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Publication details

Document type
Journal articles

Document subtype
Full paper

Title
Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities

Participants in the publication
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

Summary
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.

Date of Publication
2021-12

Institution
UNIVERSIDADE DE LISBOA

Where published
Biomedicine & Pharmacotherapy

Publication Identifiers
ISSN - 0753-3322

Publisher
Elsevier BV

Volume
144

Starting page
112362

Document Identifiers
DOI - https://doi.org/10.1016/j.biopha.2021.112362
URL - http://dx.doi.org/10.1016/j.biopha.2021.112362

Rankings
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


Export

APA
Catarina Frazão de Faria, Tânia Moreira, Pedro Lopes, Henrique Costa, Jessica R. Krewall, Callie M. Barton, Susana Santos, Douglas Goodwin, Diana Machado, Miguel Viveiros, Miguel Machuqueiro, Filomena Martins, (2021). Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities. Biomedicine & Pharmacotherapy, 144, ISSN 0753-3322. eISSN . http://dx.doi.org/10.1016/j.biopha.2021.112362

IEEE
Catarina Frazão de Faria, Tânia Moreira, Pedro Lopes, Henrique Costa, Jessica R. Krewall, Callie M. Barton, Susana Santos, Douglas Goodwin, Diana Machado, Miguel Viveiros, Miguel Machuqueiro, Filomena Martins, "Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities" in Biomedicine & Pharmacotherapy, vol. 144, 2021. 10.1016/j.biopha.2021.112362

BIBTEX
@article{52589, author = {Catarina Frazão de Faria and Tânia Moreira and Pedro Lopes and Henrique Costa and Jessica R. Krewall and Callie M. Barton and Susana Santos and Douglas Goodwin and Diana Machado and Miguel Viveiros and Miguel Machuqueiro and Filomena Martins}, title = {Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities}, journal = {Biomedicine & Pharmacotherapy}, year = 2021, volume = 144 }