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. 2020 Jun 1;5(23):14061–14068. doi: 10.1021/acsomega.0c01519

Synthesis of 1,4-Biphenyl-triazole Derivatives as Possible 17β-HSD1 Inhibitors: An in Silico Study

Hiram Hernández-López †, Socorro Leyva-Ramos ‡,*, Cesar Fernando Azael Gómez-Durán ‡, Alberto Pedraza-Alvarez ‡, Irving Rubén Rodríguez-Gutiérrez ‡, Mario Alberto Leyva-Peralta §, Rodrigo Said Razo-Hernández ∥
PMCID: PMC7301541  PMID: 32566872

Abstract

graphic file with name ao0c01519_0005.jpg

Triazoles occupy an important position in medicinal chemistry because of their various biological activities. The structural features of 1,2,3-triazoles enable them to act as a bioisostere of different functional groups such as amide, ester, carboxylic acid, and heterocycle, being capable of forming hydrogen bonds and π–π interactions or coordinate metal ions with biological targets. In this work, the synthesis of 1,2,3-triazole derivatives via copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) is reported. Overexpression of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is often found in breast cancer cells. Molecular similarity and docking analysis were used to evaluate the potential inhibitory activity of 1,2,3-triazoles synthesized over 17β-HSD1 for the treatment of mammary tumors. Our in silico analysis shows that compounds 4c, 4d, 4f, 4g, and 4j are good molecular scaffold candidates as 17β-HSD1 inhibitors.

Introduction

In search of new breast cancer treatment strategies, a few endocrine therapies have been developed. Hormone therapy is based on selective estrogen receptor modulators or antiestrogens that cause several undesired effects.1,2 The activation of 17β-estradiol (E2) responsible for the growth of estrogen-dependent breast cancer is regulated by the enzyme 17β-HSD1. The inhibition of this enzyme that is expressed in different organs but mainly in many breast cancer tissues3 is a better therapy with probably fewer side effects.

For this reason, several steroidal and nonsteroidal inhibitors of 17β-HSD1 have been developed. However, recently, nonsteroidal derivatives that act as inhibitors of 17β-HSD1 enzyme, having derivatives of thienopyrimidinones, biphenyl ethanones, 6-(hydroxyphenyl)naphthols, and bis(hydroxyphenyl)azoles, have been researched intensively, with the last one being the most promising compound.4 Biphenyltriazoles, as a bioisostere of azoles, open possibilities for evaluating several candidates as new inhibitors of the enzyme, having a platform with a straightforward methodology of synthesis that generates a library of compounds via CuAAC reaction. Besides, in conjunction with the computational study, it will be possible to evaluate better candidates for enzyme inhibition with extensive molecular screening.

Many triazole-based derivatives are available as medicines;5 however, they also have a wide range of important applications in the agrochemical,6 dendrimer,7 supramolecular,8 electrochemical,9 corrosion retardant,10 optical brightener,11 metal chelator,12 and material fields.13 Their important biological activities include anticancer,14 antitumor,15 anti-HSV-1,16 antimalarial,17 antitubercular,18 antileishmanial,19 antifungal,20 antibacterial,21 antimicrobial,22 antidiabetic,23 antihypertensive,24 anti-inflammatory,25 anti-Alzheimer,26 antiepileptic,27 and anticonvulsant.28

Their importance in the field of medicinal chemistry is due to high dipole moment, rigidity, and capability to bind with various kinds of enzymes and receptors via weak interactions such as hydrogen bonds, coordination bonds, ion–dipole, dipole–dipole, and cation−π and π stacking interactions when they bind with the biological target.29 Thus, 1,2,3-triazole scaffolds are of interest for drug development because these systems act as a bioisostere of different functional groups such as amide, ester, carboxylic acid, and heterocycle,30 and they also are highly stable under basic, acidic, reductive, oxidative, and enzymatic conditions due to high aromatization.31,32

The 1,2,3-triazole ring system can be easily built via Huisgen’s 1,3-dipolar cycloaddition of azides and alkynes by copper-catalyzed click reaction (CuAAC), allowing the production of a large number of 1,4-disubstituted-1,2,3-triazoles in high regioselectivity, broad substrate scope, favorable kinetic, excellent yield, insensitivity toward oxygen and water, and pure product isolation. This reaction can be performed in the presence of a wide variety of functional groups, facile and gentle conditions, wide pH range tolerance, and compatibility with a variety of solvents.

The click conjugation includes direct utilization of copper(I) salts, either added directly or generated by reduction of copper(II) or oxidation of Cu(0) and copper complexes.33 There are also examples of CuAAC reactions by the heterogeneous catalyst using materials such as alumina, silica, polymers, zeolites, or activated carbon as supports.34−36 Other catalytic systems used are Ru-, Zn-, Ag-, Ni-, Pt-, and Pd-catalyzed click.37−39 The efficiency of the azide/alkyne click reaction was improved by the use of microwave irradiation and ultrasonication.37,40,41

1,2,3-triazole is a building block with many attributes for the development of new anticancer agents,14 such as an inhibitor of human methionine aminopeptidase type 2 (hMetAP2),42 inhibition of human cancer cell lines such as breast adenocarcinoma (MCF-7) and human hepatocellular carcinoma (HepG2),43 cytotoxic activity against several cancer cell lines,44,45 antiproliferative activity,46 and so on.47 To further enrich the structure–activity relationship of triazole in the enzyme inhibition, herein, the generation of a diverse library de triazole analogues using the CuAAC reaction is reported, as well as their inhibitory potency over 17β-HSD1.

Ten new triazole derivatives have been synthesized with good yields and evaluated as nonsteroidal inhibitors of 17β-HS1 for the treatment of estrogen-dependent diseases. The desired derivatives of triazoles were generated by click reaction with different functional precursors. Current research efforts are mainly focused on the optimization of the side chain attached to the pharmacophore in order to develop new compounds with better pharmacological activities.

Results and Discussion

Chemistry

Aromatic azides were synthesized by the formation of benzenediazonium salt from substituted anilines with sodium nitrite in acid media, and then, sodium azide was added, having a range from good to excellent yields of reaction (Figure 1).48,49 Anilines with electron-withdrawing groups allowed to obtain 94–97% yield of aromatic azide while electron-donor groups allowed to obtain 80–87% yields. The change of aniline to aromatic azide was confirmed by the presence of N3 vibration at 2111 and 2069 cm–1 with very strong intensity and the absence of primary amine vibration at 3500 and 3300 cm–1.

Figure 1.

Figure 1

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Synthesis of the 1,2,3-triazole ring system (4a to 4j).

The formation of the 1,2,3-triazole ring was made by copper-catalyzed 1,3-dipolar cycloaddition between an aromatic azide and terminal alkyne having 65–88% yield (Figure 1).48,49 The nature of functional groups in the aromatic azide was not a determinant factor for the formation of the triazole ring.50 1,2,3-triazole was confirmed for increasing the number of vibrations in the aromatic region between 1600 and 1400 cm–1 due to C=C and the absence of N3 vibration.

In 1H NMR, a singlet signal of around 9.3 ppm was observed for triazoles. This chemical shift at downfield is due to the magnetic anisotropy effect from triazole itself and the electronegative effect of the nitrogen atoms attached at the triazole ring by the electron-withdrawing effect reducing the valence electron density around the proton. In the same way, 13C NMR showed one signal in the range 148.67–130.37 ppm corresponding to the carbon of triazole. The substituted aromatic carbon cannot be distinguished by its decreased peak height.

All compounds analyzed by mass spectrometry did not show the molecular ion, and the easy liberation of phenyl acetylene (m/z = 102.05) resulted in the production of the aromatic azide,51,52 which can act as a nucleophile or an electrophile agent at the same time generating azo or hydrazine molecules by intramolecular cyclization.

On the other hand, in UV–vis spectroscopy, the transformation of substituted anilines to azide and then to triazole molecule showed a hypsochromic shift. The most characteristic transitions of the triazolinic ring were π → π* and η → π* at 250–244 and 290 nm, respectively. The displacement of π → π* band transition of aromatic is showed as a weak conjugation with each aromatic ring, changing the space arrangement to nonplanar rings, and this result is congruent with optimal conformation by computational calculations made below.

Computational Details

Ligand Preparation and MEP

The optimized structures of all the compounds are shown in Figure S1. All the structures were in a minimum in the potential energy surface because all the vibrational frequencies were positive. From Figure 2, it can be observed that all the compounds possess a planar molecular shape with a hydrogen bond acceptor in the para position of the phenyl ring 1. Employing these structures as a starting point, we performed a molecular docking calculation to evaluate these compounds as potential inhibitors of 17β-HSD1.

Figure 2.

Figure 2

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Template structure used for the MSA. 4l, 4m, and 5a to 5d are inhibitors of 17β-HSD1.

To evaluate how the interaction of these molecules with their biological receptor may occur (neutral, positive, and negative electrostatic regions), we obtained the molecular electrostatic potential mapped over a surface of electronic iso-density value (0.002 e–/Å3). Also, from these molecular graphics, we can visualize the shape of the compounds, an important feature for the protein interaction process. The molecular electrostatic potential of all the reference molecules (Figure S2) and our triazole derivatives (Figure S3) is displayed.

In Figure S2, it can be seen how for all the reference molecules, their aliphatic part (phenyl rings) is a neutral MEP zone and that they share a similar molecular shape. Also, we can observe the negative MEP zones located over the nitrogen atoms of the triazole ring and the oxygen atoms of the OH moiety. The positive MEP zones are located over the hydrogen atom of the OH group, which are important in order to bind similarly to estradiol.

On the other hand, in our triazole derivatives, the positive zones of MEP in the corner of the molecules are lacking; instead they present a positive MEP zone over the hydrogen of the triazole ring. They possess the same negative MEP zone over the triazole ring as the reference molecules and the neutral zone over the phenyl rings. Besides, they possess a highly similar molecular shape with the reference molecules. These electronic characteristics of our molecules suggest that they will interact in the same binding site (lock–key principle) but with different binding residues. To corroborate this assumption, a molecular docking study was carried out.

Molecular Docking Analysis

All the compounds were docked in the catalytic site of 17β-HSD1. In Figures S4 and 4, the interaction of each compound with 17β-HSD1, according to the docking calculations, is displayed. All the compounds bind in the lipophilic pocket near the NADP+ cofactor (Figure 3) by embedding their unsubstituted phenyl ring. This lipophilic pocket is formed by Gly92, Leu93, Gly94, Ala291, Phe192, and Val196; it is located after a hydrophilic “bottle neck” type composed by Ser142, Tyr155, Glu194, and Lys195. This hydrophilic zone is crucial for the catalytic reaction of the estradiol, forming two HBs with Ser142 and Tyr 155.

Figure 4.

Figure 4

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Molecular docking results of the synthetized triazole derivatives. NADP+ is represented as colored spheres. Hydrogen bonds are displayed as blue dashed lines.

Figure 3.

Figure 3

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Catalytic cavity (pink color) of 17β-HSD1 in a mesh representation with estradiol (yellow sticks). The NADP+ cofactor is displayed in a sphere representation.

These regions of the catalytic cavity help us to explain the binding mode of the triazole derivatives because of the planar and cylindrical shape of our molecules, and the most hydrophobic part of these molecules (unsubstituted phenyl ring) fits in a perfectly good manner in the lipophilic pocket; meanwhile, the triazole ring forms a high number of strong HBs with the residues of the hydrophilic zone. According to our docking results, besides the similarity between the triazoles synthesized by Bey et al.4 and the estradiol, these compounds bind in the lipophilic pocket with their phenyl group with more hydrophobic character-forming HB with Gly92. Similarly, all our triazole derivatives bind in the lipophilic pocket by the phenyl ring with less electronic density, in our case, the unsubstituted ring, increasing the hydrophobic interactions and decreasing the steric repulsions. At the same time, the triazole ring strongly interacts with 17β-HSD1 by many HBs with Lys195 (HBs and cation−π interactions), Ser 142, and Tyr 155.

In Table 1, all the interaction energy values of the triazoles studied in this work are displayed. According to these results, it can be noted that two of our compounds (4a and 4e) possess a more negative interaction energy value (better binding) with 17β-HSD1 than that of the triazoles of Bey et al.,4 and other two of our compounds (4b and 4i) possess a similar interaction energy value to that of the reference triazoles (around −148 kcal/mol). We can explain these results by the aforementioned energy interaction involved in the two regions of the catalytic domain. It can be noted that our compounds with the best interaction energy are those which have an electron-withdrawing group (halogen or carbonyl group). This structural feature of these molecules enhances the interaction by HB with the residues located before the hydrophilic bottleneck, especially with Arg258.

Table 1. Interaction Energy (kcal/mol) Values of the Triazole Derivatives.
Molecule MolDock score (kcal/mol) Hbond (kcal/mol)
4a –154.93 –7.5
4b –148.98 –11.09
4c –142.18 –7.74
4d –142.85 –6.58
4e –160.25 –10.78
4f –143.89 –5.23
4g –140.84 –7.05
4h –144.34 –4.44
4i –141.05 –3.18
4j –140.44 –13.58
4l –145.92 –6.35
4m –147.12 –7.41
5a –143.29 –1.81
5b –128.11 –7.73
5c –143.29 –5.00
5d –150.28 –3.21
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From this analysis, we can conclude that one of the phenyl rings must be unsubstituted, and the other needs to have an electron-withdrawing group to facilitate the binding in the lipophilic group of the catalytic site and the electrostatic interactions and HB formation with the residues of the catalytic hydrophilic zones.

Prediction of IC50 Values

From the results of molecular docking, a mathematical model was generated for the prediction of the IC50 values of the proposed compounds (4a to 4j) based on the interaction energies. For the generation of the mathematical model, the transformation of IC50 to logarithm was used to normalize the data and resulted in eq 1 (see below).

graphic file with name ao0c01519_m001.jpg 1

This model has produced high statistical quality (R2 = 93.52, Q2 = 86.96, s = 0.196), which was obtained by relating interaction energies and log IC50 (log Y) values (Figure S5).

All the log IC50 (Yexp) experimental, calculated (Ycalc), and predicted (Ypred) activity values by our model are presented in Table 2. Also, the absolute value of the differences between Yexp and both Ycalc and Ypred is represented by errorcalc and errorpred term, respectively. Yexp versus Ypred activity plots are shown in Figure S6. The predicted calculation of the IC50 values of the proposed compounds (1 to 10) was realized using the mathematical model and the interaction energy values (Table 1). Table 3 shows the predicted IC50 values, and the values are represented in μM.

Table 2. Experimental, Calculated, and Predicted log IC50 Values of the Compounds 4l, 4m, and 5a to 5d.
molecules log Yexp log Ycalc log Ypred error calc error pred std. err calc std. err pred
4l 3.12 2.90 2.83 –0.23 –0.29 –1.29 –1.64
4m 2.92   3.31   0.39    
5a 3.21 3.30 3.35 0.09 0.15 0.59 0.94
5b 1.70 1.68 1.50 –0.02 –0.02 –0.32 –3.13
5c 2.49 2.72 2.77 0.23 0.28 1.29 1.61
5d 3.27 3.20 3.16 –0.07 –0.10 –0.44 –0.64
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Table 3. Predicted IC50 (μM) Values for Compounds 4a to 4j.
molecules IC50pred (μM)
4a 3.26
4b 1.28
4c 0.44
4d 0.48
4e 7.55
4f 0.57
4g 0.35
4h 0.61
4i 2.56
4j 0.33
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The compounds that obtained better IC50 values were the triazole derivatives 4c, 4d, 4f, 4g, and 4j, with values from 0.33 to 0.57. Comparing these results with the interaction energy values, the triazole derivatives 4a, 4b, 4e, and 4i showed better interaction energy values with the 17β-HSD1 protein and would be expected to obtain better activity (low IC50 values); however, these compounds predicted high IC50 values. These results should consider that there is no direct relation between highly negative interaction energy (binding affinity) and better IC50 values; the IC50 estimates the effect on the target activity, which does not necessarily reflect the affinity. The interaction energy values of the compounds 4c, 4d, 4f, 4g, and 4j are similar to those of the reference triazoles. From the docking and mathematical model results, we can conclude that these triazole derivatives can be used as molecular scaffolds for the design of new inhibitors of 17β-HSD1.

Conclusions

In summary, 1,2,3-triazole derivatives were successfully synthesized through the optimized Cu(I) click conditions. They were obtained in moderate to high yield and purity without chromatographic purification. Most of them showed high activity. Structures of the prepared compounds were elucidated by spectral data like UV–vis, FT-IR, 1H and 13C NMR, and MS.

In the molecular docking study, it was observed that triazole derivatives bind in the lipophilic pocket of the 17β-HSD1 protein by the aromatic ring. The triazole ring has strong interactions with the protein through hydrogen bonds with Lys195, Ser142, and Tyr155.

After analyzing the results, we can conclude that to obtain the best binding affinity with the hydrophilic catalytic zone, an unsubstituted phenyl ring is necessary to decrease steric interactions to fit into the pocket, and the other ring must contain an electron-withdrawing group to enhance HB interactions. Activity prediction showed that 4c, 4d, 4f, 4g, and 4j compounds have the best IC50 from 0.33 to 0.57 μM values. There is not a direct correlation between IC50 values and binding affinity. Finally, triazole derivatives with the best IC50 can be used as potential anticancer agents by inhibiting the protein 17β-HSD1 in breast cancer.

Methods and Materials

Chemistry

Aromatic azides were obtained from their amino analogues using the methodology described by Leyva et al.53 Reagents and solvents were purchased with commercial suppliers without further purification. The reaction describes copper-catalyzed Huisgen cycloaddition (Figure 1), where phenyl acetylene was used as a dipolarophile, and like 1–3 dipole, a series of derivatives of para-substituted aromatic azides (COOH, CONH2, COOCH3, CN, NO2, Cl, F, CH3, and OCH3) and a disubstituted aromatic azide (1-azido-4-bromo-2-methylbenzene) were used. The reaction was carried out in a mixture of water/dichloromethane (1:1), where copper sulfate added as the catalyst and sodium ascorbate as the reducing agent. The progress of the reaction was monitored by TLC using ethyl acetate/n-hexane (80:20, v/v). The reaction was left under stirring for 24 h, and the products were vacuum-filtered and recrystallized with acetonitrile.

Computational Details

Molecule Preparation

All the molecular structures of the compounds in this study were fully optimized, without symmetry constraints at a semiempirical level of precision, with the parametric method number 6 (PM6). Finally, to ensure that the geometry of all the compounds is minima on the potential energy surface, a harmonic frequency analysis was performed. Furthermore, to acquire a more precise energy value and electronic density characteristics, a single-point energy calculation at a density functional theory level of precision with the B3LYP hybrid functional54 and the 6-31+G* basis set55 for H, C, N, O, F, S, and Cl atoms and LACVP pseudopotential and basis set for the Br atom were employed.56 With these results, the construction of the electrostatic potential molecular graphics was accomplished. All the calculations were done in Spartan 18.57,58

Molecular Similarity Analysis

In order to find a possible application of our synthesized compounds, we employed the ChEMBL database59 using the biphenyl-triazole scaffold (Figure 2) as a template for the search of similar compounds with experimental biological activity. From the molecular similarity analysis (MSA), we found a series of triazole derivatives synthesized by Bey et al.,4 which were evaluated as nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) for the treatment of estrogen-dependent diseases.60 These compounds showed selectivity and a considerable inhibitory potency over 17β-HSD1 (Figure 2). Also, oxazole and thiazole derivatives with inhibitory activity over this enzyme were included in this study as a reference.

Molecular Docking Methodology

For the molecular docking calculations, we used the crystal structures of the 17β-HSD1 cocrystallized with estradiol (PDB:1FDT).61 The crystal structure for 17β-HSD1 was selected to be in accordance with the experiments done by Bey et al.4 and because of the higher structural information of 17β-HSD1 catalytic site besides its crystal resolution value (2.2 Å); according to the crystal resolution, 6MNE was the better option, but much structural information was lacking. All water molecules were removed from the crystal. For the catalytic cavity calculation (volume of 146.43 Å3), the expanded van der Waals sphere method was applied (Figure 3).

We employed the optimized geometries of all the compounds and used three different partial charge schemes: Mulliken, electrostatic, and Molegro internal scheme. From this validation process, the electrostatic partial charges, obtained from the PM6 calculation, were our final option because of the reproducibility of the crystallographic conformation of estradiol according to the root-mean-square deviation value (RMSD = 0.25 Å). As a first step, we performed a rigid docking of all the compounds with 17β-HSD1 using as search and scoring function the MolDock Optimizer and MolDock score [GRID], respectively.

The parameters employed were a 0.2 Å GRID partition and a 12 Å radius for the search sphere, a total of 30 runs with a maximum of 2000 iterations and 50 individuals per run. Finally, a flexible docking calculation was carried out, where all the residues within 6 Å were set as flexible (18 residues). For the energy analysis of the ligand, the internal electrostatic interactions, internal hydrogen bonds, and the sp2–sp2 torsions were considered. Docking calculations were performed with Molegro Virtual Docker (MVD) 6.0.56,57

Acknowledgments

We wish to thank CONACYT (SEP-82585) for its financial support and Dr. Erick Cuevas-Yáñez of the Autonomous University of Mexico State for helping with NMR spectroscopic characterization. RSRH thanks to the National Supercomputing Laboratory (NSL, Puebla) for the computer time, and Dr. Zeferino Gómez-Sandoval of the University of Colima for the software facilities.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c01519.

  • Structure of 4a–j triazole compounds confirmed by UV–vis, FTIR, 1H and 13C NMR, and MS analysis and computational details of ligand preparation, MEP, and molecular docking analysis (PDF)

Author Contributions

All the authors contributed equally to this work

The authors declare no competing financial interest.

Supplementary Material

ao0c01519_si_001.pdf (5.3MB, pdf)

References

  1. Awan A.; Esfahani K. Endocrine therapy for breast cancer in the primary care setting. Curr. Oncol. 2018, 25, 285–291. 10.3747/co.25.4139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Tremont A.; Lu J.; Cole J. T. Endocrine Therapy for Early Breast Cancer: Updated Review. Ochsner J. 2017, 17, 405–411. 10.1043/TOJ-17-0036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Kruchten P.; Werth R.; Bey E.; Oster A.; Marchais-Oberwinkler S.; Frotscher M.; Hartmann R. W. Selective inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17βHSD1) reduces estrogen responsive cell growth of T47-D breast cancer cells. J. Steroid Biochem. Mol. Biol. 2009, 114, 200–206. 10.1016/j.jsbmb.2009.02.006. [DOI] [PubMed] [Google Scholar]
  4. Bey E.; Marchais-Oberwinkler S.; Werth R.; Negri M.; Al-Soud Y. A.; Kruchten P.; Oster A.; Frotscher M.; Birk B.; Hartmann R. W. Design, Synthesis, Biological Evaluation and Pharmacokinetics of Bis(hydroxyphenyl) substituted Azoles, Thiophenes, Benzenes, and Aza-Benzenes as Potent and Selective Nonsteroidal Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1). J. Med. Chem. 2008, 51, 6725–6739. 10.1021/jm8006917. [DOI] [PubMed] [Google Scholar]
  5. Dheer D.; Singh V.; Shankar R. Medicinal attributes of 1,2,3-triazoles: Current developments. Bioorg. Chem. 2017, 71, 30–54. 10.1016/j.bioorg.2017.01.010. [DOI] [PubMed] [Google Scholar]
  6. Yan W.; Wang X.; Li K.; Li T.-X.; Wang J.-J.; Yao K.-C.; Cao L.-L.; Zhao S.-S.; Ye Y.-H. Design, synthesis, and antifungal activity of carboxamide derivatives possessing 1,2,3-triazole as potential succinate dehydrogenase inhibitors. Pestic. Biochem. Physiol. 2019, 156, 160–169. 10.1016/j.pestbp.2019.02.017. [DOI] [PubMed] [Google Scholar]
  7. Arseneault M.; Wafer C.; Morin J.-F. Recent advances in click chemistry applied to dendrimer synthesis. Molecules 2015, 20, 9263–9294. 10.3390/molecules20059263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Schulze B.; Schubert U. S. Beyond click chemistry - supramolecular interactions of 1,2,3-triazoles. Chem. Soc. Rev. 2014, 43, 2522–2571. 10.1039/c3cs60386e. [DOI] [PubMed] [Google Scholar]
  9. Kirsch C.; Pulst M.; Samiullah M. H.; Ruda P.; Hasan N.; Kressler J. 1,2,3-Triazole mediated Li+ -ion conductivity in poly(ethylene oxide) based electrolytes. Solid State Ionics 2017, 309, 163–169. 10.1016/j.ssi.2017.07.022. [DOI] [Google Scholar]
  10. Li J.; Chen D.; Zhang D.; Wang Y.; Yu Y.; Gao L.; Huang M. Preparation of triazole compounds via click chemistry reaction and formation of the protective self-assembled membrane against copper corrosion. Colloid. Surface. Physicochem. Eng. Aspect. 2018, 550, 145–154. 10.1016/j.colsurfa.2018.04.030. [DOI] [Google Scholar]
  11. Huo J.; Hu Z.; Chen D.; Luo S.; Wang Z.; Gao Y.; Zhang M.; Chen H. Preparation and characterization of poly-1,2,3-triazole with chiral 2(5H)-furanone moiety as potential optical brightening agents. ACS Omega 2017, 2, 5557–5564. 10.1021/acsomega.7b00196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Mokadem Z.; Mekki S.; Saïdi-Besbes S.; Agusti G.; Elaissari A.; Derdour A. Triazole containing magnetic core-silica shell nanoparticles for Pb+2, Cu+2 and Zn+2. Arabian J. Chem. 2017, 10, 1039–1051. 10.1016/j.arabjc.2016.12.008. [DOI] [Google Scholar]
  13. Torres I.; González-Domínguez J. M.; Díaz-Ortiz A.; Romero-Nieto C.; Rominger F.; Vázquez E.; Carrillo J. R.; Prieto P. Modulation of waveguide behaviour of an ICT 2H-Benzo[d][1,2,3]Triazole derivative with graphene. Org. Electron. 2019, 68, 1–8. 10.1016/j.orgel.2019.01.033. [DOI] [Google Scholar]
  14. Xu Z.; Zhao S.-J.; Liu Y. 1,2,3-Triazole-containing hybrids as potential anticancer agents: Current developments, action mechanisms and structure-activity relationships. Eur. J. Med. Chem. 2019, 183, 111700. 10.1016/j.ejmech.2019.111700. [DOI] [PubMed] [Google Scholar]
  15. Singh H.; Kumar M.; Nepali K.; Gupta M. K.; Saxena A. K.; Sharma S.; Bedi P. M. S. Triazole tethered C5-curcuminoid-coumarin based molecular hybrids as novel antitubulin agents: Design, synthesis, biological investigation and docking studies. Eur. J. Med. Chem. 2016, 116, 102–115. 10.1016/j.ejmech.2016.03.050. [DOI] [PubMed] [Google Scholar]
  16. Jordão A. K.; Ferreira V. F.; Souza T. M. L.; de Souza Faria G. G.; Machado V.; Abrantes J. L.; de Souza M. C. B. V.; Cunha A. C. Synthesis and anti-HSV-1 activity of new 1,2,3-triazole derivatives. Bioorg. Med. Chem. 2011, 19, 1860–1865. 10.1016/j.bmc.2011.02.007. [DOI] [PubMed] [Google Scholar]
  17. Kumar K.; Pradines B.; Madamet M.; Amalvict R.; Benoit N.; Kumar V. 1H-1,2,3-triazole tethered isatin-ferrocene conjugates: Synthesis and in vitro antimalarial evaluation. Eur. J. Med. Chem. 2014, 87, 801–804. 10.1016/j.ejmech.2014.10.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Keri R. S.; Patil S. A.; Budagumpi S.; Nagaraja B. M. Triazole: A promising antitubercular agent. Chem. Biol. Drug Des. 2015, 86, 410–423. 10.1111/cbdd.12527. [DOI] [PubMed] [Google Scholar]
  19. Guimarães T. T.; Pinto M. d. C. F. R.; Lanza J. S.; Melo M. N.; do Monte-Neto R. L.; de Melo I. M. M.; Diogo E. B. T.; Ferreira V. F.; Camara C. A.; Valença W. O.; de Oliveira R. N.; Frézard F.; da Silva Júnior E. N. Potent naphthoquinones against antimony-sensitive and -resistant Leishmania parasites: Synthesis of novel α- and nor-α-lapachone-based 1,2,3-triazoles by copper-catalyzed azide-alkyne cycloaddition. Eur. J. Med. Chem. 2013, 63, 523–530. 10.1016/j.ejmech.2013.02.038. [DOI] [PubMed] [Google Scholar]
  20. González-Calderón D.; Mejía-Dionicio M. G.; Morales-Reza M. A.; Ramírez-Villalva A.; Morales-Rodríguez M.; Jauregui-Rodríguez B.; Díaz-Torres E.; González-Romero C.; Fuentes-Benítes A. Azide-enolate 1,3-dipolar cycloaddition in the synthesis of novel triazole-based miconazole analogues as promising antifungal agents. Eur. J. Med. Chem. 2016, 112, 60–65. 10.1016/j.ejmech.2016.02.013. [DOI] [PubMed] [Google Scholar]
  21. Zhang B. Comprehensive review on the anti-bacterial activity of 1,2,3-triazole hybrids. Eur. J. Med. Chem. 2019, 168, 357–372. 10.1016/j.ejmech.2019.02.055. [DOI] [PubMed] [Google Scholar]
  22. Kant R.; Kumar D.; Agarwal D.; Gupta R. D.; Tilak R.; Awasthi S. K.; Agarwal A. Synthesis of newer 1,2,3-triazole linked chalcone and flavone hybrid compounds and evaluation of their antimicrobial and cytotoxic activities. Eur. J. Med. Chem. 2016, 113, 34–49. 10.1016/j.ejmech.2016.02.041. [DOI] [PubMed] [Google Scholar]
  23. Chinthala Y.; Thakur S.; Tirunagari S.; Chinde S.; Domatti A. K.; Arigari N. K.; K.V.N.S S.; Alam S.; Jonnala K. K.; Khan F.; Tiwari A.; Grover P. Synthesis, docking and ADMET studies of novel chalcone triazoles for anti-cancer and anti-diabetic activity. Eur. J. Med. Chem. 2015, 93, 564–573. 10.1016/j.ejmech.2015.02.027. [DOI] [PubMed] [Google Scholar]
  24. Koteswara Reddy M.; Kumar K. S.; Sreenivas P.; Krupadanam G. L. D.; Reddy K. J. Synthesis of novel 1,4-disubstituted-1,2,3-triazole semi synthetic analogues of forskolin by click reaction. Tetrahedron Lett. 2011, 52, 6537–6540. 10.1016/j.tetlet.2011.08.154. [DOI] [Google Scholar]
  25. Assis S. P. d. O.; Silva M. T. d.; Silva F. T. d.; Sant’Anna M. P.; Tenório C. M. B. d. A.; Santos C. F. B. d.; Fonseca C. S. M. d.; Seabra G.; Lima V. L. M.; Oliveira R. N. d. Design and synthesis of triazole-phthalimide hybrids with anti-inflammatory activity. Chem. Pharm. Bull. 2019, 67, 96–105. 10.1248/cpb.c18-00607. [DOI] [PubMed] [Google Scholar]
  26. Yazdani M.; Edraki N.; Badri R.; Khoshneviszadeh M.; Iraji A.; Firuzi O. Multi-target inhibitors against Alzheimer disease derived from 3-hydrazinyl 1,2,4-triazine scaffold containing pendant phenoxy methyl-1,2,3-triazole: Design, synthesis and biological evaluation. Bioorg. Chem. 2019, 84, 363–371. 10.1016/j.bioorg.2018.11.038. [DOI] [PubMed] [Google Scholar]
  27. Yadav D.; Singh N.; Kim T. W.; Kim J. Y.; Park N.-J.; Baeg J.-O. Highly regioselective and sustainable solar click reaction: A new post-synthetic modified triazole organic polymer as a recyclable photocatalyst for regioselective azide-alkyne cycloaddition reaction. Green Chem. 2019, 21, 2677–2685. 10.1039/c9gc00894b. [DOI] [Google Scholar]
  28. Song M.-X.; Deng X.-Q. Recent developments on triazole nucleus in anticonvulsant compounds: A review. J. Enzym. Inhib. Med. Chem. 2018, 33, 453–478. 10.1080/14756366.2017.1423068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Massarotti A.; Aprile S.; Mercalli V.; Del Grosso E.; Grosa G.; Sorba G.; Tron G. C. Are 1,4- and 1,5-disubstituted 1,2,3-triazoles good pharmacophoric groups?. ChemMedChem 2014, 9, 2497–2508. 10.1002/cmdc.201402233. [DOI] [PubMed] [Google Scholar]
  30. Bonandi E.; Christodoulou M. S.; Fumagalli G.; Perdicchia D.; Rastelli G.; Passarella D. The 1,2,3-triazole ring as a bioisostere in medicinal chemistry. Drug Discov. Today 2017, 22, 1572–1581. 10.1016/j.drudis.2017.05.014. [DOI] [PubMed] [Google Scholar]
  31. Whiting M.; Muldoon J.; Lin Y.-C.; Silverman S. M.; Lindstrom W.; Olson A. J.; Kolb H. C.; Finn M. G.; Sharpless K. B.; Elder J. H.; Fokin V. V. Inhibitors of HIV-1 protease by using in situ click chemistry. Angew. Chem. Int. Ed. 2006, 45, 1435–1439. 10.1002/anie.200502161. [DOI] [PubMed] [Google Scholar]
  32. Lugato B.; Stucchi S.; Ciceri S.; Iannone M. N.; Turolla E. A.; Giuliano L.; Chinello C.; Todde S.; Ferraboschi P. A novel versatile precursor suitable for 18F-radiolabeling via “click chemistry”. J. Label. Compd. Radiopharm. 2017, 60, 466–480. 10.1002/jlcr.3529. [DOI] [PubMed] [Google Scholar]
  33. Neumann S.; Biewend M.; Rana S.; Binder W. H. The CuAAC: Principles, homogeneous and heterogeneous catalysts, and novel developments and applications. Macromol. Rapid Commun. 2020, 41, 1900359. 10.1002/marc.201900359. [DOI] [PubMed] [Google Scholar]
  34. Khalili D.; Kavoosi L.; Khalafi-Nezhad A. Copper aluminate spinel in click chemistry: An efficient heterogeneous nanocatalyst for the highly regioselective synthesis of triazoles in water. Synlett 2019, 30, 2136–2142. 10.1055/s-0039-1690719. [DOI] [Google Scholar]
  35. Chassaing S.; Bénéteau V.; Pale P. When CuAAC ’Click Chemistry’ goes heterogeneous. Catal. Sci. Technol. 2016, 6, 923–957. 10.1039/c5cy01847a. [DOI] [Google Scholar]
  36. Chavan P. V.; Charate S. P.; Desai U. V.; Rode C. V.; Wadgaonkar P. P. Bentonite-clay-supported cuprous iodine nanoparticles (BENT-CuI NPs): A new heterogeneous catalyst in diversity-oriented synthesis of 1,2,3-triazoles in aqueous medium. ChemistrySelect 2019, 4, 7144–7150. 10.1002/slct.201900421. [DOI] [Google Scholar]
  37. Arafa W. A. A.; Nayl A. E.-A. A. Water as a solvent for Ru-catalyzed click reaction: Highly efficient recyclable catalytic system for triazolocoumarins synthesis. Appl. Organomet. Chem. 2019, 33, e5156 10.1002/aoc.5156. [DOI] [Google Scholar]
  38. Vorona S. V.; Zevatskii Y. E.; Myznikov L. V. Zinc (II) chloride as phase transfer catalyst and as catalyst of cycloaddition azide ion to heterocumulenes and terminal alkynes in organic solvents. ChemistrySelect 2019, 4, 10846–10850. 10.1002/slct.201903162. [DOI] [Google Scholar]
  39. Wang C.; Ikhlef D.; Kahlal S.; Saillard J.-Y.; Astruc D. Metal-catalyzed azide-alkyne “click” reactions: Mechanistic overview and recent trends. Coord. Chem. Rev. 2016, 316, 1–20. 10.1016/j.ccr.2016.02.010. [DOI] [Google Scholar]
  40. Wang K.; Sprunt S.; Twieg R. J. The synthesis of [1,2,3]-triazole-based bent core liquid crystals via microwave-mediated ’Click Reaction’ and their mesomorphic behaviour. Liq. Cryst. 2019, 46, 257–271. 10.1080/02678292.2018.1493755. [DOI] [Google Scholar]
  41. Stefani H. A.; Ferreira F. P.; Vieira A. S. One-pot, three-step reaction of 5-[(trimethylsilyl)ethynyl]pyrrolidin-2-one with azides catalyzed by CuI: Synthesis of a novel class of 1,4-disubstituted 1,2,3-triazoles. Aust. J. Chem. 2012, 65, 1443–1450. 10.1071/ch12255. [DOI] [Google Scholar]
  42. Kallander L. S.; Lu Q.; Chen W.; Tomaszek T.; Yang G.; Tew D.; Meek T. D.; Hofmann G. A.; Schulz-Pritchard C. K.; Smith W. W.; Janson C. A.; Ryan M. D.; Zhang G.-F.; Johanson K. O.; Kirkpatrick R. B.; Ho T. F.; Fisher P. W.; Mattern M. R.; Johnson R. K.; Hansbury M. J.; Winkler J. D.; Ward K. W.; Veber D. F.; Thompson S. K. 4-aryl-1,2,3-triazole: A novel template for a reversible methionine aminopeptidase 2 inhibitor, optimized to inhibit angiogenesis in vivo. J. Med. Chem. 2005, 48, 5644–5647. 10.1021/jm050408c. [DOI] [PubMed] [Google Scholar]
  43. Queiroz T. M.; Orozco E. V. M.; Silva V. R.; Santos L. S.; Soares M. B. P.; Bezerra D. P.; Porto A. L. M. Semi-synthesis of β-keto-1,2,3-triazole derivatives from ethinylestradiol and evaluation of the cytotoxic activity. Heliyon 2019, 5, e02408 10.1016/j.heliyon.2019.e02408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Odlo K.; Hentzen J.; dit Chabert J. F.; Ducki S.; Gani O. A. B. S. M.; Sylte I.; Skrede M.; Flørenes V. A.; Hansen T. V. 1,5-disubstituted 1,2,3-triazoles as cis-restricted analogues of combretastatin A-4: Synthesis, molecular modeling and evaluation as cytotoxic agents and inhibitors of tubulin. Bioorg. Med. Chem. 2008, 16, 4829–4838. 10.1016/j.bmc.2008.03.049. [DOI] [PubMed] [Google Scholar]
  45. Yoon J.; Ryu J.-S. A rapid synthesis of lavendustin-mimetic small molecules by click fragment assembly. Bioorg. Med. Chem. Lett. 2010, 20, 3930–3935. 10.1016/j.bmcl.2010.05.014. [DOI] [PubMed] [Google Scholar]
  46. Peterson L. B.; Blagg B. S. J. Click chemistry to probe Hsp90: Synthesis and evaluation of a series of triazole-containing novobiocin analogues. Bioorg. Med. Chem. Lett. 2010, 20, 3957–3960. 10.1016/j.bmcl.2010.04.140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Agalave S. G.; Maujan S. R.; Pore V. S. Click chemistry: 1,2,3-triazoles as pharmacophores. Chem.—Asian J. 2011, 6, 2696–2718. 10.1002/asia.201100432. [DOI] [PubMed] [Google Scholar]
  48. Some of the synthesized azides had already been reported in the literature.; 2a:Obushak N. D.; Pokhodylo N. T.; Pidlypnyi N. I.; Matiichuk V. S. Synthesis of 1,2,4- and 1,3,4-oxadiazoles from 1-aryl-5-methyl-1H-1,2,3-triazole-4-carbonyl chlorides. Russ. J. Org. Chem. 2008, 44, 1522–1527. 10.1134/s1070428008100217. [DOI] [Google Scholar]; 2b:Meng X.; Chen W.; Zhang Y.; Chen Y.; Chen B. NBS-mediated aziridination between styrenes and amides under transition metal-free conditions. J. Heterocycl. Chem. 2014, 51, 937–942. 10.1002/jhet.1555. [DOI] [Google Scholar]; 2c:Aldrich C.; Grimes K. D.; Gupte A. Copper(II)-catalyzed conversion of aryl/heteroaryl boronic acids, boronates, and trifluoroborates into the corresponding azides: Substrate scope and limitations. Synthesis 2010, 9, 1441–1448. 10.1055/s-0029-1218683. [DOI] [PMC free article] [PubMed] [Google Scholar]; 2d:Bakulev V. A.; Efimov I. V.; Belyaev N. A.; Rozin Y. A.; Volkova N. N.; El’tsov O. S. Novel method for the synthesis of 4-(azol-5-yl)-1,2,3-triazoles. Chem. Heterocycl. Compd. 2012, 47, 1593–1595. 10.1007/s10593-012-0952-z. [DOI] [Google Scholar]; 2e:Khan A.; Prasad S.; Parmar V. S.; Sharma S. K. Design and synthesis of novel triazolyl benzoxazine derivatives and evaluation of their antiproliferative and antibacterial activity. J. Heterocycl. Chem. 2016, 53, 1264–1275. 10.1002/jhet.2387. [DOI] [Google Scholar]; 2f:Brunner W. H.; Kustatscher J. Einwirkung aromatischer diazoniumsalze auf ungesättigte verbindungen. Monatsh. Chem. Verw. Teile Anderer Wiss. 1951, 82, 100–106. 10.1007/bf01044195. [DOI] [Google Scholar]; 2g, 2j:Bhardwaj M.; Jamwal B.; Paul S. Novel Cu(0)-Fe3O4@SiO2/NH2cel as an efficient and sustainable magnetic catalyst for the synthesis of 1,4-disubstituted-1,2,3-triazoles and 2-substituted-benzothiazoles via one-pot strategy in aqueous media. Catal. Lett. 2016, 146, 629–644. 10.1007/s10562-015-1672-7. [DOI] [Google Scholar]; 2h:Ishmetova R.I.; Yachevskii D. S.; Ignatenko N. K.; Slepukhin P. A.; Efimov I. V.; Bakulev V. A.; Rusinov G. L.; Filyakova V.I.; Charushin V. N. Terminal bis-acetylenes derived from 1,2-bis(1H-tetrazol-5-yl)ethane. Russ. Chem. Bull. 2016, 65, 1268–1271. 10.1007/s11172-016-1446-4. [DOI] [Google Scholar]; 1-Azide-4-bromo-2-methyl-benzene (2i), ambar liquid and 84% yield. UV–vis in methanol, λmax (nm): 213, 258 (π → π* C=C, Ar), 297 (η → π*, azide). FTIR–ATR (cm–1): 2917 (CH3); 2111, 2069 (N3); 1591, 1479 (C=C, Ar); 1389 (CH3); 1100 (C–Br); 859, 801 (oop C–H, Ar). See Supporting Information file.
  49. 1,2,3-Triazoles already reported in the literature.; 4f:Dai P.-F.; Ning X.-S.; Wang H.; Cui X.-C.; Liu J.; Qu J.-P.; Kang Y.-B. Cleavange of C(aryl)-CH3 bonds in the absence of directing groups under transition metal free conditions. Angew. Chem. Int. Ed. 2019, 58, 5392–5395. 10.1002/anie.201901783. [DOI] [PubMed] [Google Scholar]; 4g:Uozumi Y.; Nagaosa M. Azidation of arylboronic acids in water catalyzed by magnetic CuFe2O4 NPs. Synfacts 2013, 9, 1127. 10.1055/s-0033-1339740. [DOI] [Google Scholar]; 4h:Kloss F.; Köhn U.; Jahn B. O.; Hager M. D.; Görls H.; Schubert U. S. Metal-free 1,5-regioselective azide-alkyne [3+2]-cycloaddition. Chem.—Asian. J. 2011, 6, 2816–2824. 10.1002/asia.201100404. [DOI] [PubMed] [Google Scholar]; 4j:Bhardwaj M.; Jamwal B.; Paul S. Novel Cu(0)-Fe3O4@SiO2/NH2cel as an efficient and sustainable magnetic catalyst for the synthesis of 1,4-disubstituted-1,2,3-triazoles and 2-substituted-benzothiazoles via one-pot strategy in aqueous media. Catal. Lett. 2016, 146, 629–644. 10.1007/s10562-015-1672-7. [DOI] [Google Scholar]; . In An example of spectroscopy characterization of new 1,2,3-triazoles synthesized: 4-(4-phenyl-1H-1,2,3-triazol-1-yl)-benzoic acid (4a). A white solid with mp of 334–336 °C and 88% yield. UV–vis in methanol λmax (nm): 206, 274 (π → π* C=C, Ar); 248 (π → π*, triazole); 290 (η → π*, triazole). FTIR–ATR (cm–1): 3200–2500 (O–H); 3136 (C–H, Ar); 1678 (C=O); 1604, 1424 (C=C, Ar); 1315 (C–N); 1289, 1231 (C–O); 859, 762, 685 (C–H, oop Ar). 1H NMR (DMSO-d6, ppm): δ 7.37 (br t, 1H), 7.48 (br t, 2H), 7.94 (br d, 2H), 8.10 (br d, 2H), 8.15 (br d, 2H), 9.40 (s, 1H). The proton of COOH was not observed since it resonates at very high frequency range δ 11–14 ppm, the spectrum was cut at 12 ppm. 13C NMR (DMSO-d6, ppm): δ 120.09, 125.82 (3C), 128.84, 129.47 (2C), 130.44, 139.95, 148.02, 177.20. MS(ESI): 116.01, 165.03, 192.02, 220.01, 251.03, 252.03, 279.05, 280.05. See Supporting Information file
  50. Meldal M.; Tornøe C. W. Cu-Catalyzed Azide–Alkyne Cycloaddition. Chem. Rev. 2008, 108, 2952–3015. 10.1021/cr0783479. [DOI] [PubMed] [Google Scholar]
  51. Brantley J. N.; Wiggins K. M.; Bielawski C. W. Unclicking the Click: Mechanically Facilitated 1,3-Dipolar Cycloreversions. Science 2011, 333, 1606–1609. 10.1126/science.1207934. [DOI] [PubMed] [Google Scholar]
  52. Liebfarth F. A.; Hawker C. J. Mechanically throwing a reaction into reverse. Science 2011, 333, 1582–1583. 10.1126/science.1210892. [DOI] [PubMed] [Google Scholar]
  53. Leyva E.; de Loera D.; Jiménez-Cataño R. Spontaneous conversion of 2-azido-3-nitropyridines to pyridofuroxans. Tetrahedron Lett. 2010, 51, 3978–3979. 10.1016/j.tetlet.2010.05.118. [DOI] [Google Scholar]
  54. Rimon G.; Sidhu R. S.; Lauver D. A.; Lee J. Y.; Sharma N. P.; Yuan C.; Frieler R. A.; Trievel R. C.; Lucchesi B. R.; Smith W. L. Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 28–33. 10.1073/pnas.0909765106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Orlando B. J.; Malkowski M. G. Crystal structure of rofecoxib bound to human cyclooxygenase-2. Acta Crystallogr., Sect. F: Struct. Biol. Commun. 2016, 72, 772–776. 10.1107/s2053230x16014230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Yang J.-M.; Chen C.-C. GEMDOCK: A generic evolutionary method for molecular docking. Proteins 2004, 55, 288–304. 10.1002/prot.20035. [DOI] [PubMed] [Google Scholar]
  57. Thomsen R.; Christensen M. H. MolDock: A New Technique for High-Accuracy Molecular Docking. J. Med. Chem. 2006, 49, 3315–3321. 10.1021/jm051197e. [DOI] [PubMed] [Google Scholar]
  58. Spartan’14; Wavefunction Inc., 2014. Available from www.wavefun.com.
  59. Halgren T. A. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J. Comput. Chem. 1996, 17, 490–519. . [DOI] [Google Scholar]
  60. Stewart J. J. P. Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements. J. Mol. Model. 2007, 13, 1173–1213. 10.1007/s00894-007-0233-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Pérez D. J.; Sarabia O.; Villanueva-García M.; Pineda-Urbina K.; Ramos-Organillo Á.; Gonzalez-Gonzalez J.; Gómez-Sandoval Z.; Razo-Hernández R. S. In silico receptor-based drug design of X,Y-benzenesulfonamide derivatives as selective COX-2 inhibitors. Compt. Rendus Chem. 2017, 20, 169–180. 10.1016/j.crci.2016.05.015. [DOI] [Google Scholar]

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