TY - JOUR
T1 - Anti-mycobacterium tuberculosis activity of esters of quinoxaline 1,4-Di-N-oxide
AU - Palos, Isidro
AU - Luna-Herrera, Julieta
AU - Lara-Ramírez, Edgar E.
AU - Loera-Piedra, Alejandra
AU - Fernández-Ramírez, Emanuel
AU - Guadalupe Aguilera-Arreola, Ma
AU - Paz-González, Alma D.
AU - Monge, Antonio
AU - Wan, Baojie
AU - Franzblau, Scott
AU - Rivera, Gildardo
N1 - Publisher Copyright:
© 2018 by the authors.
PY - 2018
Y1 - 2018
N2 - Tuberculosis continues to be a public health problem in the world, and drug resistance has been a major obstacle in its treatment. Quinoxaline 1,4-di-N-oxide has been proposed as a scaffold to design new drugs to combat this disease. To examine the efficacy of this compound, this study evaluates methyl, ethyl, isopropyl, and n-propyl esters of quinoxaline 1,4-di-N-oxide derivatives in vitro against Mycobacterium tuberculosis (pansusceptible and monoresistant strains). Additionally, the inhibitory effect of esters of quinoxaline 1,4-di-N-oxide on M. tuberculosis gyrase supercoiling was examined, and a stability analysis by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was also carried out. Results showed that eight compounds (T-007, T-018, T-011, T-069, T-070, T-072, T-085 and T-088) had an activity similar to that of the reference drug isoniazid (minimum inhibitory concentration (MIC) = 0.12 µg/mL) with an effect on nonreplicative cells and drug monoresistant strains. Structural activity relationship analysis showed that the steric effect of an ester group at 7-position is key to enhancing its biological effects. Additionally, T-069 showed a high stability after 24 h in human plasma at 37 ◦C.
AB - Tuberculosis continues to be a public health problem in the world, and drug resistance has been a major obstacle in its treatment. Quinoxaline 1,4-di-N-oxide has been proposed as a scaffold to design new drugs to combat this disease. To examine the efficacy of this compound, this study evaluates methyl, ethyl, isopropyl, and n-propyl esters of quinoxaline 1,4-di-N-oxide derivatives in vitro against Mycobacterium tuberculosis (pansusceptible and monoresistant strains). Additionally, the inhibitory effect of esters of quinoxaline 1,4-di-N-oxide on M. tuberculosis gyrase supercoiling was examined, and a stability analysis by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was also carried out. Results showed that eight compounds (T-007, T-018, T-011, T-069, T-070, T-072, T-085 and T-088) had an activity similar to that of the reference drug isoniazid (minimum inhibitory concentration (MIC) = 0.12 µg/mL) with an effect on nonreplicative cells and drug monoresistant strains. Structural activity relationship analysis showed that the steric effect of an ester group at 7-position is key to enhancing its biological effects. Additionally, T-069 showed a high stability after 24 h in human plasma at 37 ◦C.
KW - 4-di-N-oxide
KW - DNA gyrase
KW - Drug resistance
KW - Esters
KW - Mycobacterium tuberculosis
KW - Quinoxaline 1
UR - http://www.scopus.com/inward/record.url?scp=85048956196&partnerID=8YFLogxK
U2 - 10.3390/molecules23061453
DO - 10.3390/molecules23061453
M3 - Artículo
C2 - 29914062
AN - SCOPUS:85048956196
SN - 1420-3049
VL - 23
JO - Molecules
JF - Molecules
IS - 6
M1 - 1453
ER -