Identification of 3-(piperazinylmethyl)benzofuran derivatives as novel type II CDK2 inhibitors: design, synthesis, biological evaluation, and in silico insights

Wagdy M Eldehna; Raed M Maklad; Hadia Almahli; Tarfah Al-Warhi; Eslam B Elkaeed; Mohammed A S Abourehab; Hatem A Abdel-Aziz; Ahmed M El Kerdawy

doi:10.1080/14756366.2022.2062337

Identification of 3-(piperazinylmethyl)benzofuran derivatives as novel type II CDK2 inhibitors: design, synthesis, biological evaluation, and in silico insights

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1227-1240. doi: 10.1080/14756366.2022.2062337.

Authors

Wagdy M Eldehna^{1

2}, Raed M Maklad^{2

3}, Hadia Almahli⁴, Tarfah Al-Warhi⁵, Eslam B Elkaeed⁶, Mohammed A S Abourehab⁷, Hatem A Abdel-Aziz⁸, Ahmed M El Kerdawy^{9

10}

Affiliations

¹ School of Biotechnology, Badr University in Cairo, Badr City, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
³ Institute of Drug Discovery and Development, Kafrelsheikh University, Kafrelsheikh, Egypt.
⁴ Department of Chemistry, University of Cambridge, Cambridge, UK.
⁵ Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
⁶ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
⁷ Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
⁸ Department of Applied Organic Chemistry, National Research Center, Dokki, Egypt.
⁹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
¹⁰ Department of Pharmaceutical Chemistry, School of Pharmacy, NewGiza University (NGU), Cairo, Egypt.

Abstract

In the current work, a hybridisation strategy was adopted between the privileged building blocks, benzofuran and piperazine, with the aim of designing novel CDK2 type II inhibitors. The hybrid structures were linked to different aromatic semicarbazide, thiosemicarbazide, or acylhydrazone tails to anchor the designed inhibitors onto the CDK2 kinase domain. The designed compounds showed promising CDK2 inhibitory activity. Compounds 9h, 11d, 11e and 13c showed potent inhibitory activity (IC₅₀ of 40.91, 41.70, 46.88, and 52.63 nM, respectively) compared to staurosporine (IC₅₀ of 56.76 nM). Moreover, benzofurans 9e, 9h, 11d, and 13b showed promising antiproliferative activities towards different cancer cell lines, and non-significant cytotoxicity on normal lung fibroblasts MRC-5 cell line. Furthermore, a cell cycle analysis as well as Annexin V-FITC apoptosis assay on Panc-1 cell line were performed. Molecular docking simulations were performed to explore the ability of target benzofurans to adopt the common binding pattern of CDK2 type II inhibitors.

Keywords: Kinase inhibitors; apoptotic agents; benzofuran synthesis; molecular docking; pancreatic cancer.

MeSH terms

Antineoplastic Agents* / chemistry
Benzofurans* / pharmacology
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzofurans
Protein Kinase Inhibitors
benzofuran

Grants and funding

The authors extend their appreciation to the Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R25), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The authors thank the Deanship of Scientific Research at Umm Al-Qura University for supporting this work by Grant Code: (22UQU4290565DSR010).