2. Academic Validation
  3. Optimization and SAR investigation of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as EGFR and BRAFV600E dual inhibitors with potent antiproliferative and antioxidant activities

Optimization and SAR investigation of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as EGFR and BRAFV600E dual inhibitors with potent antiproliferative and antioxidant activities

  • Bioorg Chem. 2022 Mar;120:105616. doi: 10.1016/j.bioorg.2022.105616.
Hesham A M Gomaa 1,  Mohamed E Shaker 2,  Sami I Alzarea 3,  O M Hendawy 4,  Fatma A M Mohamed 5,  Ahmed M Gouda 6,  Asmaa T Ali 7,  Martha M Morcoss 8,  Mostafa H Abdelrahman 9,  Laurent Trembleau 10,  Bahaa G M Youssif 11
Affiliations

Affiliations

  • 1 Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia. Electronic address: [email protected].
  • 2 Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 3 Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.
  • 4 Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia; Department of Clinical Pharmacology, Faculty of Medicine, Beni-Suef University, Egypt.
  • 5 Clinical Laboratory Science Department, College of Applied Medical Sciences, Jouf University, Aljouf 72341, Saudi Arabia; Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.
  • 6 Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
  • 7 Biochemistry Department, Faculty of Pharmacy, Nahda University, 62513 Beni-Suef, Egypt.
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Nahda University, 62513 Beni-Suef, Egypt.
  • 9 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
  • 10 School of Natural and Computing Sciences, University of Aberdeen, Meston Building, Aberdeen AB24 3UE, United Kingdom. Electronic address: [email protected].
  • 11 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Electronic address: [email protected].
PMID: 35078049 DOI: 10.1016/j.bioorg.2022.105616
Abstract

Using a single drug to treat Cancer with dual-targeting is an unusual approach when compared to other drug combinations. Dual-targeting agents were developed as a result of insufficient efficacy and drug resistance when single-targeting agents were used. As a result, the 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives 13-22 have been developed as dual EGFR and BRafV600E inhibitors. The target compounds were synthesized and tested in vitro against four Cancer cell lines, with compounds 15, and 19-22 demonstrating potent antiproliferative activity. In vitro studies revealed that these compounds have dual inhibitory effect on EGFR and BRafV600E. Compounds 15, and 19-22 exhibited inhibitions of EGFR with IC50 ranging from 32 nM to 63 nM which were superior to erlotinib (IC50 = 80 ± 10 nM). Compounds 20, 21 and 22 showed promising inhibitory activity of BRafV600E (IC50 = 55, 45 and 51 nM, respectively) and were found to be potent inhibitors of Cancer cell proliferation (GI50 = 51, 35 and 44 nM, respectively). Compounds 20, 21 and 22 showed good antioxidant activity comparable to the reference Trolox. Lastly, the best active dual inhibitors were docked inside EGFR and BRafV600E active sites to clarify their binding modes.

Keywords

Antiproliferative; BRAF(V600E); EGFR; Indole; Melanoma cell.

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