2. Academic Validation
  3. Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations

Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations

  • J Med Chem. 2022 Dec 16. doi: 10.1021/acs.jmedchem.2c01668.
Ahmed A Al-Karmalawy 1,  Mohamed S Nafie 2,  Moataz A Shaldam 3,  Ayman Abo Elmaaty 4,  Samar A Antar 5 6,  Anwar A El-Hamaky 7,  Mohamed A Saleh 8 9,  Ahmed Elkamhawy 10 11,  Haytham O Tawfik 7
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt.
  • 2 Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy, Port Said University, Port Said 42526, Egypt.
  • 5 Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta 34518, Egypt.
  • 6 Center for Vascular and Heart Research, Fralin Biomedical Research Institute, Virginia Tech, Roanoke, Virginia 24016, United States.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
  • 8 Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, The United Arab Emirates.
  • 9 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 10 BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea.
  • 11 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
PMID: 36525642 DOI: 10.1021/acs.jmedchem.2c01668
Abstract

Telomerase is an outstanding biological target for Cancer treatment. BIBR1532 is a non-nucleoside selective Telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising Telomerase inhibitors. Therefore, two novel series of pyridazine-linked to cyclopenta[b]thiophene (8a-f) and tetrahydro-1-benzothiophene (9a-f) were synthesized. A quantitative real-time polymerase chain reaction was utilized to investigate the Telomerase inhibitory activity of candidates. Notably, 8e and 9e exhibited the best inhibition profiles. Moreover, 8e showed strong antitumor effects against both MCF-7 and A549 Cancer cell lines. The effects of 8e on the cell cycle and Apoptosis were measured. Besides, 8e was evaluated for its in vivo antitumor activity using solid Ehrlich carcinoma. The reduction in both the tumor weight and volume was greater than doxorubicin. Also, molecular docking and ADME studies were performed. Finally, a SAR study was conducted to gain further insights into the different Telomerase inhibition potentials upon variable structural modifications.

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