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(Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia.

ABSTRACT: The enzyme tyrosine kinase BCR-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the (phenylamino)pyrimidine-pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All compounds were evaluated for their inhibitory activities against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase BCR-Abl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds showed promising results, with IC₅₀ values between 1.0 and 7.3 μM, and were subjected to molecular docking studies. The results suggest that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One compound showed the greatest interaction affinity for BCR-Abl-1 in the docking studies.

SUBMITTER: Pimentel LCF

PROVIDER: S-EPMC8450943 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Searching Anti-Zika Virus Activity in 1H-1,2,3-Triazole Based Compounds.

Project description:Zika virus (ZIKV) is a mosquito-borne virus belonging to the Flaviviridae family and is responsible for an exanthematous disease and severe neurological manifestations, such as microcephaly and Guillain-Barré syndrome. ZIKV has a single strand positive-sense RNA genome that is translated into structural and non-structural (NS) proteins. Although it has become endemic in most parts of the tropical world, Zika still does not have a specific treatment. Thus, in this work we evaluate the cytotoxicity and antiviral activities of 14 hybrid compounds formed by 1H-1,2,3-triazole, naphthoquinone and phthalimide groups. Most compounds showed low cytotoxicity to epithelial cells, specially the 3b compound. After screening with all compounds, 4b was the most active against ZIKV in the post-infection test, obtaining a 50% inhibition concentration (IC50) of 146.0 µM and SI of 2.3. There were no significant results for the pre-treatment test. According to the molecular docking compound, 4b was suggested with significant binding affinity for the NS5 RdRp protein target, which was further corroborated by molecular dynamic simulation studies.

| S-EPMC8510480 | biostudies-literature

Regioselective Synthesis and Molecular Docking Studies of 1,5-Disubstituted 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases.

Project description:1,2,3-triazoles are versatile building blocks with growing interest in medicinal chemistry. For this reason, organic chemistry focuses on the development of new synthetic pathways to obtain 1,2,3-triazole derivatives, especially with pyridine moieties. In this work, a novel series of 1,5-disubstituted-1,2,3-triazoles functionalized with pyrimidine nucleobases were prepared via 1,3-dipolar cycloaddition reaction in a regioselective manner for the first time. The N1-propargyl nucleobases, used as an alkyne intermediate, were obtained in high yields (87-92%) with a new two-step procedure that selectively led to the monoalkylated compounds. Then, FeCl3 was employed as an efficient Lewis acid catalyst for 1,3-dipolar cycloaddition between different aryl and benzyl azides and the N1-propargyl nucleobases previously synthesized. This new protocol allows the synthesis of a series of new 1,2,3-triazole derivatives with good to excellent yields (82-92%). The ADME (Absorption, Distribution, Metabolism, and Excretion) analysis showed good pharmacokinetic properties and no violations of Lipinsky's rules, suggesting an appropriate drug likeness for these new compounds. Molecular docking simulations, conducted on different targets, revealed that two of these new hybrids could be potential ligands for viral and bacterial protein receptors such as human norovirus capsid protein, SARS-CoV-2 NSP13 helicase, and metallo-β-lactamase.

| S-EPMC9735522 | biostudies-literature

1,2,3-Triazole Derivatives as Novel Antifibrinolytic Drugs.

Project description:Fibrinolysis is a natural process that ensures blood fluidity through the removal of fibrin deposits. However, excessive fibrinolytic activity can lead to complications in different circumstances, such as general surgery or severe trauma. The current antifibrinolytic drugs in the market, aminocaproic acid (EACA) and tranexamic acid (TXA), require high doses repetitively to maintain their therapeutic effect. These high doses are related to a number of side effects such as headaches, nasal symptoms, or gastrointestinal discomfort and severely limit their use in patients with renal impairment. Therefore, the discovery of novel antifibrinolytics with a higher specificity and lower dosage could vastly improve the applicability of these drugs. Herein, we synthesized a total of ten compounds consisting of a combination of three key moieties: an oxadiazolone, a triazole, and a terminal amine. The IC50 of each compound was calculated in our clot lysis assays, and the best candidate (1) provided approximately a 2.5-fold improvement over the current gold standard, TXA. Molecular docking and molecular dynamics were used to perform a structure-activity relationship (SAR) analysis with the lysine binding site in the Kringle 1 domain of plasminogen. This analysis revealed that 1,2,3-triazole was crucial for the activity, enhancing the binding affinity through pi-pi stacking and polar interactions with Tyr72. The results presented in this work open the door to further investigate this new family as potential antifibrinolytic drugs.

| S-EPMC9736318 | biostudies-literature

Discovery of Icotinib-1,2,3-Triazole Derivatives as IDO1 Inhibitors.

Project description:Tumor immunotherapy is considered to be a highlight in cancer treatment in recent years. Indoleamine 2,3-dioxygenase 1 (IDO1) is closely related to the over expression of many cancers, and is therefore a promising target for tumor immunotherapy. To search for novel IDO1-targeting therapeutic agents, 22 icotinib-linked 1,2,3-triazole derivatives were prepared and evaluated for their inhibitory activity against IDO1. The structures of the prepared compounds were confirmed with1H NMR, 13C NMR and HR MS. IDO1 inhibitory activity assay results indicated that 10 of those compounds showed remarkable inhibitory activity against IDO1, among which compound a17 was the most potent with IC50value of 0.37 ?M. The binding model between the prepared compounds and IDO1 was studied with molecular modeling study. The current study suggested that icotinib-1,2,3-triazole derivatives could be used as potential inhibitors that preferentially bind to the ferrous form of IDO1 through the formation of coordinate bond with the haem iron.

| S-EPMC7555427 | biostudies-literature

Discovery of Novel 1,2,3-triazole Derivatives as IDO1 Inhibitors.

Project description:Indoleamine 2,3-dioxygenase 1 (IDO1) has received much attention as an immunomodulatory enzyme in the field of cancer immunotherapy. While several IDO1 inhibitors have entered clinical trials, there are currently no IDO1 inhibitor drugs on the market. To explore potential IDO1 inhibitors, we designed a series of compounds with urea and 1,2,3-triazole structures. Organic synthesis and IDO1 enzymatic activity experiments verified the molecular-level activities of the designed compounds, and the IC50 value of compound 3a was 0.75 μM. Molecular docking and quantum mechanical studies further explained the binding mode and reaction potential of compound 3a with IDO1. Our research has resulted in a series of novel IDO1 inhibitors, which is beneficial to the development of drugs targeting IDO1 in numerous cancer diseases.

| S-EPMC9695734 | biostudies-literature

Library of 1,4-disubstituted 1,2,3-triazole analogs of oxazolidinone RNA-binding agents.

Project description:The design and synthesis of small molecules that target RNA is immensely important in antibacterial therapy. We had previously reported on the RNA binding of a series of 4,5-disubstituted 2-oxazolidinones that bind to a highly conserved bulge region of bacterial RNA. This biological target T box antitermination system, which is found mainly in Gram-positive bacteria, regulates the expression of several amino acid related genes. In an effort to amplify our library, we have prepared a library of 1,4-disubstituted 1,2,3-triazole analogs that entails an isosteric replacement of the oxazolidinone nucleus. The synthesis of the new analogs was enhanced via copper(I) catalysis of an azide and alkyne cycloaddition reaction. A total of 108 1,4-disubstituted 1,2,3-triazole compounds have been prepared. All compounds were evaluated as RNA binding agents.

| S-EPMC2925680 | biostudies-literature

Synthesis of 1,2,3-triazole-thymol derivatives as potential antimicrobial agents.

Project description:BackgroundThymol as a natural biological template can be modified chemically since the hydroxyl group makes it a candidate for structural modification. Thus, this study incorporated the triazole moiety on thymol and the chlorination of thymol moiety to help improve its biological potency.Materials and methodsA series of ten 1,2,3-triazole-thymol derivatives 1-10 were synthesized from thymol, by a click reaction between O-propargyl terminal alkyne of thymol and its chlorothymol with benzyl azide and substituted benzyl azides. Their structures were confirmed by spectroscopic methods (1H-NMR, 13C-NMR, IR, GC-MS-EI/CI and LC-ESI-QTOF-MS). The Well diffusion method using Müeller-Hinton agar plates was used to demonstrate the antimicrobial activities of the synthesized triazole-thymol derivatives on selected bacterial strains; Escherichia coli ATCC 25922, Staphylococcus aureus ATCC25923, Methicillin resistant S. aureus (MRSA), Pseudomonas aeruginosa ATCC 29853, E. coli ESBL, K l ebsiella pneumoniae NCTC 13438 and Meropenem Resistant E. coli.ResultsAll the synthesized triazole-thymol derivatives showed significant but variable antibacterial activity against the seven medically important bacterial strains tested. The compound 4-((4-chloro-2-isopropyl-5-methylphenoxy)methyl)-1-(2-nitrobenzyl)-1H-1,2,3triazole (9) demonstrated a higher antibacterial activity with a mean zone of inhibition (38.7 mm) compared with ampicillin as the positive control which gave a zone size of 30.0 mm. In addition, the compound showed a three-fold potency than the parent compound, thymol (11.0 mm) against MRSA at a concentration of 100 μg/ml.ConclusionThese results provide additional evidence of the exploitation of natural products like thymol as leads for drug development against medically important bacterial pathogens.

| S-EPMC9547220 | biostudies-literature

Synthesis and Antimicrobial Activity of 4-Substituted 1,2,3-Triazole-Coumarin Derivatives.

Project description:A new series of coumarin-1,2,3-triazole conjugates with varied alkyl, phenyl and heterocycle moieties at C-4 of the triazole nucleus were synthesized using a copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of corresponding O-propargylated coumarin (3) or N-propargylated coumarin (6) with alkyl or aryl azides. Based on their minimal inhibitory concentrations (MICs) against selected microorganisms, six out of twenty-six compounds showed significant antibacterial activity towards Enterococcus faecalis (MIC = 12.5-50 µg/mL). Moreover, the synthesized triazoles show relatively low toxicity against human erythrocytes.

| S-EPMC6017388 | biostudies-literature

Synthesis and Antitumor Activity of 1-Substituted 1,2,3-Triazole-Mollugin Derivatives.

Project description:A new series of mollugin-1,2,3-triazole derivatives were synthesized using a copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of corresponding O-propargylated mollugin with aryl azides. All the compounds were evaluated for their cytotoxicity on five human cancer cell lines (HL-60, A549, SMMC-7721, SW480, and MCF-7) using MTS assays. Among the synthesized series, most of them showed cytotoxicity and most of all, compounds 14 and 17 exhibited significant cytotoxicity of all five cancer cell lines.

| S-EPMC8198100 | biostudies-literature

Synthesis and Antitumor Activity of Erlotinib Derivatives Linked With 1,2,3-Triazole.

Project description:Cervical cancer is one of the most important cause of cancer-related death and presents a major public health problem in many countries. To search for more novel antitumor agents against cervical cancer, 14 erlotinib-linked 1,2,3-triazole compounds were designed, synthesized, and evaluated for their anti-tumor activity. The compounds were confirmed by 1H NMR, 13C NMR, and high-resolution mass spectra (HR MS). Antitumor activity assay results indicated that six of those compounds have remarkable inhibitory activity against human cervical cancer HeLa cells in vitro, among which compound 4m was the most potent with IC50 of 3.79 μM, and compounds 4k, 4i, 4l, 4d, and 4n also demonstrated remarkable antitumor activity with IC50 of 3.79, 4.16, 4.36, 7.02, and 8.21 μM. We found three of the most potent compounds 4d, 4k, and 4l induced potent apoptosis and cell cycle arrest in HeLa cells, and compounds 4d and 4l significantly restrained the cell colony formation and showed moderate epidermal growth factor receptor (EGFR) inhibitory activity with IC50 of 13.01 and 1.76 μM. Therefore, these experiments indicate that these erlotinib-linked 1,2,3-triazole compounds are potential to act as effective anticancer agents against cervical cancer.

| S-EPMC8802806 | biostudies-literature

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