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Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities
Authors
Callie M. Barton
Henrique Costa
+10 more
Catarina Frazão de Faria
Douglas Goodwin
Jessica R. Krewall
Pedro Lopes
Diana Machado
Miguel Machuqueiro
Filomena Martins
Tânia Moreira
Susana Santos
Miguel Viveiros
Publication date
1 December 2021
Publisher
'Elsevier BV'
Doi
Cite
Abstract
Funding Information: We acknowledge Diogo Vila Vi?osa for valuable discussions. We acknowledge financial support from Funda??o para a Ci?ncia e a Tecnologia, Portugal through projects PTDC/MED-QUI/29036/2017, PTDC/BIA-MIC-30692/2017, UIDB/00100/2020, UIDP/00100/2020, UIDB/04046/2020, UIDP/04046/2020, and UID/Multi/04413/2020, and Grants CEECIND/02300/2017 and DL57/CEECIND/0256/2017. Contributions from JRK, CMB, and DCG supported in part by a grant from the National Science Foundation, USA (MCB 1616059). Funding Information: We acknowledge Diogo Vila Viçosa for valuable discussions. We acknowledge financial support from Fundação para a Ciência e a Tecnologia , Portugal through projects PTDC/MED-QUI/29036/2017 , PTDC/BIA-MIC-30692/2017 , UIDB/00100/2020 , UIDP/00100/2020 , UIDB/04046/2020 , UIDP/04046/2020 , and UID/Multi/04413/2020 , and Grants CEECIND/02300/2017 and DL57/CEECIND/0256/2017 . Contributions from JRK, CMB, and DCG supported in part by a grant from the National Science Foundation , USA ( MCB 1616059 ). Publisher Copyright: © 2021 The AuthorsIsoniazid (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.publishersversionpublishe
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Last time updated on 14/02/2022
Repositório da Universidade Nova de Lisboa
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Last time updated on 05/12/2021