific inhibitors against M. bovis BCG and MTB strain with GI50/GI90 (> 100 µg/mL).Thus, all the most active compounds were relatively non-toxic against MCF-7, HCT 116 and A549 cell lines with (GI50/GI90) of > 100.

Table 3 In vitro cytotoxicity of selected 2,4 thiazolidinedione conjugates
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Selectivity index

Selectivity index indicates that the highly potent compound is only active against mycobacteria but it is non-toxic against host human cell lines. Compound 8g, 8h, 8j and 8l showed very high SI, which is a good inhibitor of M. bovis BCG strain and results are described in Table 4.

Table 4 Selectivity index against dormant M. bovis BCG and MTB
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The compound 8g, 8h, 8j and 8l showed very higher selectivity index, which is actually good inhibitor of MTB strain and detail study are shown in Table 4. According to a study on the drug susceptibility of TB, antitubercular activity was considered to be specific when the selectivity index was > 10 [65]. This study suggested that, compounds 8g, 8h, 8j and 8l display highest selectivity index > 10, suggesting that these compounds act as a highly potent anti-mycobacterial agent, and thus they should be modification for next level.

Antibacterial activity

To determine the specificity of most potent compounds 8g, 8h, 8j and 8l were evaluated for their antibacterial activity against four bacteria strains (Gram-negative strains: P. flurescense, E. coli, Gram-positive strains: B. subtillus, S. aureus). All the active compounds exhibited higher specificity toward MTB, BCG strains and it is inactive against bacterial strains and detailed study is described in Table 5.

Table 5 Antibacterial activity IC90 (µg/mL)
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Experimental

Methods and material

All reagents were purchased from Merck and Spectrochem used without further purification. Melting points of all the synthesized compounds were determined in open capillary tube and are uncorrected. 1H NMR spectra were recorded on a Bruker DRX-400 MHz NMR spectrometer and 13C NMR spectra were recorded on a Bruker DRX-100 MHz NMR in DMSO-d6 using tetramethylsilane (TMS) as an internal standard and chemical shifts are in δ ppm. High-resolution mass spectra (HRMS) were recorded on Agilent 6520 (QTOF) ESI-HRMS instrument. The purity of each of the compound was checked by thin-layer chromatography (TLC) using silica gel, (60F254) and visualization was accomplished by iodine/ultraviolet light.

Typical experimental procedure for the synthesis of 4-(prop-2-yn-1-yloxy)benzaldehyde (2)

To the stirred solution of appropriate 4-hydroxybenzaldehyde 1 (20 mmol) in N,N-dimethylformamide (DMF) (20 mL), K2CO3 (24 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, which results into the oxyanion. To this mixture, propargyl bromide (20 mmol) was added and stirred for 4 h. The progress of the reaction was monitored by TLC using ethyl acetate/hexane as a solvent system. The reaction was quenched by crushed ice and extracted in ethyl acetate (20 mL × 3). The combined organic layers wash with brine solution (2 × 15 mL) and dried over NaSO4. The solvent was removed under reduced pressure and used for the further reaction without purification.

General experimental procedure for the synthesis of 5-(4 (ethynyloxy)benzylidene)thiazolidine-2,4-dione (4)

A mixture of 4-(prop-2-yn-1-yloxy)benzaldehyde 2 (0.5 mmol), thiazolidine-2,4-dione 3 (0.5 mmol), and sodium acetate (0.5 mmol) were dissolved in glacial acetic acid (5 mL) and were reflux at 100 °C for 5 h. The progress of the reaction was monitored by TLC using ethyl acetate/hexane as a solvent system. The reaction was quenched by crushed ice and extracted in ethyl acetate (20 mL × 3). The combined organic layers wash with brine solution (2 × 15 mL) and dried over NaSO4. The solvent was removed under reduced pressure. The solvent was removed under reduced pressure and used for the further reaction without purification.

General experimental procedure for the synthesis of substituted 2-(4-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-phenylacetamide (8a–l)

To the stirred solution of 5-(4-(ethynyloxy)benzylidene)thiazolidine-2,4-dione 4 (0.5 mmol), substituted 2-Azido-N-phenylacetamides 7a–l (0.5 mmol) and copper diacetate (CuOAc)2 (20 mol.%) in t-BuOH-H2O (3:1, 8 mL) were added and the resulting mixture was stirred at room temperature for 20 h. The progress of the reaction was monitored by TLC using ethyl acetate/hexane as a solvent system. The reaction mixture was quenched with crushed ice and extracted with ethyl acetate (2 × 15 mL). The organic extracts were washed with brine solution (2 × 15 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford the corresponding crude compounds. The obtained crude compounds were recrystallized using DMF.

2-(4-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-phenylacetamide (8a)

Compound 8a was obtained via 1,3-dipolar cycloaddition reaction between alkyne 4 and azide 7a for 20 h.yellow solid; Mp: 214-216 °C; Yield: 89%; FT-IR (cm−1): 3267 (N–H stretching), 1728 and 1635 (C=O stretching); 1H NMR (400 MHz, DMSO-d6, δ ppm): 10.62 (s, 1H, NH), 9.41 (s, 1H, NH), 8.30 (s, 1H, triazole), 7.97 (s, 1H, –CH = C), 7.72-7.69 (m, 2H, Ar–H), 7.61-7.58 (m, 2H, Ar–H), 7.40-7.38 (m, 2H, Ar–H), 7.17–7.16 (m, 1H, Ar–H), 7.06–6.99 (m, 3H, Ar–H), 5.36 (s, 2H, –OCH2) and 5.30 (s, 2H, –NCH2CO–); 13C NMR (100 MHz, DMSO-d6, δ ppm): 169.55, 166.90, 161.25, 160.29, 143.31, 135.96, 132.79, 130.93, 130.85, 129.84, 129.38, 127.55, 125.27, 124.16, 56.93 and 48.91; HRMS (ESI-qTOF): Calcd for C21H18N5O4S [M + H]+, 436.3442: found: 436.3420.

2-(4-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(o-tolyl)acetamide (8b)

Compound 8b was obtained via 1,3-dipolar cycloaddition reaction between alkyne 4 and azide 7b for 20 h.yellow solid; Mp: 232–234 °C; Yield: 84%; FT-IR (cm−1): 3250 (N–H stretching), 1732 and 1658 (C=O stretching); 1H NMR (400 MHz, DMSO-d6, δ ppm): 10.49 (s, 1H, NH), 9.40 (s, 1H, NH), 8.26 (s, 1H, triazole), 7.78 (s, 1H, –CH = C), 7.38–7.27 (m, 4H, Ar–H), 7.13–6.92 (m, 4H, Ar–H), 5.36 (s, 2H, –OCH2), 5.17 (s, 2H, –NCH2CO–) and 2.27 (s, 3H, -CH3); 13C NMR (100 MHz, DMSO-d6, δ ppm): 171.32, 168.33, 161.90, 160.38, 143.31, 139.79, 137.09, 135.01, 132.80, 130.94, 130.86, 129.67, 129.46, 127.49, 125.28, 124.20, 121.29, 57.85, 47.70 and 22.39; HRMS (ESI-qTOF): Calcd for C22H20N5O4S [M + H]+, 450.3526: found: 450.3579.

4-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(m-tolyl)acetamide (8c)

Compound 8c was obtained via 1,3-dipolar cycloaddition reaction between alkyne 4 and azide 7c for 20 h.yellow solid; Mp: 240–242 °C; Yield: 82%; FT-IR (cm−1): 3246 (N–H stretching), 1742 and 1636 (C = O stretching); 1H NMR (400 MHz, DMSO-d6, δ ppm): 10.42 (s, 1H, NH), 9.33 (s, 1H, NH), 8.31 (s, 1H, triazole), 7.83 (s, 1H, –CH = C), 7.54 (s, 1H, Ar–H), 7.54–7.42 (m, 2H, Ar–H), 7.37–7.34 (m, 2H, Ar–H), 7.23–7.19 (m, 2H, Ar–H), 6.91–6.89 (m, 1H, Ar–H), 5.35 (s, 2H, –OCH2), 5.29 (s, 2H, –NCH2CO–) and 2.27 (s, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6, δ ppm): 171.35, 167.36, 161.89, 160.35, 143.91, 139.79, 136.15, 133.23, 129.67, 129.63, 129.47, 127.53, 125.80, 124.50, 124.20, 121.57, 115.74, 58.44, 48.91 and 22.10; HRMS (ESI-qTOF): Calcd for C22H20N5O4S [M + H]+, 450.3520: found: 450.3576.

2-(4-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(p-tolyl)acetamide (8d)

Compound 8d was obtained via 1,3-dipolar cycloaddition reaction between alkyne 4 and azide 7d for 20 h.yellow solid; Mp: 248–250 °C; Yield: 86%; FT-IR (cm−1): 3254 (N–H stretching), 1696 and 1641 (C=O stretching); 1H NMR (400 MHz, DMSO-d6, δ ppm): 10.66 (s, 1H, NH), 9.47 (s, 1H, NH), 8.39 (s, 1H, triazole), 7.88 (s, 1H, –CH=C), 7.64–7.62 (m, 2H, Ar–H), 7.53-7.44 (m, 4H, Ar–H), 7.42–7.40 (m, 2H, Ar–H), 5.40 (s, 4H, –OCH2, –NCH2CO–) and 2.28 (s, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6, δ ppm): 169.56, 165.72, 131.20, 157.04, 144.94, 141.62, 139.87, 128.78, 128.29, 127.76, 124.38, 124.20, 124.07, 123.34, 118.80, 58.44, 48.92 and 21.76; HRMS (ESI-qTOF): Calcd for C22H20N5O4S [M + H]+, 450.3552: found: 450.3578.

2-(4-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-methoxyphenyl)acetamide (8e)

Compound 8e was obtained via 1,3-dipolar cycloaddition reaction between alkyne 4 and azide 7e for 20 h. Pale yellow solid; Mp: 204–206 °C; Yield: 81%; FT-IR (cm−1): 3275 (N–H stretching), 1738 and 1639 (C = O stretching); 1H NMR (400 MHz, DMSO-d6, δ ppm): 10.38 (s, 1H, NH), 9.53 (s, 1H, NH), 8.33 (s, 1H, triazole), 7.84 (s, 1H, –CH = C), 7.55–7.47 (m, 4H, Ar–H), 7.39–7.35 (m, 1H, Ar–H), 7.23-7.20 (m, 1H, Ar–H), 6.93-6.91 (m, 2H, Ar–H), 5.34 (s, 2H, –OCH2), 5.31 (s, 2H, –NCH2CO–) and 3.73 (s, 3H, -OCH3); 13C NMR (100 MHz, DMSO-d6, δ ppm): 170.47, 167.19, 161.96, 160.38, 143.33, 141.16, 138.80, 135.94, 132.27, 130.80, 129.46, 127.47, 125.43, 122.06, 119.79, 115.72, 59.28, 55.71 and 48.56; HRMS (ESI-qTOF): Calcd for C22H20N5O5S [M + H]+, 466.2638: found: 466.2695.

2-(4-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(3-methoxyphenyl)acetamide (8f)

Compound 8f was obtained via 1,3-dipolar cycloaddition reaction between alkyne 4 and azide 7f for 20 h.for 20 h. yellow solid; Mp: 216-218 °C; Yield: 80%; FT-IR (cm−1): 3205 (N–H stretching), 1701 and 1632 (C = O stretching); 1H NMR (400 MHz, DMSO-d6, δ ppm): 10.41 (s, 1H, NH), 9.47 (s, 1H, NH), 8.32 (s, 1H, triazole), 7.97 (s, 1H, –CH = C), 7.70 (s, 1H, Ar–H), 7.48–7.46 (m, 2H, Ar–H), 7.18–7.13 (m, 3H, Ar–H), 7.08-7.06 (m, 1H, Ar–H), 6.23-6.22 (m, 1H, Ar–H), 5.35 (s, 2H, –OCH2), 5.31 (s, 2H, –NCH2CO–) and 3.84 (s, 3H, -OCH3); 13C NMR (100 MHz, DMSO-d6, δ ppm): 168.68, 165.97, 162.06, 160.26, 143.91, 139.15, 135.94, 133.78, 131.72, 129.62, 129.37, 127.60, 125.78, 124.49, 121.56, 115.71, 58.98, 55.42 and 48.55; HRMS (ESI-qTOF): Calcd for C22H20N5O5S [M + H]+, 466.3125: found:466.3167.

2-(4-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide (8g)

Compound 8g was obtained via 1,3-dipolar cycloaddition reaction between alkyne 4 and azide 7g for 20 h. Pale yellow solid; Mp: 226–228 °C; Yield: 82%; FT-IR (cm−1): 3165 (N–H stretching), 1701 and 1614 (C = O stretching); 1H NMR (400 MHz, DMSO-d6, δ ppm): 10.34 (s, 1H, NH), 9.55 (s, 1H, NH), 8.31 (s, 1H, triazole), 7.88 (s, 1H, –CH = C), 7.58–7.49 (s, 3H, Ar–H), 7.28–7.19 (m, 5H, Ar–H), 5.17 (s, 2H, –OCH2) and5.11 (s, 2H, –NCH2CO–); 13C NMR (100 MHz, DMSO-d6, δ ppm): 169.83, 167.48, 161.96, 160.36, 141.16, 138.59, 136.15, 133.53, 129.63, 127.50, 125.79, 124.50, 122.06, 115.74, 58.13, 55.13 and 49.19; HRMS (ESI-qTOF): Calcd for C22H20N5O5S [M + H]+, 466.3762: found: 466.3736.

N-(2-chlorophenyl)-2-(4-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)acetamide (8h)

Compound 8h was obtained via 1,3-dipolar cycloaddition reaction between alkyne 4 and azide 7h for 20 h. Yellow solid; Mp: 228–230 °C; Yield: 80%; FT-IR (cm−1): 3271 (N–H stretching), 1740 and 1620 (C=O stretching); 1H NMR (400 MHz, DMSO-d6, δ ppm): 10.56 (s, 1H, NH), 9.34 (s, 1H, NH), 8.25 (s, 1H, triazole), 7.91 (s, 1H, –CH = C), 7.82–7.78 (m, 1H, Ar–H), 7.72–7.64 (m, 1H, Ar–H), 7.50–7.22 (m, 6H, Ar–H), 5.34 (s, 2H, –OCH2) and 5.31 (s, 2H, –NCH2CO–); 13C NMR (100 MHz, DMSO-d6, δ ppm): 169.28, 165.76, 160.90, 157.34, 142.47, 139.90, 136.65, 134.01, 132.30, 130.38, 128.27, 127.80, 124.07, 123.89, 123.41, 123.04, 118.84, 56.65 and 49.79; HRMS (ESI-qTOF): Calcd for C21H17ClN5O4S [M + H]+, 470.3252: found: 470.3287.

N-(3-chlorophenyl)-2-(4-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)acetamide (8i)

Compound 8i was obtained via 1,3-dipolar cycloaddition reaction between alkyne 4 and azide 7i for 20 h. Yellow solid; Mp: 246–248 °C; Yield: 78%; FT-IR (cm−1): 3273 (N–H stretching), 1740 and 1618 (C = O stretching); 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.89 (s, 1H, NH), 9.21 (s, 1H, NH), 8.12 (s, 1H, triazole), 7.91 (s, 1H, –CH=C), 7.73 (s, 1H, Ar–H), 7.55–7.48 (m, 2H, Ar–H), 7.33–7.31 (m, 1H, Ar–H), 7.16-7.12 (m, 1H, Ar–H), 7.04–6.97 (m, 2H, Ar–H), 6.86–6.84 (m, 1H, Ar–H), 5.28 (s, 2H, –OCH2) and 5.11 (s, 2H, –NCH2CO–); 13C NMR (100 MHz, DMSO-d6, δ ppm): 170.76, 165.92, 160.88, 156.76, 141.14, 139.83, 136.79, 133.23, 130.79, 128.40, 127.87, 125.62, 124.22, 123.49, 122.19, 120.59, 118.71, 56.91 and 48.54; HRMS (ESI-qTOF): Calcd for C21H17ClN5O4S [M + H]+, 470.3248: found: 470.3288.

N-(4-chlorophenyl)-2-(4-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)acetamide (8j)

Compound 8j was obtained via 1,3-dipolar cycloaddition reaction between alkyne 4 and azide 7j for 20 h. Yellow solid; Mp: 250–252 °C; Yield: 84%; FT-IR (cm−1): 3254 (N–H stretching), 1702 and 1647 (C=O stretching); 1H NMR (400 MHz, DMSO-d6, δ ppm): 10.11 (s, 1H, NH), 9.43 (s, 1H, NH), 8.32 (s, 1H, triazole), 7.82 (s, 1H, –CH = C), 7.53–7.45 (m, 4H, Ar–H), 7.37–0.32 (m, 2H, Ar–H), 7.24–7.19 (m, 2H, Ar–H), 5.48 (s, 2H, –OCH2) and 5.29 (s, 2H, –NCH2CO–); 13C NMR (100 MHz, DMSO-d6, δ ppm): 168.06, 165.70, 161.74, 156.47, 144.59, 139.58, 130.15, 130.06, 128.20, 127.77, 124.00, 123.35, 118.90, 116.34, 116.12, 58.41 and 48.91; HRMS (ESI-qTOF): Calcd for C21H17ClN5O4S [M + H]+, 470.3272: found: 470.3284.

2-(4-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(3-nitrophenyl)acetamide (8k)

Compound 8 k was obtained via 1,3-dipolar cycloaddition reaction between alkyne 4 and azide 7 k for 20 h.Brown solid; Mp: 242–244 °C; Yield: 74%; FT-IR (cm−1): 3170 (N–H stretching), 1709 and 1642 (C=O stretching); 1H NMR (400 MHz, DMSO-d6, δ ppm): 10.69 (s, 1H, NH), 9.38 (s, 1H, NH), 8.32 (s, 1H, triazole), 7.95 (s, 1H, –CH = C), 7.77 (s, 1H, Ar–H), 7.71–7.68 (m, 1H, Ar–H), 7.46–7.43 (m, 1H, Ar–H), 7.39–7.35 (m, 1H, Ar–H), 7.17–7.14 (m, 2H, Ar–H), 7.07–7.04 (m, 2H, Ar–H), 5.39 (s, 2H, –OCH2) and 5.31 (s, 2H, –NCH2CO–); 13C NMR (100 MHz, DMSO-d6, δ ppm): 169.89, 165.87, 161.25, 157.03, 148.53, 140.91, 137.71, 136.49, 134.25, 131.40, 130.30, 129.19, 128.18, 127.19, 127.09, 126.88, 56.11 and 49.94; HRMS (ESI-qTOF): Calcd for C21H17N6O6S [M + H]+, 481.2836: found: 481.2852.

2-(4-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-nitrophenyl)acetamide (8l)

Compound 8l was obtained via 1,3-dipolar cycloaddition reaction between alkyne 4 and azide 7l for 20 h. Brown solid; Mp: 254–256 °C; Yield: 72%; FT-IR (cm−1): 3042 (N–H stretching), 1743 and 1687 (C=O stretching); 1H NMR (400 MHz, DMSO-d6, δ ppm): 10.08 (s, 1H, NH), 9.55 (s, 1H, NH), 8.53 (s, 1H, triazole), 7.70 (s, 1H, –CH = C), 7.51–7.47 (m, 2H, Ar–H), 7.28–7.01 (m, 4H, Ar–H), 6.99–6.81 (m, 2H, Ar–H) and 5.00 (s, 2H, –OCH2, –NCH2CO–); 13C NMR (100 MHz, DMSO-d6, δ ppm): 172.06, 169.19, 161.75, 157.85, 150.43, 143.01, 140.08, 139.47, 136.47, 133.02, 130.33, 129.08, 127.53, 127.39, 57.48 and 48.73; HRMS (ESI-qTOF): Calcd for C21H17N6O6S [M + H]+, 481.2876: found: 481.2848.

Conclusions

Synthesis of 1,2,3-triazoles-incorporated 2,4 thiazolidinedione conjugates (8a–l) and their antitubercular activity against M. Bovis BCG and MTB strain has been reported. Four compounds 8g, 8h, 8j and 8l of the series exhibited good to excellent activity against M. bovis BCG with IC90 range 1.20–2.70 and MTB H37Ra with IC90 range 1.24–2.65 µg/mL, respectively. Most potent compounds displayed low cytotoxicity against MCF-7, HCT 116 and A549 cell line using MTT assay, suggest that these molecules possess highly pharmacodynamic properties. Most of the active compounds 8g, 8h, 8j and 8l exhibit high selectivity index > 10 against MCF-7, HCT 116 and A549 which indicated that they act as a prominent antitubercular agent. All these results suggest that the potential and significance of emergent novel 1,2,3-triazoles-incorporated 2,4 thiazolidinedione conjugates to treat mycobacterial infections.