Synthesis and evaluation of rifabutin analogs against Mycobacterium avium and H(37)Rv, MDR and NRP Mycobacterium tuberculosis.
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.
Figueiredo
Ricardo
R
Instituto Nacional de Engenharia, Tecnologia e Inovação, I.P., Estrada do Paço do Lumiar, 1649-038 Lisboa, Portugal.
Moiteiro
Cristina
C
Medeiros
M Augusta
MA
da Silva
P Almeida
PA
Ramos
D
D
Spies
F
F
Ribeiro
M O
MO
Lourenço
M Cristina S
MC
Júnior
I N
IN
Gaspar
M Manuela
MM
Cruz
M Eugénia M
ME
Curto
M João Marcelo
MJ
Franzblau
S G
SG
Orozco
H
H
Aguilar
D
D
Hernandez-Pando
R
R
Costa
M Céu
MC
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*
D000995:Antitubercular Agents; D017828:Rifabutin