1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

The 1,2,3-triazole ring is a major pharmacophore system among nitrogen-containing heterocycles. These five-membered heterocyclic motifs with three nitrogen heteroatoms can be prepared easily using ‘click’ chemistry with copper- or ruthenium-catalysed azide-alkyne cycloaddition reactions. Recently, the ‘linker’ property of 1,2,3-triazoles was demonstrated, and a novel class of 1,2,3-triazole-containing hybrids and conjugates was synthesised and evaluated as lead compounds for diverse biological targets. These lead compounds have been demonstrated as anticancer, antimicrobial, anti-tubercular, antiviral, antidiabetic, antimalarial, anti-leishmanial, and neuroprotective agents. The present review summarises advances in lead compounds of 1,2,3-triazole-containing hybrids, conjugates, and their related heterocycles in medicinal chemistry published in 2018. This review will be useful to scientists in research fields of organic synthesis, medicinal chemistry, phytochemistry, and pharmacology.     

A rapid synthesis of lavendustin-mimetic small molecules by click fragment assembly

Lavendustin-mimetic small molecules modifying the linker –CH₂–NH– with an 1,2,3-triazole ring have been synthesized via a click chemistry. Two pharmacophoric fragments of lavendustin were varied to investigate chemical space and the auxophoric –CH₂–NH– was altered to an 1,2,3-triazole for rapid click conjugation. The small molecules were evaluated against HCT116 colon cancer and CCRF-CEM leukemia cell lines. Among 28 analogues, 3-phenylpropyl ester 26b inhibited CCRF-CEM leukemia cell growth with GI₅₀ value of 0.9 μM.     

Click chemistry based synthesis,cytotoxic activity and molecular docking of novel triazole-thienopyrimidine hybrid glycosides targeting EGFR

In the current study, new thienopyrimidine conjugates bearing 1,2,3-triazole core and different sugar moieties have been designed and synthesized by Cu(I)-catalysed click dipolar cycloaddition. The cytotoxic activity of the synthesised conjugates 2, 5, 7, and 13–18 was studied against HCT-116 and MCF-7 cell lines by the MTT assay. The triazole glycosides 16 and 18 provided significant cytotoxic activities against HCT-116 cell lines comparable to that of doxorubicin and other studied compounds. The cytotoxic behaviour against MCF-7 exhibited that all the investigated compounds were more potent than doxorubicin. Moreover, all screened targets were evaluated against mutant EGFR kinase type L858R and the results revealed that the acetylated 1,2,3-triazole glycosides 13–18 exhibited excellent EGFR inhibitory activity in comparison with gefitinib. Furthermore, molecular modelling studies were performed to investigate the binding affinity of the most active compounds to EGFR enzyme.     

Bionanoconjugation via click chemistry: The creation of functional hybrids of lipases and gold nanoparticles

A simple and versatile method for the preparation of functional enzyme-gold nanoparticle conjugates using "click" chemistry has been developed. In a copper-catalyzed 1,2,3-triazole cycloaddition, an acetylene-functionalized Thermomyces lanuginosus lipase has been attached to azide-functionalized water-soluble gold nanoparticles under retention of enzymatic activity. The products have been characterized by gel electrophoresis and a fluorometric lipase activity assay. It is estimated that the equivalent of approximately seven fully active lipase molecules are attached to each nanoparticle.     

Synthesis and antimicrobial activity of beta-lactam-bile acid conjugates linked via triazole

Synthesis of novel 1,2,3-triazole-linked beta-lactam-bile acid conjugates 17-24 using 1,3-dipolar cycloaddition reaction of azido beta-lactam and terminal alkyne of bile acids in the presence of Cu(I) catalyst (click chemistry) have been realized. These molecules were evaluated in vitro for their antifungal and antibacterial activities. Most of the compounds exhibited significant antifungal and moderate antibacterial activity against all the tested strains.     

Synthesis and cytotoxic evaluation of novel ester-triazole-linked triterpenoid–AZT conjugates

Betulinic acid and analogous naturally occurring triterpenoid acids were transformed into the corresponding propargyl esters and subsequently deployed as substrates for a click chemistry-mediated coupling with azidothymidine (AZT) en route to novel 1,2,3-triazole-tethered triterpenoid–AZT conjugates. Twelve new hybrids were thus prepared and assessed in terms of their cytotoxic activity, revealing an interesting anticancer activity of five triterpenoid–AZT hybrids on KB and Hep-G2 tumor cell lines.     

Synthesis,computational study and biological evaluation of 9-acridinyl and 1-coumarinyl-1,2,3-triazole-4-yl derivatives as topoisomerase II inhibitors

Topoisomerase (IIB) inhibitors have been involved in the therapies of tumour progression and have become a major focus for the development of anticancer agents. New three-component hybridised ligands, 1,4-disubstituted-1,2,3-triazoles (8–17), were synthesised via a 1,3-dipolar cycloaddition reaction of 9-azidoacridine/3-azidocoumarin with N/O-propargyl small molecules under click reaction conditions. Cancer cell growth inhibition of the synthesised triazoles was tested against human cell-lines in the NCI-60-cell-panel, and the most active compounds tested against topoisomerase (IIB)-enzymes. The acridinyl ligands (8–10) revealed 60–97% cell growth inhibition in six cancer cell-panels. Cell-cycle analysis of MCF7 and DU-145 cells treated with the active acridinyl ligands exhibited cell-cycle arrest at G2/M phase and proapoptotic activity. In addition, compound 8 displayed greater inhibitory activity against topoisomerase (IIB) (IC₅₀ 0.52 µM) compared with doxorubicin (IC₅₀ 0.83 µM). Molecular dynamics simulation studies showed the acridine–triazole–pyrimidine hybrid pharmacophore was optimal with respect to protein–ligand interaction and fit within the binding site, with optimal orientation to allow for intercalation with the DNA bases (DG13, DC14, and DT9).     

Small molecule purine and pseudopurine derivatives: synthesis,cytostatic evaluations and investigation of growth inhibitory effect in non-small cell lung cancer A549

Novel halogenated purines and pseudopurines with diverse aryl-substituted 1,2,3-triazoles were prepared. While p-(trifluoromethyl)-substituted 1,2,3-triazole in N-9 alkylated purine and 3-deazapurine was critical for strong albeit unselective activity on pancreatic adenocarcinoma cells CFPAC-1,1-(p-fluorophenyl)-1,2,3-triazole derivative of 7-deazapurine showed selective cytostatic effect on metastatic colon cancer cells SW620. Importantly, 1-(p-chlorophenyl)-1,2,3-triazole-tagged benzimidazole displayed the most pronounced and highly selective inhibitory effect in nM range on non-small cell lung cancer A549. This compound revealed to target molecular processes at the extracellular side and inside the plasma membrane regulated by GPLD1 and growth factor receptors PDGFR and IGF-1R leading to the inhibition of cell proliferation and induction of apoptosis mediated by p38 MAP kinase and NF-κB, respectively. Further optimisation of this compound as to reduce its toxicity in normal cells may lead to the development of novel agent effective against lung cancer.     

Design,Synthesis and Cytotoxicity of New Coumarin-1,2,3-triazole Derivatives: Evaluation of Anticancer Activity and Molecular Docking Studies

A library of new coumarin-1,2,3-triazole hybrids 7a – l were synthesized from 4-(diethylamino)-2-hydroxybenzaldehyde precursor through a series of reactions including Vilsmeier-Haack reaction and condensation reaction to achieve key intermediate oxime and further performed click reaction by using different aromatic azides. We screened all molecules in silico against crystal structure of Serine/threonine-protein kinase 24 (MST3), based on these results all molecules were screened for their cytotoxicity against human breast cancer MCF-7 and lung cancer A-549 cell lines. Compound 7 b (p-bromo) showed best activity against both cell lines MCF-7 and A-549 with IC₅₀ value of 29.32 and 21.03 μM, respectively, in comparison to Doxorubicin corresponding IC₅₀ value of 28.76 and 20.82 μM. Another compound 7 f (o-methoxy) also indicated good activity against both cell lines with IC₅₀ value of 29.26 and 22.41 μM. The toxicity of all compounds tested against normal HEK-293 cell lines have not shown any adverse effects.     

BODIPY-17α-ethynylestradiol conjugates: Synthesis,fluorescence properties and receptor binding affinities

In vivo imaging of estrogen receptor (ER) densities in human breast cancer is a potential tool to stage disease, guide treatment protocols and follow-up on treatment outcome. Both positron emission tomography (PET) and fluorescence imaging have received ample attention to detect ligand-ER interaction. In this study we prepared BODIPY-estradiol conjugates using 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) as fluorescent probe and estradiol derivatives as ligand and established their relative binding affinity (RBA) for the ERα. The synthesis of the conjugates involves attachment of a BODIPY moiety to the C17α-position of estradiol using Sonogashira or click reactions of iodo-BODIPY or aza-BODIPY with various 17α-ethynylestradiol (EE2) derivatives. The highest RBA for the ERα was observed with the EE2-BODIPY conjugate (7) featuring a linear eight carbon spacer chain. Cell uptake studies and in vivo imaging experiments in an ER-positive mouse tumor model are in progress.     

Synthesis of 1,2,3-triazole-linked pyrrolobenzodiazepine conjugates employing 'click' chemistry: DNA-binding affinity and anticancer activity

1,2,3-Triazole based molecules are useful pharmacophores for several DNA-alkylating and cross-linking agents. A series of A/C8, C/C2 and A/C8-C/C2-linked 1,2,3-triazole-PBD conjugates have been synthesized by employing 'click' chemistry. These molecules have exhibited promising DNA-binding affinity and anticancer activity in selected human cancer cell lines.     

Synthesis of 3-phenylpyrazolopyrimidine-1,2,3-triazole conjugates and evaluation of their Src kinase inhibitory and anticancer activities

A series of two classes of 3-phenylpyrazolopyrimidine-1,2,3-triazole conjugates were synthesized using click chemistry approach. All compounds were evaluated for inhibition of Src kinase and human ovarian adenocarcinoma (SK-Ov-3), breast carcinoma (MDA-MB-361), and colon adenocarcinoma (HT-29). Hexyl triazolyl-substituted 3-phenylpyrazolopyrimidine exhibited inhibition of Src kinase with an IC₅₀ value of 5.6 μM. 4-Methoxyphenyl triazolyl-substituted 3-phenylpyrazolopyrimidine inhibited the cell proliferation of HT-29 and SK-Ov-3 by 73% and 58%, respectively, at a concentration of 50 μM.     

Design,synthesis and anticancer activity of novel pyrimidine and pyrimidine-thiadiazole hybrid glycosides

Abstract

New 1,3,4-thiadiazole thioglycosides linked to substituted pyrimidines were synthesized via glycosylation of 1,3,4-thiadiazole thiol compounds. Also, novel 1,2,3-triazole derivatives linked to carbohydrate units were prepared using the standard click chemistry conditions employing the Cu(I)-catalyzed azide-alkyne cycloaddition of substituted-aryl-azides with a selection of alkyne-functionalized sugars. The chemical structures of the new derivatives were verified using various spectroscopic techniques, such as IR, ¹H NMR, ¹³C NMR and elemental analyses. The cytotoxic activities of the prepared compounds were investigated in vitro against human liver cancer (HepG-2) and human breast adenocarcinoma (MCF7) cell lines. In addition, the biological evaluation of the new compounds involved the investigation of their effects on a human normal retinal pigmented epithelial cell line (RPE1) using the MTT assay.     

Synthesis and binding ability of 1,2,3-triazole-based triterpenoid receptors for recognition of Hg2+ ion

A novel type of receptors based on 1,2,3-triazole glycyrrhetinic acid derived from natural triterpenoid molecules has been synthesized via click chemistry and they showed high selectivity and affinity for Hg²⁺ ion by both the 1,2,3-triazole rings and aldehyde groups.     

Synthesis and biological evaluation of 3-hydroxymethyl-5-(1H-1,2,3-triazol) isoxazolidines

A synthetic approach towards a series of 3-hydroxymethyl-5-(1H-1,2,3-triazol)isoxazolidines has been reported, according to a procedure based on the cycloaddition reaction, under microwave irradiation, of a nitrone with 1-vinyl triazoles, prepared by a click reaction of azides with alkynes. Biological tests show that the synthesized compounds are able to inhibit proliferation of follicular and anaplastic human thyroid cancer cell lines, with IC₅₀ values ranging from 3.87 to 8.76 μM. The obtained compounds induce caspase-3 activation and DNA fragmentation prevalently in follicular human thyroid cancer cell lines.     

Synthesis and biological evaluation of 4-(1,2,3-triazol-1-yl)coumarin derivatives as potential antitumor agents

In this research, a series of 4-(1,2,3-triazol-1-yl)coumarin conjugates were synthesized and their anticancer activities were evaluated in vitro against three human cancer cell lines, including human breast carcinoma MCF-7 cell, colon carcinoma SW480 cell and lung carcinoma A549 cell. To increase the biological potency, structural optimization campaign was conducted focusing on the C-4 position of 1,2,3-triazole and the C-6, C-7 positions of coumarin. In addition, to further evaluate the role of 1,2,3-triazole and coumarin for antiproliferative activity, 9 compounds possessing 4-(piperazin-1-yl)coumarin framework and 3 derivatives baring quinoline core were also synthesized. By MTT assay in vitro, most of the compounds display attractive antitumor activities, especially 23. Further flow cytometry assays demonstrate that compound 23 exerts the antiproliferative role through arresting G₂/M cell-cycle and inducing apoptosis.     

Synthesis of quinoline coupled [1,2,3]-triazoles as a promising class of anti-tuberculosis agents

A series of quinoline coupled 1,2,3-triazoles compounds have been synthesized by ‘click chemistry’ from azidomethyl quinoline with different alkynes. The efficiency and fidelity of the Cu(I)-catalyzed azide–alkyne reaction are substantiated by good yields and exclusive formation of the expected 1,4-disubstituted triazole product. All the synthesized compounds were screened for anti-tubercular activity against Mycobacterium tuberculosis H37Rv by luciferase reporter phage (LRP) assay. Quinoline coupled triazole sugar hybrid, 20 is the most potent compound in the series with 76.41% and 78.37% reduction calculated based on percentage reduction in Relative Light Units at 5 and 25 μg/mL, respectively.     

Synthesis and biological evaluation of 4beta-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxins as potential anticancer agents

A series of novel 4beta-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin derivatives were synthesized by employing Cu(I)-catalyzed click chemistry and evaluated for their anticancer activity against a panel of seven human cancer cell lines (HT-29, HCT-15, 502713, HOP-62, A-549, MCF-7, and SF-295). The compounds 9b, 9c, 9e, 9f, and 9h showed significant cytotoxic activities especially against HT-29, HCT-15, 502713 cell lines.     

1,2,3-Triazole Fused Quinoline-Peptidomimetics: Studies on Synthesis, DNA Binding and Photonuclease Activity

Abstract  

We present, simple approach for the accession of 1,2,3-triazole fused quinoline peptide analogues from 3-(azidomethyl)-2-chloroquinoline in a three-step mechanistic pathway. The UV–Visible absorbance plot shows dynamic interaction of parent triazole derivative with CT DNA as efficient DNA intercalator (K _b = 4.6 × 10⁻⁴ M⁻¹). Finally, the efficient DNA damage was observed on photo-irradiation at 360 nm in the presence of 2-(9H-Fluoren-9-ylmethoxycarbonylamino)-propionic acid 1-(2-chloro-quinolin-3-ylmethyl)-1H-[1,2,3]triazole-4-ylmethyl ester (6a).     

Design,synthesis and biological evaluation of novel 1,2,3-triazole linked coumarinopyrazole conjugates as potent anticholinesterase,anti-5-lipoxygenase,anti-tyrosinase and anti-cancer agents

A series of new 1,2,3-triazole linked coumarinopyrazole conjugates 4a-e and 5a-e have been synthesized via the Copper(I)-catalysed Alkyne-Azide Cycloaddition (CuAAC). Going through the reaction of compound 2 with the 3-propargyl bromide gave a mixture of propargylated regioisomers 3 + 3′ used as a dipolarophile to access to triazoles 4a-e and 5a-e. The structures of the prepared cycloadducts were determined by ¹H, ¹³C and 2D-NMR techniques and by HRMS analysis. All the synthesized derivatives have been evaluated for their anticholinesterase, anti-5-lipoxygenase, anti-tyrosinase, and cytotoxic activities.