Using cycloalkyl and electron-donating groups to decrease
the carbonyl
electrophilicity, a novel series of 2-(quinoline-4-yloxy)acetamides
was synthesized and evaluated as in vitro inhibitors
of Mycobacterium tuberculosis (Mtb) growth. Structure–activity
relationship studies led to selective and potent antitubercular agents
with minimum inhibitory concentrations in the submicromolar range
against drug-sensitive and drug-resistant Mtb strains. An evaluation
of the activity of the lead compounds against a spontaneous qcrB mutant strain indicated that the structures targeted
the cytochrome bc
1 complex. In addition,
selected molecules inhibited Mtb growth in a macrophage model of tuberculosis
infection. Furthermore, the leading compound was chemically stable
depending on the context and showed good kinetic solubility, high
permeability, and a low rate of in vitro metabolism.
Finally, the pharmacokinetic profile of the compound was assessed
after oral administration to mice. To the best of our knowledge, for
the first time, a 2-(quinoline-4-yloxy)acetamide was obtained with
a sufficient exposure, which may enable in vivo effectiveness
and its further development as an antituberculosis drug candidate.
Tuberculosis (TB) is one of the main causes of death from a single pathological agent,
Mycobacterium tuberculosis
(
Mtb
). In addition, the emergence of drug-resistant TB strains has exacerbated even further the treatment outcome of TB patients. It is thus needed the search for new therapeutic strategies to improve the current treatment and to circumvent the resistance mechanisms of
Mtb
. The shikimate kinase (SK) is the fifth enzyme of the shikimate pathway, which is essential for the survival of
Mtb
. The shikimate pathway is absent in humans, thereby indicating SK as an attractive target for the development of anti-TB drugs. In this work, a combination of in silico and in vitro techniques was used to identify potential inhibitors for SK from
Mtb
(
Mt
SK). All compounds of our in-house database (Centro de Pesquisas em Biologia Molecular e Funcional, CPBMF) were submitted to in silico toxicity analysis to evaluate the risk of hepatotoxicity. Docking experiments were performed to identify the potential inhibitors of
Mt
SK according to the predicted binding energy. In vitro inhibitory activity of
Mt
SK-catalyzed chemical reaction at a single compound concentration was assessed. Minimum inhibitory concentration values for in vitro growth of pan-sensitive
Mtb
H37Rv strain were also determined. The mixed approach implemented in this work was able to identify five compounds that inhibit both
Mt
SK and the in vitro growth of
Mtb
.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10822-022-00495-w.
We found that cells from
Mycobacterium smegmatis
, a model organism safer and easier to study than the disease-causing mycobacterial species, when depleted of an enzyme from the shikimate pathway, are auxotrophic for the three aromatic amino acids (AroAAs) that serve as building blocks of cellular proteins:
l-
tryptophan,
l
-phenylalanine, and
l
-tyrosine. That supplementation with only AroAAs is sufficient to rescue viable cells with the shikimate pathway inactivated was unexpected, since this pathway produces an end product, chorismate, that is the starting compound of essential pathways other than the ones that produce AroAAs.
Tuberculosis remains a global health problem that affects millions of people around the world. Despite recent efforts in drug development, new alternatives are required. Herein, a series of 27 N-(4-(benzyloxy)benzyl)-4-aminoquinolines were synthesized and evaluated for their ability to inhibit the M. tuberculosis H37Rv strain. Two of these compounds exhibited minimal inhibitory concentrations (MICs) similar to the first-line drug isoniazid. In addition, these hit compounds were selective for the bacillus with no significant change in viability of Vero and HepG2 cells. Finally, chemical stability, permeability and metabolic stability were also evaluated. The obtained data show that the molecular hits can be optimized aiming at the development of drug candidates for tuberculosis treatment.
Tuberculosis has been described as a global health crisis since the 1990s, with an estimated 1.4 million deaths in the last year. Herein, a series of 20 1H-indoles were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Furthermore, the top hit compounds were active against multidrug-resistant strains, without cross-resistance with first-line drugs. Exposing HepG2 and Vero cells to the molecules for 72 h showed that one of the evaluated structures was devoid of apparent toxicity. In addition, this 3-phenyl-1H-indole showed no genotoxicity signals. Finally, time-kill and pharmacodynamic model analyses demonstrated that this compound has bactericidal activity at concentrations close to the Minimum Inhibitory Concentration, coupled with a strong time-dependent behavior. To the best of our knowledge, this study describes the activity of 3-phenyl-1H-indole against Mtb for the first time.
Determining the vulnerability of a potential target allows us to assess whether its partial inhibition will impact bacterial growth. Here, we evaluated the vulnerability of the enzyme 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAHPS) from
M. tuberculosis
by silencing the DAHPS-coding
aroG
gene in different contexts. These results could lead to the development of novel and potent anti-tubercular agents in the near future.
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