1. New insight into structure-activity of furan-based salicylate synthase (MbtI) inhibitors as potential antitubercular agents
- Author
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Chiarelli, Laurent, Mori, Matteo, Beretta, Giangiacomo, Gelain, Arianna, Pini, Elena, Sammartino, Josè Camilla, Stelitano, Giovanni, Barlocco, Daniela, Costantino, Luca, Lapillo, Margherita, Poli, Giulio, Caligiuri, Isabella, Rizzolio, Flavio, Bellinzoni, Marco, Tuccinardi, Tiziano, Villa, Stefania, Meneghetti, Fiorella, University of Pavia, Università degli Studi di Milano [Milano] (UNIMI), University of Modena and Reggio Emilia, Partenaires INRAE, University of Pisa - Università di Pisa, National Cancer Institute of Aviano, University of Ca’ Foscari [Venice, Italy], Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), This work was funded by University of Milan (Linea B), and the Italian Ministry of Education, University and Research (MIUR): Dipartimenti di Eccellenza Programme (2018–2022) - Dept. of Biology and Biotechnology 'L. Spallanzani', University of Pavia., Università degli Studi di Pavia = University of Pavia (UNIPV), Università degli Studi di Milano = University of Milan (UNIMI), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
- Subjects
MESH: Mycobacterium bovis ,drug design ,[PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph] ,Short Communication ,mycobactins ,Antitubercular Agents ,Lyases ,Settore BIO/11 - Biologia Molecolare ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Microbial Sensitivity Tests ,Structure-Activity Relationship ,MESH: Structure-Activity Relationship ,MESH: Molecular Docking Simulation ,[CHIM.CRIS]Chemical Sciences/Cristallography ,antimycobacterial agent ,Tuberculosis ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Enzyme Inhibitors ,Furans ,molecular modelling ,siderophores ,Binding Sites ,Molecular Docking Simulation ,Mycobacterium bovis ,Pharmacology ,Drug Discovery3003 Pharmaceutical Science ,MESH: Microbial Sensitivity Tests ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,lcsh:RM1-950 ,MESH: Furans ,MESH: Antitubercular Agents ,MESH: Lyases ,lcsh:Therapeutics. Pharmacology ,MESH: Binding Sites ,MESH: Enzyme Inhibitors ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] - Abstract
Starting from the analysis of the hypothetical binding mode of our previous furan-based hit (I), we successfully achieved our objective to replace the nitro moiety, leading to the disclosure of a new lead exhibiting a strong activity against MbtI. Our best candidate 1 h displayed a Ki of 8.8 µM and its antimycobacterial activity (MIC99 = 250 µM) is conceivably related to mycobactin biosynthesis inhibition. These results support the hypothesis that 5-phenylfuran-2-carboxylic derivatives are a promising class of MbtI inhibitors., GRAPHICAL ABSTRACT
- Published
- 2019
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