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
  • 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.