[1, 8]-Naphthyridine derivatives as dual inhibitor of alkaline phosphatase and carbonic anhydrase

BMC Chemistry

Research

Salman Alamery¹  Arif Ahmed Mohammed¹  Jamshed Iqbal²  Abid Mahmood²  Syeda Abida Ejaz³  Peter Langer⁴  Salman Alrokayan⁵  Tajamul Hussain⁶ 

[1] Biochemistry Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia;Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, 22060, Abbottabad, Pakistan;Department of Pharmaceutical Chemistry, Faculty of Pharmacv, The Islamia University of Bahawalpur, 63100, Bahawalpur, Pakistan;Institut Für Chemie, Universität Rostock, A.-Einstein-Str. 3a, 18059, Rostock, Germany;Research Chair for Biomedical Application of Nanomaterials, Biochemistry Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia;Biochemistry Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia;Research Chair for Biomedical Application of Nanomaterials, Biochemistry Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia;Centre of Excellence in Biotechnology Research, King Saud University, 11451, Riyadh, Saudi Arabia;

关键词: Carbonic anhydrase;    Alkaline phosphatase;    [1, 8]-Naphthyridine derivatives;    Simulation studies;    DFT studies;   

DOI  :  10.1186/s13065-023-01052-8

 received in 2023-06-05, accepted in 2023-10-02,  发布年份 2023

来源: Springer

【 摘 要 】

[1,8]-Naphthyridine derivatives have been reported to possess important biological activities and may serve as attractive pharmacophores in the drug discovery process. [1,8]-Naphthyridine derivatives (1a-1l) were evaluated for inhibitory potential for isozymes of carbonic anhydrase (CA) and alkaline phosphatase (ALP). CAs have been reported to carry out reversible hydration of CO2 into HCO3−, secretion of electrolytes, acid–base regulation, bone resorption, calcification, and biosynthetic reactions. Whereas ALPs hydrolyze monophosphate esters with the release of inorganic phosphate and play an important role in bone mineralization. Both enzymes have been found to be over-expressed and raised functional activities in patients suffering from rheumatoid arthritis. The discovery of dual inhibitors of these enzymes may provide a synergistic effect to cure bone disorders such as rheumatoid arthritis and ankylosing spondylitis. Among the test compounds, the most potent inhibitors for CA-II, CA-IX, and CA-XII were 1e, 1g, and 1a with IC50 values of 0.44 ± 0.19, 0.11 ± 0.03 and 0.32 ± 0.07 µM, respectively. [1,8]-Naphthyridine derivatives (1a–1l) were approximately 4 folds more potent than standard CA inhibitor acetazolamide. While in the case of ALPs, the most potent compounds for b-TNAP and c-IAP were 1b and 1e with IC50 values of 0.122 ± 0.06 and 0.107 ± 0.02 µM, respectively. Thus, synthesized derivatives proved to be 100 to 800 times more potent as compared to standard inhibitors of b-TNAP and c-IAP (Levamisole and L-phenyl alanine, respectively). In addition, selectivity and dual inhibition of [1,8]-Naphthyridine derivatives confer precedence over known inhibitors. Molecular docking and molecular simulation studies were also conducted in the present studies to define the type of interactions between potential inhibitors and enzyme active sites.

【 授权许可】

CC BY   
© Springer Nature Switzerland AG 2023

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