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Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Activity of Rifabutin and Hemi-synthetic Derivatives Against Mycobacterium abscessus

Author(s): Ivy B. Ramis*, Ricardo Figueiredo, Daniela F. Ramos, Priscila C.B. Halicki, Andrea von Groll, Miguel Viveiros, Maria do Ceu Costa and Pedro E.A. da Silva

Volume 14, Issue 4, 2018

Page: [394 - 399] Pages: 6

DOI: 10.2174/1573406414666171204102633

Price: $65

Abstract

Background: Mycobacterium abscessus causes a wide range of clinical diseases that are difficult to treat. This microorganism is resistant not only to the classical antituberculosis agents but also to most of the antimicrobials that are currently available, resulting in limited therapeutic options and treatment failure. This scenario stresses the need to search for new drugs with activity against M. abscessus.

Objective: To evaluate in vitro the antimycobacterial activity and cytotoxicity of rifabutin (RFB 1) and ten derivatives (2-11) against M. abscessus ATCC 19977.

Method: The minimum inhibitory concentration (MIC) of the molecules was determined by the microdilution broth method according to the guideline described in CLSI. The toxicity evaluation was carried in 96-well microplates, using the cell line J774A.1 (ATCC TIB-67).

Result: From the eleven molecules tested, RFB 1 and RFB 4 were the compounds showing higher activities against M. abscessus, with MICs of 0.9 and 1.0 µM, respectively. The R1 and R2 moieties seem to have deciding influence over the final activity. Furthermore, N-oxide derivatives 9, 10, and 11 were also active against M. abscessus, with MICs of 7.2 µM, 1.8 µM and 3.8 µM, respectively. An explanatory hypothesis for the better activities of compounds RFB 1, RFB 4, RFB 10 and RFB 11 considers the likely hydrogen bonding between ligands and receptor, balancing the global flexibility and interaction energies. RFB 1 and its most effective derivatives were found to be not toxic.

Conclusion: Besides RFB 1, its derivatives 4, 10 and 11 show potential for clinical development in the M. abscessus treatment.

Keywords: Antimycobacterial, cytotoxicity, drug resistance, Mycobacterium abscessus, rifabutin, susceptibility testing.

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