Chalcones and their B-aryl analogues as myeloperoxidase inhibitors: In silico, in vitro and ex vivo investigations

Author(s):Show less -

dos Santos, Mariana Bastos ^[1] ; Marques, Beatriz Carvalho ^[1] ; Ayusso, Gabriela Miranda ^[1] ; Rocha Garcia, Mayara Aparecida ^[1] ; Paracatu, Luana Chiquetto ^[2] ; Pauli, Ivani ^[3] ; Bolzani, Vanderlan Silva ^[4] ; Andricopulo, Adriano Defini ^[3] ; Ximenes, Valdecir Farias ^[2] ; Zeraik, Maria Luiza ^[5] ; Regasini, Luis Octavio ^[1]

Affiliation

^[1] Sao Paulo State Univ Unesp, Inst Biosci Humanities & Exact Sci, BR-15054000 Sao Jose Do Rio Preto, SP - Brazil

^[2] Sao Paulo State Univ UNESP, Fac Sci, Dept Chem, BR-17033360 Bauru, SP - Brazil

^[3] Univ Sao Paulo, Phys Inst Sao Carlos, BR-13563120 Sao Carlos, SP - Brazil

^[4] Sao Paulo State Univ, Inst Chem, Dept Organ Chem, BR-14800900 Araraquara, SP - Brazil

^[5] State Univ Londrina UEL, Dept Chem, BR-86051990 Londrina, Parana - Brazil

• Document type: Journal article
• Source: BIOORGANIC CHEMISTRY; v. 110, MAY 2021.
• Web of Science Citations: 1

Abstract

In the present study, a series of chalcones and their B-aryl analogues were prepared and evaluate as inhibitors of myeloperoxidase (MPO) chlorinating activity, using in vitro and ex vivo assays. Among these, B-thiophenyl chalcone (analogue 9) demonstrated inhibition of in vitro and ex vivo MPO chlorinating activity, exhibiting IC50 value of 0.53 and 19.2 mu M, respectively. Potent ex vivo MPO inhibitors 5, 8 and 9 were not toxic to human neutrophils at 50 mu M, as well as displayed weak 2,2-diphenyl-1-pycrylhydrazyl radical (DPPH center dot) and hypochlorous acid (HOCl) scavenger abilities. Docking simulations indicated binding mode of MPO inhibitors, evidencing hydrogen bonds between the amino group at 4' position (ring A) of chalcones with Gln91, Asp94, and Hys95 MPO residues. In this regard, the efficacy and low toxicity promoted aminochalcones and arylic analogues to the rank of hit compounds in the search for new non-steroidal anti-inflammatory compounds. (AU)

• FAPESP's process: 16/00580-5 - Chalcone-Histone Deacetylase Inhibitor Hybrids as Cytotoxic Agents and Wnt/beta-catenin pathway blockers: Synthesis and Breast Cells and Zebrafish Evaluations
• Grantee: Mariana Bastos dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/18330-0 - Synthesis and biological evaluation of curcumin-cinnamaldehyde hybrids as bacterial cell division inhibitors
• Grantee: Luis Octávio Regasini
• Support Opportunities: Regular Research Grants
• FAPESP's process: 09/53989-4 - Acquisition of a nuclear magnetic resonance spectrometer for studies of biomolecules
• Grantee: Raghuvir Krishnaswamy Arni
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 18/15083-2 - Synthesis and biological evaluation of isobavachalcone (IBC) and analogs as potential agents against tuberculosis
• Grantee: Luis Octávio Regasini
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/50926-0 - INCT 2014: biodiversity and natural products
• Grantee: Vanderlan da Silva Bolzani
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants