TY - JOUR
T1 - Substituted N-Phenyl-5-(2-(phenylamino)thiazol-4-yl)isoxazole-3-carboxamides Are Valuable Antitubercular Candidates that Evade Innate Efflux Machinery
AU - Azzali, Elisa
AU - Machado, Diana
AU - Kaushik, Amit
AU - Vacondio, Federica
AU - Flisi, Sara
AU - Cabassi, Clotilde Silvia
AU - Lamichhane, Gyanu
AU - Viveiros, Miguel
AU - Costantino, Gabriele
AU - Pieroni, Marco
PY - 2017/8/24
Y1 - 2017/8/24
N2 - Tuberculosis remains one of the deadliest infectious diseases in the world, and the increased number of multidrug-resistant and extremely drug-resistant strains is a significant reason for concern. This makes the discovery of novel antitubercular agents a cogent priority. We have previously addressed this need by reporting a series of substituted 2-aminothiazoles capable to inhibit the growth of actively replicating, nonreplicating persistent, and resistant Mycobacterium tuberculosis strains. Clues from the structure-activity relationships lining up the antitubercular activity were exploited for the rational design of improved analogues. Two compounds, namely N-phenyl-5-(2-(p-tolylamino)thiazol-4-yl)isoxazole-3-carboxamide 7a and N-(pyridin-2-yl)-5-(2-(p-tolylamino)thiazol-4-yl)isoxazole-3-carboxamide 8a, were found to show high inhibitory activity toward susceptible M. tuberculosis strains, with an MIC90 of 0.125-0.25 μg/mL (0.33-0.66 μM) and 0.06-0.125 μg/mL (0.16-0.32 μM), respectively. Moreover, they maintained good activity also toward resistant strains, and they were selective over other bacterial species and eukaryotic cells, metabolically stable, and apparently not susceptible to the action of efflux pumps.
AB - Tuberculosis remains one of the deadliest infectious diseases in the world, and the increased number of multidrug-resistant and extremely drug-resistant strains is a significant reason for concern. This makes the discovery of novel antitubercular agents a cogent priority. We have previously addressed this need by reporting a series of substituted 2-aminothiazoles capable to inhibit the growth of actively replicating, nonreplicating persistent, and resistant Mycobacterium tuberculosis strains. Clues from the structure-activity relationships lining up the antitubercular activity were exploited for the rational design of improved analogues. Two compounds, namely N-phenyl-5-(2-(p-tolylamino)thiazol-4-yl)isoxazole-3-carboxamide 7a and N-(pyridin-2-yl)-5-(2-(p-tolylamino)thiazol-4-yl)isoxazole-3-carboxamide 8a, were found to show high inhibitory activity toward susceptible M. tuberculosis strains, with an MIC90 of 0.125-0.25 μg/mL (0.33-0.66 μM) and 0.06-0.125 μg/mL (0.16-0.32 μM), respectively. Moreover, they maintained good activity also toward resistant strains, and they were selective over other bacterial species and eukaryotic cells, metabolically stable, and apparently not susceptible to the action of efflux pumps.
KW - NONREPLICATING MYCOBACTERIUM-TUBERCULOSIS
KW - MULTIDRUG-RESISTANT TUBERCULOSIS
KW - BIOLOGICAL EVALUATION
KW - RATIONAL DESIGN
KW - 2-AMINOTHIAZOLE DERIVATIVES
KW - GROWTH-INHIBITORS
KW - DRUG DEVELOPMENT
KW - AGENTS
KW - DISCOVERY
KW - THERAPY
UR - https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.7b00793?rand=btu66bk0
U2 - 10.1021/acs.jmedchem.7b00793
DO - 10.1021/acs.jmedchem.7b00793
M3 - Article
C2 - 28749666
SN - 0022-2623
VL - 60
SP - 7108
EP - 7122
JO - Journal Of Medicinal Chemistry
JF - Journal Of Medicinal Chemistry
IS - 16
ER -