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Design, Synthesis and Biological Evaluation of New HDAC1 and HDAC2 Inhibitors Endowed with Ligustrazine as a Novel Cap Moiety

Authors Al-Sanea MM, Gotina L, Mohamed MFA, Grace Thomas Parambi D, Gomaa HAM, Mathew B, Youssif BGM, Alharbi KS, Elsayed ZM, Abdelgawad MA, Eldehna WM

Received 9 November 2019

Accepted for publication 6 January 2020

Published 4 February 2020 Volume 2020:14 Pages 497—508


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Tuo Deng

Mohammad M Al-Sanea,1 Lizaveta Gotina,2 Mamdouh FA Mohamed,3 Della Grace Thomas Parambi,1 Hesham A M Gomaa,4,5 Bijo Mathew,6 Bahaa G M Youssif,7 Khalid Saad Alharbi,8 Zainab M Elsayed,9 Mohamed A Abdelgawad,1,10 Wagdy M Eldehna9,11

1Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 2014, Saudi Arabia; 2Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Daejeon, Korea; 3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt; 4Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 2014, Saudi Arabia; 5Department of Biochemistry, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt; 6Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, Kerala 678557, India; 7Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt; 8Department of Pharmacology, College of Pharmacy, Jouf University, Sakakah 72341, Saudi Arabia; 9Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt; 10Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef 62514, Egypt; 11Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt

Correspondence: Mohammad M Al-Sanea
Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 2014, Saudi Arabia
Tel +966 594076460

Introduction: Histone deacetylases (HDACs) represent one of the most validated cancer targets. The inhibition of HDACs has been proven to be a successful strategy for the development of novel anticancer candidates.
Methods: This work describes design and synthesis of a new set of HDAC inhibitors ( 7a-c and 8a, b) utilizing ligustrazine as a novel cap moiety, and achieving the pharmacophoric features required to induce the desired inhibition.
Results: The newly synthesized derivatives were evaluated for their potential inhibitory activity toward two class I histone deacetylases, namely HDAC1 and HDAC2. The tested ligustrazine-based compounds were more potent toward HDAC2 (IC50 range: 53.7– 205.4 nM) than HDAC1 (IC50 range: 114.3– 2434.7 nM). Furthermore, the antiproliferative activities against two HDAC-expressing cancer cell lines; HT-29 and SH-SY5Y were examined by the MTT assay. Moreover, a molecular docking study of the designed HDAC inhibitors ( 7a-c and 8a,b) was carried out to investigate their binding pattern within their prospective targets; HDAC1 (PDB-ID: 4BKX) and HDAC2 (PDB-ID: 6G3O).
Discussion: Compound 7a was found to be the most potent analog in this study toward HDAC1 and HDAC2 with IC50 values equal 114.3 and 53.7 nM, respectively. Moreover, it was the most effective counterpart (IC50 = 1.60 μM), with 4.7-fold enhanced efficiency than reference drug Gefitinib (IC50 = 7.63 μM) against SH-SY5Y cells. Whereas, compound 8a (IC50 = 1.96 μM) was the most active member toward HT-29 cells, being 2.5-times more potent than Gefitinib (IC50 = 4.99 μM). Collectively, these results suggest that 7a merits further optimization and development as an effective new HDACI lead compound.

Keywords: HDACs Inhibitors, Ligustrazine, Anticancer agents, In silico study, Synthesis

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