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  3. Design, synthesis, biological evaluation, and in silico studies of novel pyridopyridine derivatives as anticancer candidates targeting FMS kinase

Design, synthesis, biological evaluation, and in silico studies of novel pyridopyridine derivatives as anticancer candidates targeting FMS kinase

  • Eur J Med Chem. 2024 Aug 5:274:116557. doi: 10.1016/j.ejmech.2024.116557.
Anusha Sebastian 1,  Reinad R Abu Rabah 1,  Seyed-Omar Zaraei 1,  Srinivasulu Vunnam 1,  Shaista Sultan 1,  Hanan S Anbar 2,  Randa El-Gamal 3,  Hamadeh Tarazi 4,  Nadin Sarg 1,  Dima W Alhamad 1,  Salma A Al Shamma 1,  Afnan I Shahin 1,  Hany A Omar 5,  Taleb H Al-Tel 6,  Mohammed I El-Gamal 7
Affiliations

Affiliations

  • 1 Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 2 Department of Pharmaceutical Sciences, Dubai Pharmacy College for Girls, Dubai, 19099, United Arab Emirates.
  • 3 Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.
  • 4 Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 5 Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
  • 6 Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates. Electronic address: alteltaleb@gmail.com.
  • 7 Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. Electronic address: drmelgamal2002@gmail.com.
PMID: 38850857 DOI: 10.1016/j.ejmech.2024.116557
Abstract

Design and synthesis of novel 4-carboxamidopyrido[3,2-b]pyridine derivatives as novel rigid analogues of sorafenib are reported herein. The target compounds showed potent antiproliferative activities against a panel of NCI-60 Cancer cell lines as well as hepatocellular carcinoma cell line. Compounds 8g and 9f were among the most promising derivatives in terms of effectiveness and safety. Therefore, they were further examined to demonstrate their ability to induce Apoptosis and alter cell cycle progression in hepatocellular carcinoma cells. The most potent compounds were tested against a panel of kinases that indicated their selectivity against FMS kinase. Compounds 8g and 8h showed the most potent activities against FMS kinase with IC50 values of 21.5 and 73.9 nM, respectively. The two compounds were also tested in NanoBRET assay to investigate their ability to inhibit FMS kinase in cells (IC50 = 563 nM (8g) and 1347 nM (8h) vs. IC50 = 1654 nM for sorafenib). Furthermore, compounds 8g and 8h possess potent inhibitory activities against macrophages when investigated in bone marrow-derived macrophages (BMDM) assay (IC50 = 56 nM and 167 nM, respectively, 164 nM for sorafenib). The safety and selectivity of these compounds were confirmed when tested against normal cell lines. Their safety profile was further confirmed using hERG assay. In silico studies were carried out to investigate their binding modes in the active site of FMS kinase, and to develop a QSAR model for these new motifs.

Keywords

Anti-inflammatory; Anticancer; CSF-1R kinase inhibitors; FMS kinase inhibitors; Pyridopyridine; Urea.

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