Discovery of New Pyrazolopyridine, Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design, Synthesis, Docking Studies, and Anti-Proliferative Activity

Abstract

New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from 6-(naphthalen-2-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (1). The chloro, methoxy, cholroacetoxy, imidazolyl, azide, and arylamino derivatives were prepared to obtain the pyridine-−C2 functionalized derivatives. The derived pyrazolpyridine-N-glycosides were synthesized via heterocyclization of the C2-thioxopyridine derivative followed by glycosylation using glucose and galactose. The furopyridine derivative 14 and the tricyclic pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine 15 were prepared via heterocyclization of the ester derivative followed by a reaction with formamide. The newly synthesized compounds were evaluated for their ability to in vitro inhibit the CDK2 enzyme. In addition, the cytotoxicity of the compounds was tested against four different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549). The CDK2/cyclin A2 enzyme inhibitory results revealed that pyridone 1, 2-chloro-6-(naphthalen-2-yl)-4-(thiophen-2-yl)nicotinonitrile (4), 6-(naphthalen-2-yl)-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (8), S-(3-cyano-6-(naphthaen-2-yl)-4-(thiophen-2-yl)pyridin-2-yl) 2-chloroethanethioate (11), and ethyl 3-amino-6-(naphthalen-2-yl)-4-(thiophen-2-yl)furo[2,3-b]pyridine-2-carboxylate (14) are among the most active inhibitors with IC50 values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC50 0.394 μM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC50 ranges of 31.3–49.0, 19.3–55.5, 22.7–44.8, and 36.8–70.7 μM, respectively compared to doxorubicin (IC50 40.0, 64.8, 24.7 and 58.1 µM, respectively). Furthermore, a molecular docking study suggests that most of the target compounds have a similar binding mode as a reference compound in the active site of the CDK2 enzyme. The structural requirements controlling the CDK2 inhibitory activity were determined through the generation of a statistically significant 2D-QSAR model.

Pyrazolopyridine: An efficient pharmacophore in recent drug design and development

“…2.1 | Sulfur-containing heterocycles (Thiophenes, thioglycosides, and thiazoles) Overexpression of cyclin-dependent kinase-2 (CDK2) is evident in various human cancer types (Peyressatre et al, 2015), and thus, CDK2 is the principal target for most of the anticancer drugs (Chen et al, 2020;El-Sattar et al, 2021). Based on this fact, Abdel-Rahman et al designed and synthesized pyrazolopyridine analogs and other heterocyclic molecules as antiproliferative agents as well as CDK2 inhibitors (Abdel-Rahman et al, 2021). In initial CDK2 inhibitory activity, among pyrazolopyridines, compound 1 (Figure 1) exerted potent activity (IC 50 = 0.65 μM).…”

Synthesis of 1-Amino-3-oxo-2,7-naphthyridines via Smiles Rearrangement: A New Approach in the Field of Chemistry of Heterocyclic Compounds

“…Furthermore, it is well known that fused derivatives of furo[2,3- b ]pyridine show high biological activity [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Along this line we have previously synthesized several condensed furo[2,3- b ]pyridines based on the cyclopenta[ c ]pyridines, 5,6,7,8-tetrahydroisoquinolines and pyrano[3,4- c ]pyridines, obtaining compounds with neurotropic [ 25 , 26 ], antimicrobial [ 27 ], antitumor [ 28 ] and potent antiviral [ 29 ] activities.…”

The Role of Pyrazolopyridine Derivatives on Different Steps of Herpes Simplex Virus Type-1 In Vitro Replicative Cycle

“…Among the various compounds with biological activities, the 1 H -pyrazolo[3,4- b ]pyridine system is known to have anticancer, antimalarial, anti-inflammatory, analgesic, antibacterial, and antiprotozoal activities [ 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Moreover, some chemical modifications confer to the biological activity of these derivatives against Alzheimer’s disease and the HIV-1 enzyme reverse transcriptase (RT) [ 33 , 34 ].…”