New insight into structure-activity of furan-based salicylate synthase (MbtI) inhibitors as potential antitubercular agents

Laurent Chiarelli (1) , Matteo Mori (2) , Giangiacomo Beretta (2) , Arianna Gelain (2) , Elena Pini (2) , Josè Camilla Sammartino (1) , Giovanni Stelitano (1) , Daniela Barlocco (2) , Luca Costantino (3) , Margherita Lapillo (4) , Giulio Poli (4) , Isabella Caligiuri (5) , Flavio Rizzolio (5, 6) , Marco Bellinzoni (7) , Tiziano Tuccinardi (4) , Stefania Villa (2) , Fiorella Meneghetti (2)

1 UNIPV - Università degli Studi di Pavia = University of Pavia
2 UNIMI - Università degli Studi di Milano = University of Milan
3 University of Modena and Reggio Emilia
4 University of Pisa - Università di Pisa
5 National Cancer Institute of Aviano
6 University of Ca’ Foscari [Venice, Italy]
7 Microb. Struc. (UMR_3528 / U-Pasteur_5) - Microbiologie structurale - Structural Microbiology

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.

Keywords: Tuberculosis; antimycobacterial agent; drug design; molecular modelling; mycobactins; siderophores

Domains: Cristallography; Structural Biology [q-bio.BM]; Biochemistry, Molecular Biology; Bioinformatics [q-bio.QM]; Biological Physics [physics.bio-ph]; Cellular Biology

Laurent Chiarelli, Matteo Mori, Giangiacomo Beretta, Arianna Gelain, Elena Pini, et al.. New insight into structure-activity of furan-based salicylate synthase (MbtI) inhibitors as potential antitubercular agents. Journal of Enzyme Inhibition and Medicinal Chemistry, 2019, 34 (1), pp.823-828. ⟨10.1080/14756366.2019.1589462⟩. ⟨pasteur-03257047⟩