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

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 c...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	KatG Molecular dynamics Permeability Activation Synthesis MIC Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/77aea5961a6b413c9ab4b7c7f8177256
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spelling	oai:doaj.org-article:77aea5961a6b413c9ab4b7c7f81772562021-11-14T04:30:20ZDesigning new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities0753-332210.1016/j.biopha.2021.112362https://doaj.org/article/77aea5961a6b413c9ab4b7c7f81772562021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S075333222101146Xhttps://doaj.org/toc/0753-3322Isoniazid (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.Catarina Frazão de FariaTânia MoreiraPedro LopesHenrique CostaJessica R. KrewallCallie M. BartonSusana SantosDouglas GoodwinDiana MachadoMiguel ViveirosMiguel MachuqueiroFilomena MartinsElsevierarticleKatGMolecular dynamicsPermeabilityActivationSynthesisMICTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 144, Iss , Pp 112362- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	KatG Molecular dynamics Permeability Activation Synthesis MIC Therapeutics. Pharmacology RM1-950
spellingShingle	KatG Molecular dynamics Permeability Activation Synthesis MIC Therapeutics. Pharmacology RM1-950 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
description	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.
format	article
author	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
author_facet	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
author_sort	Catarina Frazão de Faria
title	Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities
title_short	Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities
title_full	Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities
title_fullStr	Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities
title_full_unstemmed	Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities
title_sort	designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/77aea5961a6b413c9ab4b7c7f8177256
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Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities

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