Synthesis and evaluation of rifabutin analogs against Mycobacterium avium and H(37)Rv, MDR and NRP Mycobacterium tuberculosis

Bioorg Med Chem. 2009 Jan 15;17(2):503-11. doi: 10.1016/j.bmc.2008.12.006.

Ricardo Figueiredo ¹, Cristina Moiteiro, M Augusta Medeiros, P Almeida da Silva, D Ramos, F Spies, M O Ribeiro, M Cristina S Lourenço, I N Júnior, M Manuela Gaspar, M Eugénia M Cruz, M João Marcelo Curto, S G Franzblau, H Orozco, D Aguilar, R Hernandez-Pando, M Céu Costa

Affiliations

Affiliation

1 Instituto Nacional de Engenharia, Tecnologia e Inovação, I.P., Estrada do Paço do Lumiar, 1649-038 Lisboa, Portugal.

PMID: 19119013 DOI: 10.1016/j.bmc.2008.12.006

Abstract

Clinical utility of rifabutin 1 (RBT), a potent Antibiotic used in multidrug regimens for tuberculosis (TB) as well as for infections caused by Mycobacterium avium complex (MAC), has been hampered due to dose-limiting toxicity. RBT analogs 2-11 were synthesized and evaluated against M. avium 1581 and Mycobacterium tuberculosis susceptible and resistant strains in vitro. A selection of candidates were also assayed against non-replicating persistent (NRP) M. tuberculosis. Subsequent in vivo studies with the best preclinical candidate drugs 5 and 8, in a model of progressive pulmonary tuberculosis of Balb/C mice infected either with H(37)Rv drug-sensible strain or with multidrug resistant (MDR) clinical isolates, resistant to all primary Antibiotics including rifampicin, were performed. The results disclosed here suggest that 5 and 8 have potential for clinical application.

Name
Email *

	Sorry, but the email address you supplied was invalid.