title: Synthesis and evaluation of rifabutin analogs against Mycobacterium avium and H(37)Rv, MDR and NRP Mycobacterium tuberculosis.
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.
authors.affiliation: Instituto Nacional de Engenharia, Tecnologia e Inovação, I.P., Estrada do Paço do Lumiar, 1649-038 Lisboa, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Figueiredo
authors.forename: Cristina
authors.initials: C
authors.lastname: Moiteiro
authors.forename: M Augusta
authors.initials: MA
authors.lastname: Medeiros
authors.forename: P Almeida
authors.initials: PA
authors.lastname: da Silva
authors.forename: D
authors.initials: D
authors.lastname: Ramos
authors.forename: F
authors.initials: F
authors.lastname: Spies
authors.forename: M O
authors.initials: MO
authors.lastname: Ribeiro
authors.forename: M Cristina S
authors.initials: MC
authors.lastname: Lourenço
authors.forename: I N
authors.initials: IN
authors.lastname: Júnior
authors.forename: M Manuela
authors.initials: MM
authors.lastname: Gaspar
authors.forename: M Eugénia M
authors.initials: ME
authors.lastname: Cruz
authors.forename: M João Marcelo
authors.initials: MJ
authors.lastname: Curto
authors.forename: S G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: H
authors.initials: H
authors.lastname: Orozco
authors.forename: D
authors.initials: D
authors.lastname: Aguilar
authors.forename: R
authors.initials: R
authors.lastname: Hernandez-Pando
authors.forename: M Céu
authors.initials: MC
authors.lastname: Costa
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D051379:Mice; D008807:Mice, Inbred BALB C; D009162:Mycobacterium avium / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D017828:Rifabutin