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

Adel A-H Abdel-Rahman; Amira K F Shaban; Ibrahim F Nassar; Dina S El-Kady; Nasser S M Ismail; Samy F Mahmoud; Hanem M Awad; Wael A El-Sayed

doi:10.3390/molecules26133923

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

Molecules. 2021 Jun 26;26(13):3923. doi: 10.3390/molecules26133923.

Authors

Adel A-H Abdel-Rahman¹, Amira K F Shaban¹, Ibrahim F Nassar², Dina S El-Kady³, Nasser S M Ismail⁴, Samy F Mahmoud⁵, Hanem M Awad⁶, Wael A El-Sayed^{7

8}

Affiliations

¹ Chemistry Department, Faculty of Science, Menofia University, Shbien El-Kom 32511, Egypt.
² Faculty of Specific Education, Ain Shams University, Abassia, Cairo 11772, Egypt.
³ Hormone Department, National Research Centre, Dokki, Cairo 12622, Egypt.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Future University in Egypt, Cairo 12311, Egypt.
⁵ Department of Biotechnology, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
⁶ Tanning Materials and Leather Technology Department, National Research Centre, Dokki, Cairo 12622, Egypt.
⁷ Department of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi Arabia.
⁸ Photochemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt.

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.

Keywords: CDK2; HepG2; anticancer; docking; imidazole; pyrazolo[3,4-b]pyridine; pyridine.

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Survival / drug effects
Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
Cyclin-Dependent Kinase 2 / chemistry
Dose-Response Relationship, Drug
Doxorubicin / pharmacology
Drug Design
Drug Screening Assays, Antitumor / methods*
Humans
Imidazoles / chemistry
Inhibitory Concentration 50
Molecular Docking Simulation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacology
Pyrimidines / chemistry
Pyrimidines / pharmacology
Quantitative Structure-Activity Relationship

Substances

Antineoplastic Agents
Imidazoles
Protein Kinase Inhibitors
Pyrazoles
Pyridines
Pyrimidines
pyrazolo(3,4-b)pyridine
pyrazolopyridine
imidazole
Doxorubicin
CDK2 protein, human
Cyclin-Dependent Kinase 2
pyrimidine

Grants and funding

TURSP-2020/138/Taif University, Taif, Saudi Arabia