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  3. Identification of indole-grafted pyrazolopyrimidine and pyrazolopyridine derivatives as new anti-cancer agents: Synthesis, biological assessments, and molecular modeling insights

Identification of indole-grafted pyrazolopyrimidine and pyrazolopyridine derivatives as new anti-cancer agents: Synthesis, biological assessments, and molecular modeling insights

  • Bioorg Chem. 2024 Sep 6:153:107804. doi: 10.1016/j.bioorg.2024.107804.
Wagdy M Eldehna 1,  Haytham O Tawfik 2,  Maha-Hamadien Abdulla 3,  Mohamed S Nafie 4,  Heba Aref 5,  Moataz A Shaldam 6,  Noura S Alhassan 7,  Omar Al Obeed 7,  Zainab M Elsayed 8,  Hatem A Abdel-Aziz 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St., Alexandria 21648, Egypt. Electronic address: wagdy2000@gmail.com.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt. Electronic address: haytham.omar.mahmoud@pharm.tanta.edu.eg.
  • 3 Colorectal Research Chair, Department of Surgery, College of Medicine, King Saud University, Riyadh 11472, Saudi Arabia. Electronic address: mabdulla@ksu.edu.sa.
  • 4 Department of Chemistry, College of Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt. Electronic address: mohmamed.elsayed@sharjah.ac.ae.
  • 5 Medicinal Chemistry Department, Faculty of Pharmacy, El Menoufia University, El Menoufia, Shebin El Kom 32511, Egypt.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
  • 7 Colorectal Research Chair, Department of Surgery, College of Medicine, King Saud University, Riyadh 11472, Saudi Arabia.
  • 8 Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St., Alexandria 21648, Egypt; Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt.
PMID: 39276491 DOI: 10.1016/j.bioorg.2024.107804
Abstract

In the current medical era, developing new PIM-1 inhibitors stands as a significant approach to Cancer management due to the pivotal role of PIM-1 kinase in promoting cell survival, proliferation, and drug resistance in various cancers. This study involved designing and synthesizing new derivatives of pyrazolo[1,5-a]pyrimidines (6a-i) and pyrazolo[3,4-b]pyridines (10a-i) as potential anti-cancer agents targeting PIM-1 kinase. The cytotoxicity was screened on three Cancer cell lines: A-549 (lung), PANC-1 (pancreatic), and A-431 (skin), alongside MRC5 normal lung cells to assess selectivity. Several pyrazolo[1,5-a]pyrimidines (6b, 6c, 6g, 6h, and 6i) and pyrazolo[3,4-b]pyridine (10f) demonstrated notable Anticancer properties, particularly against A-549 lung Cancer cells (IC50 range: 1.28-3.52 μM), also they exhibited significantly lower toxicity towards MRC5 normal cells. Thereafter, the compounds were evaluated for their inhibitory activity against PIM-1 kinase. Notably, 10f, bearing a 4-methoxyphenyl moiety, demonstrated good inhibition of PIM-1 with an IC50 of 0.18 μM. Additionally, 10f induced Apoptosis and arrested cell cycle progression in A-549 cells. Molecular docking and dynamics simulations provided insights into the binding interactions and compounds' stability with PIM-1 kinase. The results highlight these compounds, especially 10f, as promising selective Anticancer agents targeting PIM-1 kinase.

Keywords

Kinase inhibitors; Molecular dynamics; PIM-1 kinase; Pyrazolo[1,5-a]pyrimidines; Pyrazolo[3,4-b]pyridines.

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