Isatin 1,2,3-triazoles as potent inhibitors against caspase-3

Sixteen disubstituted 1,2,3-triazoles were prepared using the Huisgen cycloaddition reaction and evaluated as inhibitors against caspase-3. The two most potent inhibitors were found to be (S)-1-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (7f) and (S)-1-((1-benzyl-1H-1,2,3-triazol-5-yl)methyl)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (8g) with IC₅₀-values of 17 and 9 nM, respectively. Lineweaver-Burk plots revealed that these two triazoles show competitive inhibitory mechanism against caspase-3.     

Design and synthesis of novel quinazolinone-1,2,3-triazole hybrids as new anti-diabetic agents: In vitro α-glucosidase inhibition,kinetic, and docking study

A novel series of quinazolinone-1,2,3-triazole hybrids 10a-p were designed, synthesized, and evaluated for their in vitro α-glucosidase inhibitory activity leading to efficient anti-diabetic agents. All synthesized compounds exhibited good inhibitory activity against yeast α-glucosidase (IC₅₀ values in the range of 181.0–474.5 µM) even much more potent than standard drug acarbose (IC₅₀ = 750.0). Among them, quinazolinone-1,2,3-triazoles possessing 4-bromobenzyl moiety connected to 1,2,3-triazole ring (10g and 10p) demonstrated the most potent inhibitory activity towards α-glucosidase. Compound 10g inhibited α-glucosidase in a competitive manner with K_i value of 117 µM. Furthermore, the binding modes of the most potent compounds 10g and 10p in the α-glucosidase active site was studied through in silico docking studies. Also, lack of cytotoxicity of compounds 10g and 10p was confirmed via MTT assay.     

Synthesis and anticancer activity of 3′-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidine analogs and their phosphoramidates

Abstract

A series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3′-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidines (20–49) was synthesized by means of phosphorylation of 3′-[4-aryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidines (7–11) with 4-chlorophenyl phosphoroditriazolide (14), followed by a reaction with the appropriate amine. The synthesized compounds 7–11 and 20–49 were evaluated along with four known anticancer compounds for their cytotoxic activity in human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), osteosarcoma (143B) (only selected compounds 20, 24, 28, 32–36, 38, 40, 46) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Among 3′-[4-aryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidines (7–11) the highest activity in all the investigated cancer cells was displayed by 3′-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3′-deoxythymidine (9) (IC₅₀ in the range of 2.58–3.61?μM) and its activity was higher than that of cytarabine. Among phosphoramidates 20–49 the highest activity was demonstrated by N-n-propyl phosphoramidate of 3′-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3′-deoxythymidine (35) in all the cancer cells (IC₅₀ in the range of 0.97–1.94?μM). Also N-ethyl phosphoramidate of 3′-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3′-deoxythymidine (33) exhibited good activity in all the used cell lines (IC₅₀ in the range of 4.79–4.96?μM).     

Synthesis and antiproliferative activity of conformationally restricted 1,2,3-triazole analogues of combretastatins in the sea urchin embryo model and against human cancer cell lines

A series of 1,5-diaryl- and 4,5-diaryl-1,2,3-triazole derivatives of combretastatin A4 were synthesized and evaluated as antimitotic microtubule destabilizing agents using the sea urchin embryo model.Structure–activity relationship studies identified compounds substituted with 3,4,5-trimethoxyphenyl and 3,4-methylenedioxy-5-methoxyphenyl ring A and 4-methoxyphenyl ring B as potent antiproliferative agents with high cytotoxicity against a panel of human cancer cell lines including multi-drug resistant cells. 4,5-Diaryl-1,2,3-triazoles (C–C geometry) were found to be considerably more active than the respective 1,5-diaryl-1,2,3-triazoles (N–C geometry). Compound 10ad′ induced G₂/M cell cycle arrest and apoptosis in human T-leukemia Jurkat cells via caspase 2/3/9 activation and downregulation of the antiapoptotic protein XIAP. A mitotic catastrophe has been evaluated as another possible cell death mode.     

The bioisosteric modification of pyrazinamide derivatives led to potent antitubercular agents: Synthesis via click approach and molecular docking of pyrazine-1,2,3-triazoles

Tuberculosis remains as a major public health risk which causes the highest mortality rate globally and an improved regimen is required to treat the drug-resistant strains. Pyrazinamide is a first-line antitubercular drug used in combination therapy with other anti-TB drugs. Herein, we describe the modification of pyrazinamide structure using bioisosterism and rational approaches by incorporating the 1,2,3-triazole moiety. Three sets of pyrazine-1,2,3-triazoles (3a-o, 5a-o and 9a-l) are designed, synthesized and evaluated for their in vitro inhibitory potency against mycobacterium tuberculosis H₃₇Rv. The pyrazine-1,2,3-triazoles synthesized through the bioisosteric modification displayed improved activity as compared to rationally modified pyrazine-1,2,3-triazoles. Among 42 title compounds, seven derivatives demonstrated significant anti-tubercular activity with the MIC of 1.56 μg/mL, which are two-fold more potent than the parent compound pyrazinamide. Further, the synthesized pyrazinamide analogs demonstrated moderate inhibition activity against several bacterial strains and possessed an acceptable in vitro cytotoxicity profile as well. Additionally, the activity profile of pyrazine-1,2,3-triazoles was validated by performing the molecular docking studies against the Inh A enzyme. Furthermore, in silico ADME prediction revealed good oral bioavailability for the potent molecules.     

Synthesis and anti-proliferative activity of allogibberic acid derivatives containing 1,2,3-triazole pharmacophore

Sixty novel allogibberic acid derivatives containing 1,2,3-triazole pharmacophore were designed and synthesized. The key chemical processes include aromatization of the A ring in gibberellins, formation of allogibberic azides and its copper mediated Huisgen 1,3-dipolar cycloaddition with alkynes. A number of hybrids containing α,β-unsaturated ketone moiety exhibited excellent in vitro cytotoxic activities. Some of the hybrids were more selective to MCF-7 and SW480 cell lines with IC₅₀ values at least 8-fold more cytotoxic than cisplatin (DDP). The most potent compounds C43 and C45 are more cytotoxic than cisplatin (DDP) against all tested five tumor cell lines, with IC₅₀ values of 0.25–1.72?µM. Mechanism of action studies indicated that allogibberic-triazole derivative C45 could induce the S phase cell cycle arrest and apoptosis in SMMC-7721 cell lines.     

1,2,3-Triazole-based kojic acid analogs as potent tyrosinase inhibitors: Design,synthesis and biological evaluation

A series of kojic acid-derived compounds 6a-p bearing aryloxymethyl-1H-1,2,3-triazol-1-yl moiety were designed by modifying primary alcoholic group of kojic acid as tyrosinase inhibitors. The target compounds 6a-p were synthesized via click reaction. All compounds showed very potent anti-tyrosinase activity (IC₅₀s = 0.06–6.80 µM), being superior to reference drug, kojic acid. In particular, the naphthyloxy analogs 6o and 6p were found to be 31–155 times more potent than kojic acid. The metal-binding study of selected compound 6o revealed that the prototype compound possesses metal-chelating ability, particularly with Cu²⁺ ions. The promising compounds 6o and 6p had acceptable safety profile as demonstrated by cytotoxicity assay against melanoma (B16) cell line and Human Foreskin Fibroblast (HFF) cells.     

Synthesis of 2,2,4-trimethyl-1,2-dihydroquinolinyl substituted 1,2,3-triazole derivatives: Their evaluation as potential PDE 4B inhibitors possessing cytotoxic properties against cancer cells

The 2,2,4-trimethyl-1,2-dihydroquinolinyl substituted 1,2,3-triazole derivatives were designed as potential inhibitors of PDE4B. These compounds were synthesized via a multi-step sequence consisting of copper-catalyzed azide-alkyne cycloaddition (CuAAC) as a key step in aqueous media. The required alkynes were prepared from nimesulide via N-propargylation and then nitro group reduction followed by a CAN mediated modified Skraup reaction of the resulting amine. All the synthesized compounds showed PDE4B inhibitory properties in vitro at 30 μM with two compounds showing >50% inhibition that were supported by the in silico docking results of these compounds at the active site of PDE4B. Three of these PDE4 inhibitors showed promising cytotoxic properties against A549 human lung cancer cells in vitro with IC₅₀ ∼8–9 μM.     

Design,synthesis and anti-Alzheimer’s activity of novel 1,2,3-triazole-chromenone carboxamide derivatives

Alzheimer’s disease (AD) is a well-known neurodegenerative disorder affecting millions of old people worldwide and the corresponding epidemiological data highlights the significance of the disease. As AD is a multifactorial illness, various single-target directed drugs that have reached clinical trials have failed. Therefore, various factors associated with outset of AD have been considered in targeted drug discovery and development. In this work, a wide range of 1,2,3-triazole-chromenone carboxamides were designed, synthesized, and evaluated for their cholinesterase inhibitory activity. Among them, N-(1-benzylpiperidin-4-yl)-7-((1-(3,4-dimethylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-oxo-2H-chromene-3-carboxamide (11b) showed the best acetylcholinesterase inhibitory activity (IC₅₀ = 1.80 µM), however, it was inactive toward butyrylcholinesterase. It should be noted that compound 11b was evaluated for its BACE1 inhibitory activity and calculated IC₅₀ = 21.13 µM confirmed desired inhibitory activity. Also, this compound revealed satisfactory neuroprotective effect against H₂O₂-induced cell death in PC12 neurons at 50 µM as well as metal chelating ability toward Fe²⁺, Cu²⁺, and Zn²⁺ ions.     

Synthesis and evaluation of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives as xanthine oxidase inhibitors

This study mainly focused on the modification of the X² position in febuxostat analogs. A series of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives (1a-s) with an N atom occupying the X² position was designed and synthesized. Evaluation of their inhibitory potency in vitro on xanthine oxidase indicated that these compounds exhibited micromolar level potencies, with IC₅₀ values ranging from 0.21 µM to 26.13 μM. Among them, compound 1s (IC₅₀ = 0.21 μM) showed the most promising inhibitory effects and was 36-fold more potent than allopurinol, but was still 13-fold less potent than the lead compound Y-700, which meant that a polar atom fused at the X² position could be unfavorable for potency. The Lineweaver-Burk plot revealed that compound 1s acted as a mixed-type xanthine oxidase inhibitor. Analysis of the structure-activity relationships demonstrated that a more lipophilic ether tail (e.g., meta-methoxybenzoxy) at the 4′-position could benefit the inhibitory potency. Molecular modeling provided a reasonable explanation for the structure–activity relationships observed in this study.     

Cytotoxic,tubulin-interfering and proapoptotic activities of 4′-methylthio-<Emphasis Type="Italic">trans</Emphasis>-stilbene derivatives,analogues of <Emphasis Type="Italic">trans</Emphasis>-resveratrol

The aim of this study was to evaluate the cytotoxicity of a series of seven 4′-methylthio-trans-stilbene derivatives against cancer cells: MCF7 and A431 in comparison with non-tumorigenic MCF12A and HaCaT cells. The mechanism of anti-proliferative activity of the most cytotoxic trans-resveratrol analogs: 3,4,5-trimethoxy-4′-methylthio-trans-stilbene (3,4,5-MTS) and 2,4,5-trimethoxy-4′-methylthio-trans-stilbene (2,4,5-MTS) was analyzed and compared with the effect of trans-resveratrol. All the compounds that were studied exerted a stronger cytotoxic effect than trans-resveratrol did. MCF7 cells were the most sensitive to the cytotoxic effect of trans-resveratrol analogs with IC₅₀ in the range of 2.1–6.0 µM. Comparing the cytotoxicity of 3,4,5-MTS and 2,4,5-MTS, a significantly higher cytotoxic activity of these compounds against MCF7 versus MCF12A was observed, whereas no significant difference was observed in cytotoxicity against A431 and HaCaT. In the series of 4′-methylthio-trans-stilbenes, 3,4,5-MTS and 2,4,5-MTS were the most promising compounds for further mechanistic studies. The proapoptotic activity of 3,4,5-MTS and 2,4,5-MTS, estimated with the use of annexin-V/propidium iodide assay, was comparable to that of trans-resveratrol. An analysis of cell cycle distribution showed a significant increase in the percentage of apoptotic cells and G2/M phase arrest in MCF7 and A431 as a result of treatment with 3,4,5-MTS, whereas trans-resveratrol tended to increase the percentage of cells in S phase, particularly in epithelial breast cells MCF12A and MCF7. Both trans-stilbene derivatives enhanced potently tubulin polymerization in a dose-dependent manner with sulfur atom participating in the interactions with critical residues of the paclitaxel binding site of β-tubulin.     

Antifungal activity of 1′-homo-N-1,2,3-triazol-bicyclic carbonucleosides: A novel type of compound afforded by azide-enolate (3+2) cycloaddition

The first report of 1′-homo-N-1,2,3-triazol-bicyclic carbonucleosides (7a and 7b) is described herein. Azide-enolate (3+2) cycloaddition afforded the synthesis of this novel type of compound. Antifungal activity was evaluated in vitro against four filamentous fungi (Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus oryzae and Mucor hiemalis) as well as nine species of Candida spp. as yeast specimens. These pre-clinical studies suggest that compounds 7a and 7b are promising candidates for complementary biological studies due to their good activity against Candida spp.     

1,2,3-Triazole-, arylamino- and thio-substituted 1,4-naphthoquinones: Potent antitumor activity,electrochemical aspects,and bioisosteric replacement of C-ring-modified lapachones

1,2,3-Triazole-, arylamino- and thio-substituted naphthoquinones (24, 8, and 2 representatives, respectively) were synthesized in moderate yields and evaluated against several human cancer cell lines (blood, ovarian, breast, central nervous system, colon, and prostate cancers and melanoma), showing, for some of them, IC₅₀ values below 2 μM. The cytotoxic potential of the tested naphthoquinones was also assayed on non-tumor cells such as human peripheral blood mononucluear cells (PBMC) and two murine fibroblast lines (L929 and V79 cells). α-Lapachone- and nor-α-lapachone-based 1,2,3-triazoles and arylamino-substituted naphthoquinones showed potent cytotoxicity against different cancer cell lines. The compounds may represent promising new lead derivatives for anticancer drug development. The electrochemical properties of selected compounds were evaluated in an attempt to correlate them with antitumor activity.     

Biscoumarin-1,2,3-triazole hybrids as novel anti-diabetic agents: Design,synthesis, in vitro α-glucosidase inhibition,kinetic, and docking studies

A novel series of biscoumarin-1,2,3-triazole hybrids 6a-n was prepared and evaluated for α-glucosidase inhibitory potential. All fourteen derivatives exhibited excellent α-glucosidase inhibitory activity with IC₅₀ values ranging between 13.0 ± 1.5 and 75.5 ± 7.0 µM when compared with the acarbose as standard inhibitor (IC₅₀ = 750.0 ± 12.0 µM). Among the synthesized compounds, compounds 6c (IC₅₀ = 13.0 ± 1.5 µM) and 6g (IC₅₀ = 16.4 ± 1.7 µM) exhibited the highest inhibitory activity against α-glucosidase and were non-cytotoxic towards normal fibroblast cells. Kinetic study revealed that compound 6c inhibits the α-glucosidase in a competitive mode. Furthermore, molecular docking investigation was performed to find interaction modes of the biscoumarin-1,2,3-triazole derivatives.     

Synthesis and biological evaluation of bergenin-1,2,3-triazole hybrids as novel class of anti-mitotic agents

In continuation of our investigation of pharmacologically-motivated natural products, we have isolated bergenin (1) as a major compound from Mallotus philippensis, which is deployed in different Indian traditional systems of medicine. Here, a series of bergenin-1,2,3-triazole hybrids were synthesized and evaluated for their potentials against a panel of cancer cell lines. Several of the hybrid derivatives were found more potent in comparison to parent compound bergenin (1). Among them, 4j demonstrated potent activity against A-549 and HeLa cell lines with IC₅₀ values of 1.86 µM and 1.33 μM, respectively, and was equipotent to doxorubicin. Cell cycle analysis showed that 4j arrested HeLa cells at G2/M phase and lead to accumulation of Cyclin B1 protein. Cell based tubulin polymerization assays and docking studies demonstrated that 4j disrupts tubulin assembly by occupying colchicine binding pocket of tubulin.     

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

Alzheimer's disease (AD) is a complex neurological disorder with diverse underlying pathological processes. Several lines of evidence suggest that BACE1 is a key enzyme in the pathogenesis of AD and its inhibition is of particular importance in AD treatment. Ten new 3-hydrazinyl-1,2,4-triazines bearing pendant aryl phenoxy methyl-1,2,3-triazole were synthesized as multifunctional ligands against AD. We show that compounds containing Cl and NO₂ groups at the para position of the phenyl ring, namely compounds 7c (IC₅₀ = 8.55 ± 3.37 µM) and 7d (IC₅₀ = 11.42 ± 2.01 µM), possess promising BACE1 inhibitory potential. Furthermore, we assessed the neuroprotective activities of 7c and 7d derivatives in PC12 neuronal cell line, which showed moderate protection against amyloid β peptide toxicity. In addition, compound 7d demonstrated metal chelating activity and moderate antioxidant potential (IC₅₀ = 44.42 ± 7.33 µM). Molecular docking studies of these molecules revealed high-affinity binding to several amino acids of BACE1, which are essential for efficient inhibition. These results demonstrate that 1,2,4-triazine derivatives bearing an aryl phenoxy methyl-1,2,3-triazole have promising properties as therapeutic agents for AD.     

Design and synthesis of 1,2,3-triazolo-phenanthrene hybrids as cytotoxic agents

A series of new 1,2,3-triazolo-phenanthrene hybrids has been synthesized by employing Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. These compounds were evaluated for their in vitro cytotoxic potential against various human cancer cell lines viz. lung (A549), prostate (PC-3 and DU145), gastric (HGC-27), cervical (HeLa), triple negative breast (MDA-MB-231, MDA-MB-453) and breast (BT-549, 4T1) cells. Among the tested compounds, 7d displayed highest cytotoxicity against DU145 cells with IC₅₀ value of 1.5 ± 0.09 µM. Further, the cell cycle analysis shown that it blocks G0/G1 phase of the cell cycle in a dose dependent manner. In order to determine the effect of compound on cell viability, phase contrast microscopy, AO/EB, DAPI, DCFDA and JC-1 staining studies were performed. These studies clearly indicated that the compound 7d inhibited the cell proliferation of DU145 cells. Relative viscosity measurements and molecular docking studies indicated that these compounds bind to DNA by intercalation.     

Synthesis and biological evaluation of novel 7-hydroxy-4-phenylchromen-2-one–linked to triazole moieties as potent cytotoxic agents

A new series of novel 7-hydroxy-4-phenylchromen-2-one (1a)–linked 1,2,4-triazoles were synthesised using a click chemistry approach. All derivatives were subjected to 3-(4,5-dimethylthiazol-yl)-diphenyl tetrazolium bromide (MTT) cytotoxicity screening against a panel of six different human cancer cell lines (AGS, MGC-803, HCT-116, A-549, HepG2, and HeLa) to assess their cytotoxic potential. Among the tested molecules, some of the analogues showed better cytotoxic activity than that shown by the 7-hydroxy-4-phenylchromen-2-one (1a). Of the synthesised 1,2,4-triazoles,the 7-((4-(4-Chlorophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-4-phenyl-2H-chromen-2-one (4d) showed the best activity, with an IC₅₀ of 2.63?±?0.17?µM against AGS cells. Further flow cytometry assays demonstrated that compound 4d exerts its antiproliferative effects by arresting cells in the G2/M phase of the cell cycle and by inducing apoptosis. Collectively, our results indicate that the 1,2,4-triazole derivatives have a significantly stronger antitumour activity than 1,2,3-triazole derivatives. Most of the compounds exhibited better antitumour activity than the positive control drug 5-fluorouracil.     

Cytotoxic effect of <Emphasis Type="Italic">Semialarium mexicanum</Emphasis> (Miers) Mennega root bark extracts and fractions against breast cancer cells

The root bark of Semialarium mexicanum (Miers) Mennega (cancerina) is traditionally used in Mexico to treat cancer. However, there are no studies supporting its use. We evaluated whether S. mexicanum root bark induces cytotoxicity in breast cancer cells to determine if it has potential applications in the treatment of this disease. Extracts of S. mexicanum root bark in petroleum ether, ethanol, and water were obtained by ultrasound-assisted extraction. MTT and WST-1 assays were used to evaluate the cytotoxicity of the extracts toward breast cancer cells (MDA-MB-231 and MCF7), non-tumorigenic breast-derived cells (MCF 10A), and peripheral blood mononuclear cells (PBMCs). For the extract with greatest cytotoxicity, induction of apoptosis and oxidative stress were determined using flow cytometry. The extract was fractionated, and the cytotoxicity of its fractions was evaluated with the four cell types. The fractions were also analyzed by HPLC. Only the petroleum ether extract was cytotoxic for all cell types (MDA-MB-231?>?MCF 10A/MCF7?>?PBMCs). Cell death occurred by apoptosis, which could be associated with the induction of oxidative stress. Two fractions that were highly cytotoxic for breast cancer cells were obtained from this extract (IC₅₀?≤?4.15 µg/mL for the most active fraction at 72 h). The MCF 10A cells were less affected, while PBMCs were not affected after 72 h of treatment. Pristimerin was identified in both fractions and may be partially responsible for the cytotoxic effect. These results suggest that S. mexicanum root bark has a potential application in breast cancer treatment.     

Synthesis of pyrimidin-4-one-1,2,3-triazole conjugates as glycogen synthase kinase-3β inhibitors with anti-depressant activity

GSK-3 specific inhibitors are promising candidates for the treatment of devastating pathologies such as diabetes, neurodegenerative diseases and cancers. We have synthesized a library of pyrimidin-4-one-1,2,3-triazole conjugates using click-chemistry approach and evaluated them as glycogen synthase kinase-3β inhibitors. Compounds 3g, 3j, 3n and 3r were found to be most potent among the eighteen pyrimidin-4-one-1,2,3-triazole conjugates synthesized and they were further evaluated for their in vivo anti-depressant activity. Compound 3n (2-((1-(3,4-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methylthio)-3-methyl-6-phenylpyrimidin-4(3H)-one) exhibited the most potent inhibitory activity against GSK-3β with IC₅₀ value of 82 nM and was also found to exhibit significant antidepressant activity at 50 mg/kg, when compared with fluoxetine, a known antidepressant drug. The molecular docking studies were performed to elucidate the binding modes of the compounds with the GSK-3β target and two crucial interactions namely, hydrogen bond formation with Val 135 and Lys 183 residues in the active site of GSK-3β were observed.