Tipo
Artigos em Revista
Tipo de Documento
Artigo Completo
Título
Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities
Participantes na publicação
Catarina Frazão de Faria (Author)
Tânia Moreira (Author)
Pedro Lopes (Author)
Henrique Costa (Author)
Jessica R. Krewall (Author)
Callie M. Barton (Author)
Susana Santos (Author)
Douglas Goodwin (Author)
Diana Machado (Author)
Miguel Viveiros (Author)
Miguel Machuqueiro (Author)
Dep. Química e Bioquímica
BioISI
Filomena Martins (Author)
Dep. Química e Bioquímica
CQE
Resumo
Isoniazid (INH) is one of the two most effective first-line antitubercular drugs and is still used at the present time as a scaffold for developing new compounds to fight TB. In a previous study, we have observed that an INH derivative, an hydrazide N′-substituted with a C10acyl chain, was able to counterbalance its smaller reactivity with a higher membrane permeability. This resulted in an improved performance against the most prevalent Mycobacterium tuberculosis (Mtb) resistant strain (S315T), compared to INH. In this work, we have designed two new series of INH derivatives (alkyl hydrazides and hydrazones) with promising in silico properties, namely membrane permeabilities and spontaneous IN* radical formation. The kinetics, cytotoxicity, and biological activity evaluations confirmed the in silico predictions regarding the very high reactivity of the alkyl hydrazides. The hydrazones, on the other hand, showed very similar behavior compared to INH, particularly in biological tests that take longer to complete, indicating that these compounds are being hydrolyzed back to INH. Despite their improved membrane permeabilities, the reactivities of these two series are too high, impairing their overall performance. Nevertheless, the systematic data gathered about these compounds have showed us the need to find a balance between lipophilicity and reactivity, which is paramount to devise better INH-based derivatives aimed at circumventing Mtb resistance.
Data de Publicação
2021-12
Instituição
UNIVERSIDADE DE LISBOA
Suporte
Biomedicine & Pharmacotherapy
Identificadores da Publicação
ISSN - 0753-3322
Editora
Elsevier BV
Identificadores do Documento
DOI -
https://doi.org/10.1016/j.biopha.2021.112362
URL -
http://dx.doi.org/10.1016/j.biopha.2021.112362
Identificadores de Qualidade
SCIMAGO Q1 (2021) - 1194 - Medicine (miscellaneous)
SCIMAGO Q1 (2021) - 1194 - Pharmacology
Web Of Science Q1 (2021) - 7.419 - PHARMACOLOGY & PHARMACY - SCIE
Web Of Science Q1 (2021) - 7.419 - MEDICINE, RESEARCH & EXPERIMENTAL - SCIE
SCOPUS Q1 (2020) - 9.3 - Pharmacology
Keywords
KatG Molecular dynamics Permeability Activation Synthesis MIC