(2Z)-3-Hydroxy-3-(4-R-Phenyl)-Prop-2-Enedithioic Acids as New Antituberculosis Compounds
Por:
Pretelin-Castillo, Gustavo, Miranda, Mayra Silva, Espitia, Clara, Chavez-Santos, Rosa Maria, Suarez-Castro, Abel, Chacon-Garcia, Luis, Aguayo-Ortiz, Rodrigo, Martinez, Roberto
Publicada:
1 ene 2021
Resumen:
Background: Tuberculosis is an infectious disease caused by the bacillus
Mycobacterium tuberculosis. Compounds including a sulfur-containing
scaffold have been shown to be key scaffolds in various antituberculosis
agents. Interestingly, the 3-hydroxy-3-phenyl-prop-2-enedithioic acids
11a-j have, to the best of our knowledge, not been previously described
as antituberculosis agents. Purpose: In the present study, we
investigated the role of substituents attached to the phenyl ring of a
3-hydroxy-3-phenyl-prop-2-enedithioic acid scaffold (compounds 11a-j) in
inhibit-ing the growth of M. tuberculosis strain H37Rv. Methods:
(Z)-3-hydroxy-3-(4-R-phenyl)-prop-2-enedithioic acids 11b-j, with R
groups including various electron-donating or electron-withdrawing
groups, were designed by structurally modifying the lead compound 11a.
The syntheses of 11a-j involved each one-step procedure starting from
the corresponding substituted acetophenone. Compounds 11a-j were tested
against M. tuberculosis strain H37Rv to evaluate their bacterial growth
inhibitory activities. ADMET profiles were predicted by employing three
different methods. In addi-tion, molecular docking studies were carried
out, based on the molecular similarities of the synthesized compounds
with ethionamide (5), on the active site of the M. tuberculosis H37Rv
(3R)-hydroxyacyl-ACP (HadAB) dehydratase heterodimer. Results: The
antituberculosis activities of compounds 11a-j could be explained in
terms of the presence of electron-donating or electron-withdrawing
substituents on the aromatic ring of the substituted
3-hydroxy-3-phenyl)-prop-2-enedithioic acid core. The activity and
selec-tivity index (SI) value of
(Z)-3-hydroxy-3-(4-nitrophenyl)-prop-2-enedithioic acid 11e sug-gested
that this compound could be used for the design of novel
antituberculosis agents. Most of the synthesized molecules showed an
acceptable ADME profile and a low prob-ability of being toxic. Docking
studies of 11d and 11e showed them forming hydrogen bonds with the
ACys61 residue of the HadAB enzyme. Conclusion: Our results suggested
that the antituberculosis compound 11e could be used for the of novel
antituberculosis
Filiaciones:
Pretelin-Castillo, Gustavo:
Univ Nacl Autonoma Mexico, Inst Quim, Ciudad Univ, Cd Mexico 04510, Mexico
Miranda, Mayra Silva:
Univ Nacl Autonoma Mexico, Inst Invest Biomed, Catedrat CONACYT Adscrita, Ciudad Univ, Cd Mexico 04510, Mexico
Univ Nacl Autonoma Mexico, Inst Invest Biomed, Dept Inmunol, Ciudad Univ, Cd Mexico 04510, Mexico
Espitia, Clara:
Univ Nacl Autonoma Mexico, Inst Invest Biomed, Catedrat CONACYT Adscrita, Ciudad Univ, Cd Mexico 04510, Mexico
Univ Nacl Autonoma Mexico, Inst Invest Biomed, Dept Inmunol, Ciudad Univ, Cd Mexico 04510, Mexico
Chavez-Santos, Rosa Maria:
Univ Nacl Autonoma Mexico, Inst Quim, Ciudad Univ, Cd Mexico 04510, Mexico
Suarez-Castro, Abel:
Univ Michoacana, Inst Invest Quim Biol, Edificio B-1,Ciudad Univ, Morelia 58030, Michoacan, Mexico
Chacon-Garcia, Luis:
Univ Michoacana, Inst Invest Quim Biol, Edificio B-1,Ciudad Univ, Morelia 58030, Michoacan, Mexico
Aguayo-Ortiz, Rodrigo:
Univ Nacl Autonoma Mexico, Fac Quim, Dept Farm, Ciudad Univ, Cd Mexico 04510, Mexico
Martinez, Roberto:
Univ Nacl Autonoma Mexico, Inst Quim, Ciudad Univ, Cd Mexico 04510, Mexico
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