TY - JOUR
T1 - Design, synthesis and biological evaluation of novel isoniazid derivatives with potent antitubercular activity.
AU - Martins, Filomena
AU - Santos, Susana
AU - Ventura, Cristina
AU - Elvas-Leitão, Ruben
AU - Santos, Lídia
AU - Vitorino, Susana
AU - Reis, Marina
AU - Miranda, Vanessa
AU - Correia, Henrique F.
AU - Aires-de-Sousa, João
AU - Kovalishyn, Vasyl
AU - Latino, Diogo A R S
AU - Ramos, Jorge
AU - Viveiros, Miguel
N1 - Sem PDF.
Fundacao para a Ciencia e a Tecnologia (FCT) Portugal (FCT/PTDC/QUI/67933/2006; PTDC/SAU-FCF/102807/2008; PEst OE/QUI/UI0612/2013; BPD/20743/2004; BPD/63192/2009)
FCT (REDE/1501/REM/2005)
PY - 2014/4/1
Y1 - 2014/4/1
N2 - The disturbing emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) has been driving the scientific community to urgently search for new and efficient antitubercular drugs. Despite the various drugs currently under evaluation, isoniazid is still the key and most effective component in all multi-therapeutic regimens recommended by the WHO. This paper describes the QSAR-oriented design, synthesis and in vitro antitubercular activity of several potent isoniazid derivatives (isonicotinoyl hydrazones and isonicotinoyl hydrazides) against H37Rv and two resistant Mtb strains. QSAR studies entailed RFs and ASNNs classification models, as well as MLR models. Strict validation procedures were used to guarantee the models' robustness and predictive ability. Lipophilicity was shown not to be relevant to explain the activity of these derivatives, whereas shorter N-N distances and lengthy substituents lead to more active compounds. Compounds 1, 2, 4, 5 and 6, showed measured activities against H37Rv higher than INH (i.e., MIC ≤ 0.28 $M), while compound 9 exhibited a six fold decrease in MIC against the katG (S315T) mutated strain, by comparison with INH (i.e., 6.9 vs. 43.8 $M). All compounds were ineffective against H37RvINH ($katG), a strain with a full deletion of the katG gene, thus corroborating the importance of KatG in the activation of INH-based compounds. The most potent compounds were also shown not to be cytotoxic up to a concentration 500 times higher than MIC.
AB - The disturbing emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) has been driving the scientific community to urgently search for new and efficient antitubercular drugs. Despite the various drugs currently under evaluation, isoniazid is still the key and most effective component in all multi-therapeutic regimens recommended by the WHO. This paper describes the QSAR-oriented design, synthesis and in vitro antitubercular activity of several potent isoniazid derivatives (isonicotinoyl hydrazones and isonicotinoyl hydrazides) against H37Rv and two resistant Mtb strains. QSAR studies entailed RFs and ASNNs classification models, as well as MLR models. Strict validation procedures were used to guarantee the models' robustness and predictive ability. Lipophilicity was shown not to be relevant to explain the activity of these derivatives, whereas shorter N-N distances and lengthy substituents lead to more active compounds. Compounds 1, 2, 4, 5 and 6, showed measured activities against H37Rv higher than INH (i.e., MIC ≤ 0.28 $M), while compound 9 exhibited a six fold decrease in MIC against the katG (S315T) mutated strain, by comparison with INH (i.e., 6.9 vs. 43.8 $M). All compounds were ineffective against H37RvINH ($katG), a strain with a full deletion of the katG gene, thus corroborating the importance of KatG in the activation of INH-based compounds. The most potent compounds were also shown not to be cytotoxic up to a concentration 500 times higher than MIC.
KW - antitubercular activity
KW - Isoniazid derivatives
KW - Mycobacterium tuberculosis
KW - Resistance
KW - QSARs
KW - SYNTHESIS GENES
U2 - 10.1016/j.ejmech.2014.04.077
DO - 10.1016/j.ejmech.2014.04.077
M3 - Article
C2 - 24836065
VL - 81C
SP - 119
EP - 138
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -