2. Academic Validation
  3. Lead Optimization of BIBR1591 To Improve Its Telomerase Inhibitory Activity: Design and Synthesis of Novel Four Chemical Series with In Silico, In Vitro, and In Vivo Preclinical Assessments

Lead Optimization of BIBR1591 To Improve Its Telomerase Inhibitory Activity: Design and Synthesis of Novel Four Chemical Series with In Silico, In Vitro, and In Vivo Preclinical Assessments

  • J Med Chem. 2024 Jan 11;67(1):492-512. doi: 10.1021/acs.jmedchem.3c01708.
Ahmed A Al-Karmalawy 1 2,  Mai H A Mousa 3,  Marwa Sharaky 4,  Mai A E Mourad 5,  Ahmed M El-Dessouki 6,  Amir O Hamouda 7,  Radwan Alnajjar 8 9,  Abdelmoneim A Ayed 10,  Moataz A Shaldam 11,  Haytham O Tawfik 12
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.
  • 2 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6h of October City, Giza 12566, Egypt.
  • 3 Pharmaceutical Chemistry Department, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo 11786, Egypt.
  • 4 Cancer Biology Department, Pharmacology Unit, National Cancer Institute (NCI), Cairo University, Cairo 12613, Egypt.
  • 5 Medicinal Chemistry Department, Faculty of Pharmacy, Port-Said University, Port-Said 42511, Egypt.
  • 6 Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt.
  • 7 Department of Biochemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.
  • 8 Department of Chemistry, Faculty of Science, University of Benghazi, Benghazi 1308, Libya.
  • 9 PharmD, Faculty of Pharmacy, Libyan International Medical University, Benghazi 1308, Libya.
  • 10 Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt.
  • 11 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
  • 12 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
PMID: 38117230 DOI: 10.1021/acs.jmedchem.3c01708
Abstract

Herein, modifications to the previously reported BIBR1591 were conducted to obtain bioisosteric candidates with improved activities. The % inhibition of the newly afforded candidates against the Telomerase target was investigated. Notably, 6f achieved superior Telomerase inhibition (63.14%) compared to BIBR1532 and BIBR1591 (69.64 and 51.58%, respectively). In addition, 8a and 8b showed comparable promising Telomerase inhibition with 58.65 and 55.57%, respectively, which were recorded to be frontier to that of BIBR1591. 6f, 8a, and 8b were tested against five Cancer cell lines related to the lung and liver subtypes. Moreover, 6f was examined on both cell cycle progression and Apoptosis induction in HuH7 Cancer cells. Furthermore, the in vivo antitumor activity of 6f was further assessed in female mice with solid Ehrlich carcinoma. In addition, molecular docking and molecular dynamics simulations were carried out. Collectively, 6f, 8a, and 8b could be considered potential new Telomerase inhibitors to be subjected to further investigation and/or optimization.

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