Synthesis and anti-proliferative activity of a novel 1,2,3-triazole tethered chalcone acetamide derivatives

doi:10.1016/j.bmcl.2020.127304

Bioorganic & Medicinal Chemistry Letters

Volume 30, Issue 16, 15 August 2020, 127304

https://doi.org/10.1016/j.bmcl.2020.127304 Get rights and content

Highlights

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A novel series of 1,2,3-triazole tethered chalcone acetamide derivatives were efficiently synthesized.
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Evaluated for their in vitro anti-proliferative activity.
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Compound 7c exhibiting promising anti-proliferation with IC₅₀ 7.41 + 0.8 to 9.76 + 1.3 μM.
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The docking results are complementary to the experimental observations.

Abstract

A new series of 1,2,3-triazole tethered chalcone acetamide derivatives (7a-c & 8a-r) have been synthesized in excellent yields and their structures were determined by analytical and spectral (FT-IR, ¹H NMR, ¹³C NMR & HRMS) studies. The newly synthesized derivatives were evaluated for their cytotoxic activity against four human cancer cell lines, such as HeLa (Human cervical cancer), A549 (Human alveolar adenocarcinoma), MCF-7 (Human breast adenocarcinoma) and SKNSH (Human brain cancer). Among them, compound 7c exhibited good anti-proliferation activity with HeLa (IC₅₀ 7.41 + 0.8 μM), SKNSH (IC₅₀ 8.68 + 1.1 μM), MCF-7 (IC₅₀ 9.76 + 1.3 μM) and MDA-MB-231, while compounds 7a and 7b showed promising anti-proliferation against above four human cancer cell lines with IC₅₀ 7.95–11.62 μM, respectively, compared with the standard drug Doxorubicin. We explored the probable key active site and binding mode interactions in HDAC8 (PDB ID:3SFH) and EHMT2 (PDB ID:3K5K) proteins. The docking results are complementary to the experimental observations.

Graphical abstract

A novel series of new building blocks consisting of 1,2,3-triazole tethered chalcone acetamides have been synthesized in excellent yields and evaluated for their anti-proliferative activity against four human cell lines. The docking results are complementary to the experimental observations.

Section snippets

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.

Acknowledgements

The authors gratefully acknowledge the financial support through the project: DST-SERB/EEQ/2017/095 and the Council of Scientific and Industrial Research (CSIR), New Delhi, India for the award of fellowship to SV.

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Citation Excerpt :
The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) offers a versatile root to the 1,2,3-triazoles scaffolds, that could form diverse non-covalent interactions, such as van der Waals forces, dipole–dipole bonds and hydrogen bonds with various proteins, enzymes, and receptors with high resistance to enzymatic degradation, which enables their potential use in medicinal chemistry. They have been widely recognized for their diverse biological and pharmaceutical activities such as antitubercular (Pradeep Kumar et al., 2021, Badar et al., 2020), antimicrobial (Badar et al., 2020, Bitla et al., 2021), antituberculosis (Hervin et al., 2020), antiproliferative (Vanaparthi et al., 2020), antibacterial (Xu, 2020), antioxidant (Sahin et al., 2021), anticancer (Sahin et al., 2021), α-glucosidase (Shareghi-Boroujeni et al., 2021) and antifungal (Joolakanti et al., 2021) agents. In addition, some medications containing 1,2,3-triazole as an active moiety are clinically used as antimicrobial agents such as Radezolid, Cefatrizine and Tazobactam (Fig. 1).
In an attempt to rationalize the search for new potential anti-inflammatory and anti-infection agents, a new series of 1,4-and 1,5-disubstituted 1,2,3-triazoles linked benzoxazine conjugates have been synthesized via “Click Chemistry” reaction, were designed, synthesized and characterized by means of spectral and elemental data. The newly synthesized compounds have been assessed for their antimicrobial, antioxidant and anti-inflammatory potential. Results revealed that all synthesized compounds display superior activities to the standard drug against different bacterial strains especially S. aureus, M. luteus, and P. aeruginosa, with good to moderate activity towards the tested E. coli bacteria, in respect to the commercial antibiotic, tetracycline. Moreover, the antifungal activity was screened against C. albicans and C. krusei yeasts and results demonstrate potent activity as compared to the standard drug, ampicillin. The antioxidant activity was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging assays, whose results indicate that analogues 4a (IC₅₀ 1.88 ± 0.07 µM and 2.17 ± 0.02) followed by 4b (IC₅₀ 2.19 ± 0.09 µM and 2.38 ± 0.43 µM), 4d (IC₅₀ 2.30 ± 0.01 µM and 4.07 ± 0.57 µM), and 4f (2.98 ± 0.02 µM and 3.80 ± 0.01 µM), respectively, exhibited the strongest activity when compared to the standard reference, butylated hydroxytoluene (BHT) (3.52 ± 0.08 µM and 4.64 ± 0.11 µM). In addition, their anti-inflammatory activity was assessed using the xylene-induced ear edema standard technique and the results demonstrated the potency of 4a, 4b and 4d as excellent anti-inflammatory agents. Preliminary structure–activity relationship studies (SARs) provide those biological activities can be modulated by the presence of unsubstituted aromatic ring as well as the position of substituents on the phenyl moiety via electron withdrawing groups (EWGs) or electron donating groups (EDGs) effects. Docking studies on the most promising compounds 4a, 4b, and 4d into the active sites of S. aureus tyrosyl-tRNA synthetase, Candida albicans N-Myristoyltransferase, Human COX-2 enzyme, and Human Peroxiredoxin 5 revealed good binding profiles with the target proteins. The interaction's stability was further assessed using a conventional atomistic 100 ns dynamic simulation study. Hence, our results recommended the rationalized targets 4a, 4b and 4d, to be promising lead candidates for the discovery of novel dual anti-inflammatory and anti-infection agents.
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Citation Excerpt :
Therefore, hybrid molecules can attenuate the risk of multiple drug resistance as well as a drug-drug interaction which could be useful for humanity to resist microbial resistance. 1,2,3-Triazoles have attracted much attention in designing new lead molecules simply because of ease of preparation by a Cu(I)-catalyzed azide-alkyne cycloaddition and broad spectrum of pharmacological activities including anti-viral [6–8], anti-cancer [9–17], anti-bacterial [18–23], anti-fungal [24–30], α-glucosidase inhibition [31,32], anti-tubercular [33–35], anti-protozoal [36], anti-oxidant [37], anti-inflammatory [38], anti-proliferative [39,40]. 1,2,3-Triazoles have also been found to be the constituent of some of the well-known drugs such as Tazobactam, Cefatrizine, Carboxyamidotriazole and Rufinamide.
A new series of pyrazoline-amide linked 1,2,3-triazole hybrids was wisely designed and synthesized using 1,3-dipolar cycloaddition between pyrazoline linked alkynes and 2-bromo-N-arylacetamide. All the newly synthesized compounds were evaluated in vitro against different microbial strains viz. Escherichia coli, Bacillius subtilis, Staphylococcus aureus, Aspergillus niger, and Candida albicans. Pyrazoline linked terminal alkynes (4a–c) showed MIC = 0.062–0.078 μmol/mL against different bacterial and fungal strain. However, pyrazoline-amide linked 1,2,3-triazole hybrids (6a-6t) showed MIC = 0.0229–0.050 μmol/mL. Compound 6e exhibited better efficacy against E. coli and both the fungal strains compared to standard drugs used. Docking studies of the most potent compounds were carried out against bacterial DNA Gyr A and fungal 14α-steroldemethylase were also performed. The binding potential of 4a and 6e with both the target using molecular dynamics simulations was also investigated.

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Synthesis and anti-proliferative activity of a novel 1,2,3-triazole tethered chalcone acetamide derivatives

Highlights

Abstract

Graphical abstract

Section snippets

Declaration of Competing Interest

Acknowledgements

Bioorg Med Chem

Bioorg Med Chem Lett

Eur J Med Chem

Tetrahedron Lett

Bioorg Med Chem Lett

Bioorg Med Chem Lett

Eur J Med Chem

Bioorg Med Chem Lett

Bioorg Med Chem Lett