SYNTHESIS OF THIOUREA DERIVATIVES FROM M-METHOXYCINNAMIC ACID AS ANTIANGIOGENIC CANDIDATE

Authors

  • Juni Ekowati Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
  • Iwan Sahrial Hamid Faculty of Veterinary Medicine, Airlangga University, Surabaya, Indonesia
  • Kholis Amalia Nofianti Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
  • Shigeru Sasaki Institute Medicinal Chemistry, Hoshi University, Tokyo, Japan

DOI:

https://doi.org/10.11113/jt.v81.13410

Keywords:

Microwave irradiation, angiogenic inhibitor, COX-2, EGFR, celecoxib, ADMET profile

Abstract

Microwave-assisted nucleophilic acyl substitution was employed to obtain thiourea derivatives (3a, 3b, 3c) from m-methoxycinnamic acid (1). This synthesis method successfully yielded 60-70% reaction product. In vivo anti-angiogenic evaluation was conducted by chick chorioallantoic membrane model, by which each of the derivative at dose 30, 60, and 90 µg induced by bFGF and compared to celecoxib 60 µg as positive control. It was found that all of the synthesized compound at the tested dose were able to inhibit neovascularization and formation of endothelial cell of new blood vessels by 51-75%. In silico analysis predicted that the anti-angiogenesis mechanism of all the synthesized compounds is through the inhibition of EGFR kinase and COX-2. N atom acts as hydrogen bonding acceptor by residue Gly526 of COX-2. While thiourea moieties of 3a-c have hydrophobic interaction by residues Ser530, Tyr385, and Leu352. In addition, the carbonyl group of thiourea of compound 3a-c inhibit EGFR kinase through the interaction with lys745. The pKCSM data revealed that 3a-c absorbed in intestine by 89-92%, and acut toxicity in rat category 4, suggesting that the compounds show good absorption, and low toxicity. In conclusion, this study successfully synthesized thiourea derivatives, which have anti-angiogenesis activity, tested by CAM model.

Author Biographies

  • Juni Ekowati, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
    Department of Pharmaceutical Chemistry, Secretary, Ass. Prof.
  • Iwan Sahrial Hamid, Faculty of Veterinary Medicine, Airlangga University, Surabaya, Indonesia
    Department of Basic Veterinary Medicine, member, Ass.Prof.
  • Kholis Amalia Nofianti, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
    Department Pharmaceutical Chemistry, member
  • Shigeru Sasaki, Institute Medicinal Chemistry, Hoshi University, Tokyo, Japan
    Institute of Medicinal Chemistry

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Published

2019-06-25

Issue

Vol. 81 No. 4: July 2019

Section

Science and Engineering

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How to Cite

SYNTHESIS OF THIOUREA DERIVATIVES FROM M-METHOXYCINNAMIC ACID AS ANTIANGIOGENIC CANDIDATE. (2019). Jurnal Teknologi (Sciences & Engineering), 81(4). https://doi.org/10.11113/jt.v81.13410