Targeting Transcriptional CDKs 7, 8, and 9 with Anilinopyrimidine Derivatives as Anticancer Agents: Design, Synthesis, Biological Evaluation and In Silico Studies

Abstract

Cyclin-dependent kinases (CDKs) are promising targets in chemotherapy. In this study, we report a series of 2-anilinopyrimidine derivatives with CDK inhibitory activity. Twenty-one compounds were synthesized and their CDK inhibitory and cytotoxic activities were evaluated. The representative compounds demonstrate potent antiproliferative activities toward different solid cancer cell lines and provide a promising strategy for the treatment of malignant tumors. Compound 5f was the most potent CDK7 inhibitor (IC50 = 0.479 µM), compound 5d was the most potent CDK8 inhibitor (IC50 = 0.716 µM), and compound 5b was the most potent CDK9 inhibitor (IC50 = 0.059 µM). All the compounds satisfied the Lipinski’s rule of five (molecular weight < 500 Da, number of hydrogen bond acceptors <10, and octanol–water partition coefficient and hydrogen bond donor values below 5). Compound 5j is a good candidate for lead optimization because it has a non-hydrogen atom (N) of 23, an acceptable ligand efficiency value of 0.38673, and an acceptable ligand lipophilic efficiency value of 5.5526. The synthesized anilinopyrimidine derivatives have potential as anticancer agents.

Design, synthesis, and carbonic anhydrase inhibition activities of Schiff bases incorporating benzenesulfonamide scaffold: Molecular docking application

“…The crystal structures of human carbonic anhydrases IX (PDB code: 5FL4) ( Leitans et al, 2015 ) and XII (PDB code: 1JD0) ( Whittington et al, 2001 ) were obtained from the Protein Data Bank (PDB). The docking protocol used for the molecular docking of compound 8 with human carbonic anhydrase IX and XII proteins followed the same methodology described earlier ( Hamdi et al, 2022 , Abuelizz et al, 2023 , Eskandrani et al, 2023 ).…”

A DFT Study and Hirshfeld Surface Analysis of the Molecular Structures, Radical Scavenging Abilities and ADMET Properties of 2-Methylthio(methylsulfonyl)-[1,2,4]triazolo [1,5-a]quinazolines: Guidance for Antioxidant Drug Design

“…Few PAINS alerts, No PAINS (Pan-assay interference compounds) alerts were identified, suggesting a low risk of promiscuous activity or false positives. Acceptable QED and drug-likeness scores, the calculated QED, SAscore, and other metrics indicate good potential drug-likeness, especially for compound 2 (Table S3) [35,36].…”

Exploring the Chemical Reactivity, Molecular Docking, Molecular Dynamic Simulation and ADMET Properties of a Tetrahydrothienopyridine Derivative Using Computational Methods

“…The method for the molecular dynamics simulation (MDS) of EAMT with the adenosine A1 receptor (PDB: 5UEN) was based on established protocols from my previous studies [35,36]. The study involved selecting a suitable force field, generating and minimizing the initial protein-ligand complex structure, and conducting equilibration and production simulations over a 50 ns timescale.…”

“…The binding free energy calculations of EAMT with the adenosine A1 receptor (PDB: 5UEN) were performed using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. This approach was also based on the established protocols from our previous studies [35,36]. The MM-PBSA calculations provided insights into the proteinligand interactions and binding affinities, complementing the conformational and dynamic analysis obtained from the MDS.…”