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Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA

Rullah, Kamal and Mohd Aluwi, Mohd Fadhlizil Fasihi and Koeberle, Andreas and Werz, Oliver and Abdul Razak, Nur Sakinah and Wei, Leong Sze and Salim, Fatimah and Ismail, Nor Hadiani and Jantan, Ibrahim and Wai, Lam Kok (2019) Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA. Journal of Molecular Structure, 1196. pp. 844-850. ISSN 0022-2860

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The search of novel mPGES-1 inhibitors has recently intensified probably due to the superior safety in comparison to existing anti-inflammatory drugs. Although two mPGES-1 inhibitors have entered clinical trials, none has yet reached the market. In this study, we performed modifications guided by 3D-QSAR CoMFA on 2, which is an unsymmetrical curcumin derivative with low binding affinity towards mPGES-1. To counter the PAINS properties predicted for 2, the diketone linker was replaced with a pyrazole ring. On the other hand, both prenyl and carboxylate ester groups were introduced to improve the activity. When tested in vitro, 11 suppressed PGE2 biosynthesis in activated macrophages and showed promising human mPGES-1 inhibition in microsomes of interleukin-1β-stimulated A549 cells. Altogether, 11 has been identified as a potential mPGES-1 inhibitor and could be a promising lead for a novel class of mPGES-1 inhibitors.

Item Type: Article (Journal)
Additional Information: 9020/74958
Uncontrolled Keywords: 3D-QSAR, CoMFA, PGE2, mPGES-1, PAINS
Subjects: R Medicine > RS Pharmacy and materia medica > RS403 Materia Medica-Pharmaceutical Chemistry
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button): Kulliyyah of Pharmacy > Department of Pharmaceutical Chemistry
Depositing User: Dr Kamal Rullah
Date Deposited: 27 Oct 2019 01:35
Last Modified: 13 Apr 2020 12:16
URI: http://irep.iium.edu.my/id/eprint/74958

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