Synthesis, cytotoxicity of some pyrazoles and pyrazolo[1,5-a]pyrimidines bearing benzothiazole moiety and investigation of their mechanism of action

Husseiny, Ebtehal M.

doi:10.1016/j.bioorg.2020.104053

Cited by 36 publications

(25 citation statements)

References 68 publications

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“…Based on previous reports [ 95 , 96 ] Husseiny proposed and carried out the synthesis of the 2-(benzothiazol-2-yl)pyrazolo[1,5- a ]pyrimidine 181 [ 97 ] ( Scheme 52 ). The author carried out the condensation reaction between 4-(benzo[ d ]thiazol-2-yl)– N 3 -phenyl-1 H -pyrazole-3,5-diamine ( 179 ) and diethyl ethoxymethylenemalonate ( 180 ) under reflux in acetic acid.…”

Section: Antitumor Activitymentioning

confidence: 99%

Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold

2021

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Pyrazolo[1,5-a]pyrimidine (PP) derivatives are an enormous family of N-heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great deal of attention in material science recently due to their significant photophysical properties. Consequently, various researchers have developed different synthesis pathways for the preparation and post-functionalization of this functional scaffold. These transformations improve the structural diversity and allow a synergic effect between new synthetic routes and the possible applications of these compounds. This contribution focuses on an overview of the current advances (2015–2021) in the synthesis and functionalization of diverse pyrazolo[1,5-a]pyrimidines. Moreover, the discussion highlights their anticancer potential and enzymatic inhibitory activity, which hopefully could lead to new rational and efficient designs of drugs bearing the pyrazolo[1,5-a]pyrimidine core.

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Section: Antitumor Activitymentioning

confidence: 99%

Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold

2021

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“…The top-scored conformation was recorded for each compound and used for further analysis, and 2D images were captured through Discovery Studio Visualizer (2017) developed by Accelrys (BIOVIA, San Diego, CA, USA). 13 C NMR spectra (Supplementary Materials) were recorded as APT spectra showing CH and CH 3 groups as positive signals and CH 2 groups and quaternary carbons as negative signals.…”

Section: Generalmentioning

confidence: 99%

“…Furthermore, the previously reported results from literature reveal that the combination of two or more bioactive heterocyclic pharmacophores into the same molecule appears to be an effective tool for designing new chemical entities that have improved activity. Thereby, pyrazole-fused pyrimidines constitute a promising versatile class of heterocyclic scaffolds having always attracted much interest from chemists owing to their outstanding potential, such as antitumor [ 5 ], anti-inflammatory [ 6 ], anticancer and anti-5-lipoxygenase [ 7 ], antibacterial [ 8 ], antitubercular [ 9 ] and especially cytotoxic activities ( Figure 1 A–D) [ 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and In Silico Docking of New Pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine-based Cytotoxic Agents

Horchani

Heise

Hoenke

et al. 2021

IJMS

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To explore a new set of anticancer agents, a novel series of pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine derivativeshave been designed and synthesized viacyclocondensation reactions of pyrazolo-enaminone with a series of arylidenemalononitriles; compound 5 was obtained from 5-amino-4-cyanopyrazole. The structures of the target compounds were investigated by spectral techniques and elemental analysis (IR, UV–Vis, 1H NMR, 13C NMR and ESI-MS). All compounds were evaluated for their in vitro cytotoxicity employing a panel of different human tumor cell lines, A375, HT29, MCF7, A2780, FaDu as well as non-malignant NIH 3T3 and HEK293 cells. It has been found that the pyrazolo-pyrido-pyrimidine analog bearing a 4-Br-phenyl moiety was the most active toward many cell lines with EC50 values ranging between 9.1 and 13.5 µM. Moreover, in silico docking studies of the latter with six anticancer drug targets, i.e., DHFR, VEGFR2, HER-2/neu, hCA-IX, CDK6 and LOX5, were also performed, in order to gain some insights into their putative mode of binding interaction and to estimate the free binding energy of this bioactive molecule.

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“…As uncontrolled CDK2 activation in human cancer is associated with overexpression of cyclins A and E in many human cancers 12 . Thus, CDKs are considered critical targets for the development of novel anticancer drugs 9 , 10 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity

Mandour

Nassar

Aal

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives ( 4–15 ) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8 , 14 , and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC 50 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.

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Synthesis, cytotoxicity of some pyrazoles and pyrazolo[1,5-a]pyrimidines bearing benzothiazole moiety and investigation of their mechanism of action

Cited by 36 publications

References 68 publications

Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold

Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold

Synthesis and In Silico Docking of New Pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine-based Cytotoxic Agents

Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity

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