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Microwave versus conventional synthesis, anticancer, DNA binding and docking studies of some 1,2,3-triazoles carrying benzothiazole
⁎Corresponding authors. nrezki@taibahu.edu.sa (Nadjet Rezki), maouad@taibahu.edu.sa (Mohamed Reda Aouad)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Abstract
The present work describes the synthesis of new click products with a 2-mercapto-benzothiazole basic structure supporting the different functionalized side chains linked to the 1,2,3-triazole ring at position N-1 via Cu(I)-mediated click chemistry under both thermal and microwave irradiation (MWI). MWI led to higher yields in much less time than classical methods. The obtained click adducts were fully characterized using different spectroscopic experiments including IR, 1H NMR, 13C NMR and high-resolution mass spectrometry, and assessed for their anticancer activities. The maximum anticancer activities were found to be 90% of the compounds 5d and 5h with A549 and H-1229 lung cancer cell lines. The DNA binding constants of the most active compounds of 5d and 5h were 4.7 × 105 and 10.2 × 105 M−1, respectively; confirming the interactions with DNA. The anticancer mechanism was determined by the modeling studies with DNA and the binding energies of the compounds of 5d and 5h were −5.1 and −5.0 kcal mol−1; confirming the DNA binding experimental results. Finally, it was found that almost all the compounds showed good anticancer activities at 400 µg/mL concentration but the compounds 5d and 5h may be potentially anticancer candidates.
Keywords
Synthesis of benzothiazole
1,2,3-triazole
Molecular hybridization
Anticancer activities
DNA binding
DNA docking
1 Introduction
The design and the synthesis of the bioactive nitrogen-containing heterocycles are at the top of the drug discovery (Gomtsyan, 2012; Taylor et al., 2016). Heterobicyclic fragments constitute the core structure of a large number of biologically interesting medicinal scaffolds present in numerous life-saving drugs (H Zhou and Wang, 2012; Kumar et al., 2013). Among these, benzothiazole skeletons are widely well used on designing several medicinal frameworks with numerous biological belongings such as antimicrobial (Singh et al., 2013), anti-inflammatory (Kharbanda et al., 2014), anticancer (Irfan et al., 2020), antitubercular (Venugopala et al., 2019) and antiviral (Akhtar et al., 2008) activities. Moreover, the triazole nucleus is one of the most important and well known heterocycles which is a common and integral feature of a variety of natural products and medicinal agents (Malani et al., 2017; Dheer et al., 2017; Agalave et al., 2011). These fascinating motifs are present as a core structural component in a batch of drug families with broad and significant pharmacological properties such as anticancer (Xu et al., 2019), antiviral (Zhou et al., 2005), antidiabetic, (Avula et al., 2018) antidepressant (Khan et al., 2016), antibacterial (Sumangala et al., 2010) and antifungal (Dai et al., 2015) agents. The design of these promising units become challenging task in medicinal chemistry and their synthesis an understanding of the interactions that drive their formation is an essential prerequisite (Asif, 2014; El Hadrami et al., 2020). In addition, the 1,2,3-triazoles are the attractive precursors in molecular hybridization synthesis. Thus, these class of the compounds incorporate two bioactive moieties in the construction of macromolecules with high efficiency and potentiated activities (Ouahrouch et al., 2014; Sharma et al., 2014; Kant et al., 2016; Gregorić et al., 2017; Hu et al., 2017; Yan et al., 2018). Recently, benzothiazole-triazole hybrids carrying different pharmacophores have been reported from our laboratory as potential anticancer agents (Rezki, 2016; Rezki and Aouad, 2017; Aouad et al., 2018; Aouad et al., 2019).
The relative ease by which 1,2,3-triazole nucleus can be designed with several substituents enables them to cover a wide range of chemical space and further succeeding them as significant starting points for broad spectrum activity (Dheer et al., 2017; Kharb et al., 2011). In a simple way, 1,2,3-triazole derivatives can be synthesized by the 1,3-dipolar cycloaddition of an organic azide and alkyne derivatives. However, this classical method for producing such units is an extremely undesired process due to formation of mixture of 1,4- and/or 1,5-disubstituted 1,2,3-triazole. There have been perpetual efforts for expanding an alternative processes avoiding the regioselective feature. Consequently, the Cu(I)-catalyzed click protocol developed by Sharpless and others (Rostovtsev et al. 2002; Tornoe, et al. 2002; Meldal and Tornøe, 2008) has become powerful linking reaction, to build the desired regioselective 1,4-disubstituted-1,2,3-triazole-containing hybrids and conjugates associated with biological targets and as leads in medicinal chemistry, owing to its high degree of dependability and complete specificity (Anand and Kulkarni, 2017; Liu and Su, 2017; Taia et al., 2020). Therefore, taking into consideration the aforementioned and as continuation of our interest on the development of triazole-based compounds as fascinating anticancer drug candidates (Aouad, 2015; Aouad, 2016; Aouad, 2017; Rezki et al., 2017; Al-Blewi et al., 2018; Almehmadi et al., 2020), we report herein the design and synthesis of 1,2,3-triazole-benzothiazole molecular conjugates tethering different functionalities.
The targets 1,4-disubstituted-1,2,3-triazoles were synthesized by combining benzothiazole and triazole moieties through a copper(I)-catalysed azide-alkyne cyloaddition reaction (CuAAC) of the appropriate organoazides and thiopropargylated benzothiazole assisted by copper(I) catalyst. The resulted 1,2,3-triazoles were assessed for their anticancer activities in order to evaluate the synergistic effect resulting from the conjugation of benzothiazole group and the 1,2,3-triazole (Ali, 2011; Ali et al., 2014; Imran et al., 2014; Ali et al., 2015; Ali et al., 2020). The anticancer activities of the reported molecules were determined on two lung cancer cell lines (A549 and H 1299). The efforts are also made to determine the anticancer mechanism via DNA binding and modeling studies. The results are presented in this article.
2 Results and discussion
2.1 Chemistry
The results and discussion of this study are divided into four parts i.e. synthesis and characterization, anticancer activities, DNA binding and modeling studies, which are debated herein. The synthetic strategy adopted for the elaboration of novel benzothiazole-1,2,3-triazole combined systems carrying different functionalized side chains was successfully achieved via Cu(I)-catalyzed click chemistry (Schemes 1–3), under both conventional and microwave conditions (Schemes 1–4). It should be noted that MWI technology has been widely adopted as an alternative green approach to assist the click synthesis of several 1,2,3-triazole derivatives (Sujit and Basudeb, 2016; Li et al., 2018; Ashok et al., 2020). Thus, the microwave-assisted alkylation of 2-mercapto benzothiazole (1) with propargyl bromide (2); in the presence of sodium methoxide for 3 min, afforded the desired alkyne precursor 2-(prop-2-yn-1-ylthio)benzo[d]thiazole (3) in 97% yield (Scheme 1). The conventional method required heating under reflux for 2 h to afford alkyne 3 in 91% yield.![Synthesis of 2-(prop-2-yn-1-ylthio)benzo[d]thiazole (3).](/content/184/2021/14/3/img/10.1016_j.arabjc.2021.102997-fig1.png)
Synthesis of 2-(prop-2-yn-1-ylthio)benzo[d]thiazole (3).
Click synthesis of benzothiazole-1,2,3-triazole molecular conjugates tethering amide functionality 5a-p.
Click synthesis of benzothiazole-1,2,3-triazole molecular conjugates tethering ketone and/or carboxylic acid functionality 5p and 5q.
The success of the propargylation reaction has been clearly confirmed based on the spectroscopic data (Infrared, proton and carbon NMR, mass spectra) of the thiopropargylated benzothiazole 3. The characteristic signals related to the principal functional groups were evident in the IR spectrum of compound 3. The sharp band at 3300 cm−1 confirmed the presence of the acetylenic hydrogen (≡C—H), while the (—C≡C—) group appeared as a sharp band at 2140 cm−1. In addition, the absence of characteristic —NH— absorption band confirmed the incorporation of a propargyl side chain. The formation of alkyne 3 was also confirmed by 1H NMR analysis by the presence of a triplet and a doublet in the aliphatic region at δH 2.33 and 4.16 ppm relative to sp-CH and SCH2 protons, respectively. The benzothiazole aromatic protons were recorded at δH 7.31–7.94 ppm. In the 13C NMR spectrum, the diagnostic propargyl carbon signals (SCH2 and C≡C) resonated at δC 21.62, 72.39 and 78.35 ppm, respectively. The signals recorded at δC 121.11–164.60 ppm were attributed to the aromatic and -C⚌N— carbons. Upon addition of sodium ascorbate and copper sulfate as catalyst in a mixture of DMSO:H2O (1:1) as solvent at room temperature, 1,3-dipolar (alkyne-azide) cycloaddition reaction of 2-(prop-2-yn-1-ylthio)benzo[d]thiazole (3) with different substituted phenyl/benzyl acetamide azides 4a-m and phenacyl azides 4n and 4o furnished the targeted benzothiazole-1,2,3-triazole conjugates 5a-o in 80–86% yields (Scheme 2). Under MWI, 6–8 min was required to yield the same click adducts 5a-o in 90–95% yields (Table 1).
Compounds No
Conventional procedure (CP)1
Microwave procedure (MWI)2
Time (h)
Yield (%)
Time (min)
Yield (%)
5a
10
85
8
94
5b
10
82
8
92
5c
10
83
8
92
5d
10
82
8
91
5e
10
80
8
90
5f
10
84
8
93
5g
10
82
8
92
5h
10
81
8
90
5i
8
86
6
95
5j
8
84
6
94
5k
8
85
6
94
5l
8
83
6
93
5m
8
84
6
93
5n
8
83
6
91
5o
8
85
6
93
5p
10
82
8
91
5q
10
81
8
91
The synthesized benzothiazole-1,2,3-triazole molecular conjugates 5a-o were fully characterized by their spectral data (IR, 1H NMR, 13C NMR and 19F NMR). Almost all the synthesis click products displayed similar spectral patterns (1H NMR and 13C NMR). The spectral analysis of the synthesized 1,2,3-triazole 5a was discussed to confirm the success of the click reaction. The IR spectrum confirmed the structure of the 1,2,3-triazole ring through the disappearance of the absorption bands that characterized their precursors (—C≡C—, ≡C—H and N3). The spectrum also showed the existence of two bands around 1695 and 3340 cm−1 assigned to the amidic carbonyl (NHC⚌O) and amine (NH) groups, respectively.
In the 1H NMR spectrum of the click product 5a, the signal assigned to the terminal hydrogen of the ≡C—H group disappeared and one distinct signal was recorded in the aromatic region at δH 8.17 ppm typical for the 1,2,3-triazole CH proton. The spectrum also revealed the presence of the methylene protons SCH2 and —NCH2 as two singlets at δH 4.74 ppm and δH 5.30 ppm, respectively. The amide —NH— proton resonated as a singlet in the downfield region at δH 10.53 ppm. In addition, nine aromatic protons were observed in the aromatic region (δH = 7.14–8.03 ppm), and they were assigned to the protons of the benzothiazole ring as well as the phenyl acetamide ring.
The success of the click reaction was also supported by 13C NMR analysis where the absence of the sp —C≡C—carbons was apparent in the spectrum. In addition, the signal characteristic of the SCH2 carbon resonated at δC 27.81 ppm, while the NCH2 and C⚌O carbons of the acetamide linkage were recorded at δC 52.61 and 166.34 ppm, respectively. The additional signals were also recorded in the downfield area that could be attributed to the aromatic carbons of the p-fluorophenyl acetamide side chain connected to the 1,2,3-triazole core. The multiplet recorded at −118.70 to −118.62 ppm in the 19F NMR spectrum of compound 5a being related to the fluorine atom attached to the benzene ring, confirming the success of the click coupling with p-fluorophenyl acetamide azide (4a).
Finally, the last azide partners were p-azido acetophenone (4p) and/or p-azido benzoic acid (4q) giving the targeted benzothiazole-1,2,3-triazole hybrids 5p and 5q carrying ketone and/or carboxylic acid functionality in very good yields (81–82%) (Scheme 3). When the click reactions were assisted by MWI, 91% yield of triazoles 5p and 5q were obtained within 8 min (Table 1).
The structures of the newer synthesized 1,2,3-triazole molecular conjugates 5p and 5q have been elucidated based on their spectral data as described for compound 5p. Its IR spectrum revealed the appearance of a strong band round 1740 cm−1 related to the ketone carbonyl group, thus, confirming the presence of the acetophenone moiety in the assigned structure of compound 5p. The structural assignment of the 1,2,3-triazole 5p resulting from the click coupling with p-azido acetophenone was clearly confirmed by its1H NMR spectrum by the resonance of the triazolyl proton as a singlet at δH 8.99 ppm. The spectrum also showed the apparition of two singlets at δH 2.62 and 4.82 ppm assignable to the CH3 and SCH2 protons, respectively. Moreover, the four aromatic protons of the acetophenone ring were observed the aromatic area at δH 7.33–8.15 ppm. In its 13C NMR spectrum, the resonance of new signal in the aliphatic region at δC 26.71 ppm attributable to the CH3 carbon and a diagnostic ketone carbonyl carbon at δC 196.57 ppm gave additional proofs for the success of the click synthesis.
2.1.1 Comparison of conventional and microwave syntheses
The general click synthesis has been successfully achieved under conventional stirring at room temperature for 8–10 h and afforded the desired benzothiazole-1,2,3-triazole molecular conjugates 5a-q in 80–86% yields. Under MWI, the reaction time was dramatically reduced to 6–8 min with an improvement in the isolated yields (90–95%) (Table 1). Accordingly, it could be concluded that MWI has been efficiently adopted as an alternative green technology to assist click synthesis with a great reduction in the reaction time and improvement of reaction yield, as well as high purity.
2.2 Anticancer activities
The anticancer activities of the reported compounds were performed with A549 and H-1229 lung cancer cell lines. The used concentrations of the synthesized compounds were 50, 100, 200, 300 and 400 µg/mL. The findings of anticancer activities are given in Fig. 1. The reported compounds were dissolved in 0.1% DMSO and A549 and H-1229 cell lines were used as vehicle controllers. Then deposit of the compounds was delayed until the control cells reach the lethargic phase. An evaluation of this Figure was carried out and the results are summarized herein. It is clear from this Figure that there were different anticancer activities of these compounds with different concentrations, but the maximum anticancer activities observed were at 400 µg/mL. The ranges of the anticancer activities were from 49 to 90%. The maximum anticancer activities with both the cell line were 90% with compounds 5d and 5h. The order of anticancer activities in A549 cancer cell lines was 5d (90) = 5h (90) > 5i (88) > 5f (85) > 5c (84) = 5g (84) > 5q (83) > 5b (82) = 5j (82) = 5m (82) > 5e (80) > 5p (79) > 5k (78) > 5n (75) = 5o (75) > 5l (70) > 5a (49). The IC50 values ranged from 51.38 to 92.16 µg/mL.
Anticancer activities of the reported compound on (a): A549 and (b): H-1229 cancer cell lines.
Anticancer activities of the reported compound on (a): A549 and (b): H-1229 cancer cell lines.
Similarly, the results were analyzed for the anticancer activities with H-1229 cell lines and it was again found that that there were different anticancer activities of these compounds with different concentrations but the maximum anticancer activities observed were at 400 µg/mL. The ranges of the anticancer activities were from 49 to 90%. The order of anticancer activities in A549 cancer cell lines was 5d (90) = 5h (90) > 5i (88) > 5f (85) > 5c (84) = 5g (84) > 5q (83) > 5b (82) = 5j (82) = 5l (82) > 5m (82) > 5e (80) > 5p (79) > 5k (78) > 5n (75) > 5o (74) > 5a (49). The IC50 values ranged from 51.38 to 74.04 µg/mL. A comparison was made of the anticancer activities on both the cell lines i.e. A549 and H-1229 and it was observed that the anticancer activities were almost similar except for few cases. Finally, the best compounds found were 5d and 5h because of the highest anticancer activities of 90%.
2.2.1 DNA binding
For binding experiments, the absorption spectra of freshly produced drugs at a fixed concentration of (0.01 mg/mL) were studied while increasing the concentration of DNA (1.1 × 10−5, 1.3 × 10−5 and 1.5 × 10−5 M). Firstly, the absorbance of pure DNA and compounds and λmax were verified separately in tris-buffer solutions. Absorbance and λmax for each mixture were recorded using 2.0 mL of each solution with different additional concentrations. To get persistent results, five times repetition of the titration experiments were carried out (n = 5). The inherent binding constants (Kb) were worked using Benesi-Hilderbrand equation modified by Wolfe A., et al. (Wolfe et al., 1987).
The results of this set of experiments are given in Table 2. It is imperative to indicate here that these drugs produced an adduct with DNA; deactivating the DNA activity sites. The interactions of the reported molecules with DNA may be seen in the change of λmax values of free molecules. The λmax values are changed from 1 to 41 nm; indicating good interactions. This remark is particularly important and convenient to explain how the drugs will control the spread of cancer. DNA binding constant values for these drugs were in the range of 1.75 × 105 and 10.5 × 105 M-1; demonstrating the interactions with DNA as good. The results establish good binding characteristics of the synthesized drugs with DNA. Origin software was used to carry out the regression analysis for DNA binding studies. The correlation coefficients (R2) were in the range of 0.99874–0.99995. The correctness of the experiments was indicated with the values of regression coefficients which were close to unity in. Obviously, the degree of the DNA binding constants is quite high, and this showed that synthesized drugs may be highly active against various cancers. Moreover, it was also detected that the synthesized drugs showed a higher value of DNA binding constant, therefore, better anticancer activities. Different polarities of the synthesized drugs and configuration caused different values of DNA binding constants. Additionally, high values of binding constants might be due to the presence of aromatic molecules with heteroatoms in the synthesized drugs, since the heteroatoms have good tendency of interactions with DNA (Evstigneev, 2010). The results clearly showed that synthesized drugs work through DNA binding on various types of cancer. It is especially important that the highest binding constants were of the compounds 5d (10.5 × 105) and 5h (10.2 × 105); supporting the anticancer results; the highest anticancer activities of 5d and 5h. Therefore, DNA binding spectra of these most active compounds 5d and 5h are given in Fig. 2 below while the rest are given in supplementary information.
Comp. No
λmax (free) (nm)
λmax (bound to DNA) (nm)
Change
% Hypochromisma
Kbb (M−1)
5a
225
260
35
57.20
2.76 × 105
5b
222
253
31
38.19
3.3 × 105
5c
224
280
56
51.69
4.7 × 105
5d
223
281
58
77.49
10.5 × 105
5e
217
258
41
62.81
5.09 × 105
5f
226
305
79
45.85
5.1 × 105
5g
225
285
60
40.32
4.0 × 105
5h
220
267
47
31.81
10.2 × 105
5i
222
282
60
63.76
2.9 × 105
5j
224
280
56
71.57
7.0 × 105
5k
224
274
50
39.85
3.9 × 105
5l
222
282
60
61.77
1.9 × 105
5m
222
282
60
32.89
1.75 × 105
5n
212
282
70
31.77
7.78 × 105
5o
219
265
46
33.67
6.79 × 105
5p
226
261
35
29.14
7.3 × 105
5q
225
264
39
35.99
9.5 × 105
DNA binging spectra of (a): compound 5d and (b): 5h.; red, dark blue and light blue colors: 1.1 × 10−5, 1.3 × 10−5 and 1.5 × 10−5 M DNA concns.
2.2.2 Modeling study
The mechanism of anticancer activities of the reported compounds was attempted to explain by modeling with DNA. The results are given in Table 3 below. In 1,2,3-triazole compounds, there were the different numbers of hydrogen bonds in different structures. The compounds 3, 5c, 5e, 5f, 5l, 5p and 5q structures formed one hydrogen bond, while 5a, 5b, 5d, 5g, 5h, 5i, 5j and 5k formed 2 hydrogen bond. Besides, hydrophobic interactions were also different in different structures. The common hydrophobic residues which were involved in the interaction are dt8, dc9, dc13, dc15, dg15, dg10, dg16 and dg14. The binding energy range was from −3.7 to −5.1 kcal mol−1. These values clearly confirmed that the reported compounds have good tendencies to interact with DNA. All these studies clearly confirmed that the compounds showed anticancer activities via interactions with DNA. The DNA models of the most active compounds 5d and 5h are given below in Fig. 3 while the rest are given in supplementary information.
Comp. No
Affinity ss(kcal mol−1)
No. of H bonds
Residues involved in H-bonding
Hydrophobic interaction
5d
−5.1
2
—N⚌N—N⚌group (3.3)
624/B/DG‘14/OP2:: Odc15:: N2,N1,N4 & C12
dg14:: C2,C3,C4,C6,C7 & C9
dc13::C1,C4 & O2
dt8:: C12
dc13:: S1
dg10:: C1 &C2
5h
−5.0
2
127/A/DC‘9/N4:: N of —N⚌N—N⚌group (3.5)
263/A/DG‘10/O6:: H of —CONH— group (3.4)dg14:: C2,C8,C5,C7,C10 & C4
dc13::C1,C2 & O3
dt8:: C1,C9 & C5
dc9:: C1,C5 & C10
DNA models of the compounds (a): 5d and (b): 5h.
3 Conclusion
The novel 1,4-disubstituted 1,2,3-triazoles pending benzothiazole core was readily obtained in good yields via copper(I)-assisted click reaction of focused un/functionalized alkyl and/or aryl organoazides and benzothiazole-alkyne. These were characterized by proper spectroscopic methods. These compounds were screened for their anticancer activities. Most of the compounds showed>50% anticancer activities with 90% highest of the compounds 5d and 5h. The values of the DNA binding constants (1.75 × 105 to 10.5 × 105) indicated good interactions of the reported compounds with DNA. This was confirmed and supported by DNA modeling results with 3.7 to −5.1 kcal mol−1 binding energy range. All these studied confirmed that the reported compounds have good anticancer activities of>50% but the compounds 5d and 5h showed maximum anticancer activities (90%) and may be the potential anticancer candidates.
4 Experimental
4.1 Chemicals and reagent
All reagents and solvents used were of the highest quality of analytical reagent grade and were used without further purification. Fine chemicals including 4-fluoroaniline, 2-fluoro-4-iodoaniline, 2-fluoroaniline, 2,4,5-trifluoaniline, 3,4-dichloroaniline, 4-iodoaniline, 4-aminoacetophenone, 4-aminobenzoic acid and 2-mercaptobenzothiazole were purchased from BDH Chemicals Ltd., UK. The other fine chemicals used were 4-nitroaniline, benzylamine, 4-fluorobenzylamine, 4-methylbenzylamine, 4-chlorobenzylamine, 4-methoxybenzylamine, 2-bromo-4́-methoxyacetophenone, 2-bromo-4́-methoxyacetophenone, bromoacetyl bromide, triethylamine, sodium azide, sodium methoxide, propargyl bromide (80 wt% in toluene), CuSO4 and Na-ascorbate (Sigma-Aldrich, USA).
The solvents used ethyl acetate, hexane, methanol, ethanol, DCM, DMF and DMSO were purchased from Sigma-Aldrich, USA.
4.2 Instruments used
The microwave-assisted reactions were performed on microwave reactor type controllable single-mode microwave reactor (CEM Discovery) which was equipped with a magnetic stirrer as well as pressure, temperature, and power controls and a nitrogen cooling system. The maximum operating pressure of the reactor was 2 × 106 Pa and the power was set to 300 W. All reactions were monitored by TLC, using UV fluorescent Silical gel Merck 60 F254 plates, and the spots were visualized using a UV lamp (254 nm). The measurement of the melting points was performed with a Stuart Scientific SMP1. All synthesized compounds were fully characterized by 1H and 13C NMR, IR and Mass analysis. The functional groups were identified using SHIMADZU FTIR-Affinity-1S spectrometer in the range of 400–4000 cm−1. The 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were investigated with a Bruker spectrometer (400 MHz) with TMS as an internal standard to calibrate the chemical shifts (δ) reported in ppm. The mass spectral data were recorded on MALDI microflex mass spectrometer.
4.3 Synthesis of the targeted compounds
The azides 4a-q used in this study were prepared according to reported procedures. (Minvielle et al., 2013; Devender et al., 2017; Wang et al., 2017). The procedures of the synthesis of the reported compounds are described in the following section.
4.3.1 Synthesis and characterization of benzothiazole based-alkyne (3)
4.3.1.1 Conventional procedure
To the stirring solution of 2-mercaptobenzothiazole (1) (10 mmol) and sodium methoxide (11 mmol) in methanol (30 mL) was added propargyl bromide (2) (12 mmol). The reaction mixture was refluxed for 2 h until the consumption of the starting material as indicated by TLC analysis (hexane–ethyl acetate). The excess of solvent was removed by evaporation under reduced pressure. The resulting solid was washed with water and recrystallized from methanol yielding the targeted S-propargylated benzothiazole 3 as colorless crystals in 91% yield, mp: 80–81 °C (Lit. mp: 82–83 °C [26]). IR (υ, cm−1): 1590 (C⚌C), 1620 (C⚌N), 2140 (C≡C), 2955 (C—H al), 3050 (C—H ar), 3300 (≡CH). 1H NMR (400 MHz, CDCl3): δH 2.33 (t, 1H, J = 4.0 Hz, ≡CH), 4.16 (d, 2H, J = 4.0 Hz, SCH2), 7.33 (t, 1H, J = 8.0 Hz, Ar—H), 7.45 (t, 1H, J = 8.0 Hz, Ar—H), 7.79 (d, 1H, J = 8.0 Hz, Ar—H), 7.94 (d, 1H, J = 8.0 Hz, Ar—H). 13C NMR (100 MHz, CDCl3): δC 21.62 (SCH2); 72.39, 78.35 (C≡C); 121.11, 121.83, 124.56, 126.20, 135.49, 153.03, 164.60 (Ar-C, C⚌N). MS (m/z) = 205.004 [M+].
4.3.1.2 Microwave procedure
In a closed borosilicate glass vessel fitted with a silicone cap, a solution of 2-mercaptobenzothiazole (1) (1 mmol), sodium methoxide (1.1 mmol) and propargyl bromide (1.2 mmol) in methanol (5 mL) was exposed to irradiation for 3 min using a microwave reactor. The reaction was treated as described in the conventional procedure outlined earlier to give the same alkyne 3 in 97%.
4.3.2 Click procedures for the synthesis of 1,2,3-triazoles 5a-q
4.3.2.1 Conventional procedure
To a solution of propargylated benzothiazole 3 (1 mmol) in DMSO (10 mL) was added a solution of copper sulfate (0.10 g) and sodium ascorbate (0.15 g) in water (10 mL). Then, the appropriate azide 4a-q (1 mmol) was added, and the reaction mixture was stirred at room temperature for 4–10 h. The reaction was monitored via TLC (hexane–ethyl acetate), and after the completion of the reaction, iced-water was added in the mixture. The precipitate, thus, formed was collected by filtration, washed with a saturated solution of ammonium chloride and recrystallized from ethanol/DMF to give the targeted 1,2,3-triazoles 5a-q was collected purified by recrystallization from ethanol/DMF.
4.3.2.2 Microwave procedure
In a closed borosilicate glass vessel fitted with a silicone cap, a mixture of propargylated benzothiazole 3 (1 mmol), copper sulfate (0.10 g), sodium ascorbate (0.15 g), the appropriate azide 4a-q (1 mmol), water (10 mL) and DMSO (10 mL) was exposed to irradiation for 3–8 min using a microwave reactor. The reaction was treated as described in the conventional procedure outlined earlier to give the same click products 5a-q.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Appendix A
Supplementary material
Characterization of compounds 5a-q is provided and detailed in the supplementary material. Full experimental results: 1H NMR, 13C NMR and HRMS spectra as well the anticancer activity, DNA binding and modeling study can be found via a link at the end of the document. Supplementary material to this article can be found online at https://doi.org/10.1016/j.arabjc.2021.102997.
Appendix A
Supplementary material
The following are the Supplementary data to this article: