Advancement of Imidazo[1,2-a]pyridines with Improved Pharmacokinetics and Nanomolar Activity AgainstMycobacterium tuberculosis.
A set of fourteen imidazo[1,2-a]pyridine-3-carboxamides was synthesized and screened againstMycobacterium tuberculosisH37Rv. The minimum inhibitory concentrations of twelve of these agents were ≤ 1 μM against replicating bacteria and five compounds (9, 12, 16, 17and18) had MIC values ≤ 0.006 μM. Compounds13and18were screened against a panel of MDR and XDR drug resistant clinicalMtbstrains with the potency of18surpassing that of clinical candidate PA-824 by nearly 10 fold. Thein vivopharmacokinetics of compounds13and18were evaluated in male mice by oral (PO) and intravenous (IV) routes. These results indicate that readily synthesized imidazo[1,2-a]pyridine-3-carboxamides are an exciting new class of potent, selective anti-TB agents that merit additional development opportunities.
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556.
Garrett C
GC
Moraski
Lowell D
LD
Markley
Jeffrey
J
Cramer
Philip A
PA
Hipskind
Helena
H
Boshoff
Mai
M
Bailey
Torey
T
Alling
Juliane
J
Ollinger
Tanya
T
Parish
Marvin J
MJ
Miller
MDR-TB; Mycobacterium tuberculosis; XDR-TB; imidazo[1,2-a]pyridine-3-carboxamides; pharmacokinetics