Design, synthesis and molecular docking of novel pyrazolo[1,5-a][1,3,5]triazine derivatives as CDK2 inhibitors

Oudah, Khulood H.; Najm, Mazin A.A.; Samir, Nermin; Serya, Rabah A. T.; Abouzid, Khaled A. M.

doi:10.1016/j.bioorg.2019.103239

Cited by 33 publications

(18 citation statements)

References 24 publications

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“…Inhibitor and enzyme solutions were preincubated together for 15 min at room temperature prior to assay, in order to allow for the formation of the E-I complex. The inhibition constants were obtained by non-linear least-squares methods using PRISM 3 and the Cheng–Prusoff equation, as reported earlier, 29–32 and represent the mean from at least three different determinations. All CA isoforms were recombinant ones obtained in-house as reported earlier 33–35 .…”

Section: Methodsmentioning

confidence: 99%

Design and synthesis of some new benzoylthioureido benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors

Oudah¹,

Mahmoud

Awadallah

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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The present investigation reports the design and synthesis of three series of benzoylthioureido derivatives bearing either benzenesulfonamide 7a–f , benzoic acid 8a–f or ethylbenzoate 9a–f moieties. The synthesised compounds were screened for their carbonic anhydrase inhibitory activity (CAI) against four isoforms hCA I, II, IX, and XII. Compounds 7a, 7b, 7c , and 7f exhibited a potent inhibitory activity towards hCAI ( K i s = 58.20, 56.30, 33.00, and 43.00 nM), respectively compared to acetazolamide (AAZ) and SLC-0111 ( K i s = 250.00 and 5080.00 nM). Compounds 7a, 7b, 7c, 7e , and 7f elicited selectivity over h CA II ( K i s = 2.50, 2.10, 56.60,39.60 and 39.00 nM) respectively, relative to AAZ and SLC-0111( K i s = 12.10 and 960.00 nM). Also, compounds 7c , 7f, and 9e displayed selectivity against the tumour-associated isoform hCA IX ( K i s = 31.20, 30.00 and 29.00 nM) respectively, compared to AAZ and SLC-0111 ( K i s = 25.70 and 45.00 nM). Additionally, compounds 8a and 8f revealed a moderate to superior selectivity towards hCAXII ( K i s = 17.00 and 11.00 nM) relative to AAZ and SLC-0111( K i s = 5.70 and 45.00 nM). Molecular docking and ADME prediction studies were performed on the most active compounds to shed light on their interaction with the hot spots of the active site of CA isoforms, in addition to prediction of their pharmacokinetic and physicochemical properties.

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Section: Methodsmentioning

confidence: 99%

Design and synthesis of some new benzoylthioureido benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors

Oudah¹,

Mahmoud

Awadallah

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Results suggested that the most antiproliferative compounds were 59 and 60 (Figure 12). Analog 59 exhibited% inhibition ranging from 40% to 115%, and 82.38% for CDK2, and derivative 60 exhibited% inhibition ranging from 43% to 92%, and 81.96% for CDK2 [34].…”

Section: Primary Anticancer Studiesmentioning

confidence: 99%

“…In the second case, a noticeable increase in cytotoxic activities was observed. According to cancer cell lines MCF-7, MDAMB-231, HT-29, HGC-27 the derivative 31 (Figure 9) proved to be most potent with IC50 values of 4.8 µM, 8.3 µM, 9.8 µM, and 15.1 µM [34].…”

Section: Primary Anticancer Studiesmentioning

confidence: 99%

Recent Advances in the Biological Activity of s-Triazine Core Compounds

Maliszewski

Drozdowska

2022

Pharmaceuticals

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An effective strategy for successful chemotherapy relies on creating compounds with high selectivity against cancer cells compared to normal cells and relatively low cytotoxicity. One such approach is the discovery of critical points in cancer cells, i.e., where specific enzymes that are potential therapeutic targets are generated. Triazine is a six-membered heterocyclic ring compound with three nitrogen replacing carbon-hydrogen units in the benzene ring structure. The subject of this review is the symmetrical 1,3,5-triazine, known as s-triazine. 1,3,5-triazine is one of the oldest heterocyclic compounds available. Because of its low cost and high availability, it has attracted researcher attention for novel synthesis. s-Triazine has a weak base, it has much weaker resonance energy than benzene, therefore, nucleophilic substitution is preferred to electrophilic substitution. Heterocyclic bearing a symmetrical s-triazine core represents an interesting class of compounds possessing a wide spectrum of biological properties such as anti-cancer, antiviral, fungicidal, insecticidal, bactericidal, herbicidal and antimicrobial, antimalarial agents. They also have applications as dyes, lubricants, and analytical reagents. Hence, the group of 1,3,5-triazine derivatives has developed over the years. Triazine is not only the core amongst them, but is also a factor increasing the kinetic potential of the entire derivatives. Modifying the structure and introducing new substituents makes it possible to obtain compounds with broad inhibitory activity on processes such as proliferation. In some cases, s-triazine derivatives induce cell apoptosis. In this review we will present currently investigated 1,3,5-triazine derivatives with anti-cancer activities, with particular emphasis on their inhibition of enzymes involved in the process of tumorigenesis.

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“…(4), we have the binding pocket of the structure of CDK2 in complex with roscovitine [96], where we highlight the two main residues of CDK2 participating in intermolecular interactions. Previously published intermolecular contact analyses of the residues participating in interactions involving inhibitors and the ATPbinding pocket indicated the participation of mainchain oxygen and nitrogen atoms of Leu 83 and Glu 81 of CDK2 in most complexes with high specific CDK2 inhibitors [97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112].…”

Section: Biological Systemmentioning

confidence: 99%

Computational Prediction of Binding Affinity for CDK2-ligand Complexes. A Protein Target for Cancer Drug Discovery

Veit-Acosta

Azevedo

2022

CMC

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Background: CDK2 participates in the control of eukaryotic cell-cycle progression. Due to the great interest in CDK2 for drug development and the relative easiness in crystallizing this enzyme, we have over 400 structural studies focused on this protein target. This structural data is the basis for the development of computational models to estimate CDK2-ligand binding affinity. Objective: This work focuses on the recent developments in the application of supervised machine learning modeling to develop scoring functions to predict the binding affinity of CDK2. Method: We employed the structures available at the protein data bank and the ligand information accessed from the BindingDB, Binding MOAD, and PDBbind to evaluate the predictive performance of machine learning techniques combined with physical modeling used to calculate binding affinity. We compared this hybrid methodology with classical scoring functions available in docking programs. Results: Our comparative analysis of previously published models indicated that a model created using a combination of a mass-spring system and cross-validated Elastic Net to predict the binding affinity of CDK2-inhibitor complexes outperformed classical scoring functions available in AutoDock4 and AutoDock Vina. Conclusion: All studies reviewed here suggest that targeted machine learning models are superior to classical scoring functions to calculate binding affinities. Specifically for CDK2, we see that the combination of physical modeling with supervised machine learning techniques exhibits improved predictive performance to calculate the protein-ligand binding affinity. These results find theoretical support in the application of the concept of scoring function space.

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Design, synthesis and molecular docking of novel pyrazolo[1,5-a][1,3,5]triazine derivatives as CDK2 inhibitors

Cited by 33 publications

References 24 publications

Design and synthesis of some new benzoylthioureido benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors

Design and synthesis of some new benzoylthioureido benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors

Recent Advances in the Biological Activity of s-Triazine Core Compounds

Computational Prediction of Binding Affinity for CDK2-ligand Complexes. A Protein Target for Cancer Drug Discovery

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