2. Academic Validation
  3. Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAFV600E/p38α inhibitors

Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAFV600E/p38α inhibitors

  • Eur J Med Chem. 2021 Apr 5:215:113277. doi: 10.1016/j.ejmech.2021.113277.
Eslam M H Ali 1,  Rania Farag A El-Telbany 2,  Mohammed S Abdel-Maksoud 3,  Usama M Ammar 4,  Karim I Mersal 5,  Seyed-Omar Zaraei 5,  Mohammed I El-Gamal 6,  Se-In Choi 7,  Kyung-Tae Lee 7,  Hee-Kwon Kim 8,  Kwan Hyi Lee 9,  Chang-Hyun Oh 10
Affiliations

Affiliations

  • 1 Center of Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, 12055, Egypt.
  • 2 Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, 12055, Egypt.
  • 3 Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre NRC (ID: 60014618)), Dokki, Giza, 12622, Egypt.
  • 4 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0NR, Scotland, United Kingdom.
  • 5 Center of Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea.
  • 6 Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt.
  • 7 Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul, 130-701, Republic of Korea.
  • 8 Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Jeonbuk National University Medical School and Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju, 54907, Republic of Korea; Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju, 54907, Republic of Korea.
  • 9 Center of Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea.
  • 10 Center of Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea. Electronic address: choh@kist.re.kr.
PMID: 33601311 DOI: 10.1016/j.ejmech.2021.113277
Abstract

The synergistic effect of dual inhibition of serine/threonine protein kinases that are involved in the same signalling pathway of the diseases can exert superior biological benefits for treatment of these diseases. In the present work, a new series of (imidazol-5-yl)pyrimidine was designed and synthesized as dual inhibitors of BRafV600E and p38α kinases which are considered as key regulators in mitogen-activated protein kinase (MAPK) signalling pathway. The target compounds were evaluated for dual kinase inhibitory activity. The tested compounds exhibited nanomolar scale IC50 values against BRafV600E and low to sub-micromolar IC50 range against p38α. Compound 20h was identified as the most potent dual BRafV600E/p38α Inhibitor with IC50 values of 2.49 and 85 nM, respectively. Further deep investigation revealed that compound 20h possesses inhibitory activity of TNF-α production in lipopolysaccharide-induced RAW 264.7 macrophages with IC50 value of 96.3 nM. Additionally, the target compounds efficiently frustrated the proliferation of LOX-IMVI melanoma cell line. Compound 20h showed a satisfactory antiproliferative activity with IC50 value of 13 μM, while, compound 18f exhibited the highest cytotoxicity potency with IC50 value of 0.9 μM. Compound 18f is 11.11-fold more selective toward LOX-IMVI melanoma cells than IOSE-80PC normal cells. The newly reported compounds represent therapeutically promising candidates for further development of BRafV600E/p38α inhibitors in an attempt to overcome the acquired resistance of BRaf mutant melanoma.

Keywords

BRAF(V600E); Imidazol-5-ylpyrimidine; MAPK14; Melanoma; Molecular docking; TNF-α.

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