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    1. Researchers synthesized a series of novel 4-aminoquinoline compounds to optimize and study their ability to inhibit Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (MtInhA), an enzyme involved in TB pathogenesis. 2. Structure-activity relationship studies identified submicromolar MtInhA inhibitors and potent antitubercular agents. The lead compound was 87-fold more potent as an enzymatic inhibitor and 32-fold more potent against M. tuberculosis compared to the initial hit compound. 3. The novel compounds were also active against multidrug-resistant TB strains, showed no toxicity in mammalian cells, and had favorable absorption properties. They were effective in intracellular TB

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    1 s2.0 S0223523422008108 Main 1

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    1. Researchers synthesized a series of novel 4-aminoquinoline compounds to optimize and study their ability to inhibit Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (MtInhA), an enzyme involved in TB pathogenesis. 2. Structure-activity relationship studies identified submicromolar MtInhA inhibitors and potent antitubercular agents. The lead compound was 87-fold more potent as an enzymatic inhibitor and 32-fold more potent against M. tuberculosis compared to the initial hit compound. 3. The novel compounds were also active against multidrug-resistant TB strains, showed no toxicity in mammalian cells, and had favorable absorption properties. They were effective in intracellular TB

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    1. Researchers synthesized a series of novel 4-aminoquinoline compounds to optimize and study their ability to inhibit Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (MtInhA), an enzyme involved in TB pathogenesis. 2. Structure-activity relationship studies identified submicromolar MtInhA inhibitors and potent antitubercular agents. The lead compound was 87-fold more potent as an enzymatic inhibitor and 32-fold more potent against M. tuberculosis compared to the initial hit compound. 3. The novel compounds were also active against multidrug-resistant TB strains, showed no toxicity in mammalian cells, and had favorable absorption properties. They were effective in intracellular TB

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    1 s2.0 S0223523422008108 Main 1

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    marileyser
    1. Researchers synthesized a series of novel 4-aminoquinoline compounds to optimize and study their ability to inhibit Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (MtInhA), an enzyme involved in TB pathogenesis. 2. Structure-activity relationship studies identified submicromolar MtInhA inhibitors and potent antitubercular agents. The lead compound was 87-fold more potent as an enzymatic inhibitor and 32-fold more potent against M. tuberculosis compared to the initial hit compound. 3. The novel compounds were also active against multidrug-resistant TB strains, showed no toxicity in mammalian cells, and had favorable absorption properties. They were effective in intracellular TB

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    European Journal of Medicinal Chemistry 245 (2023) 114908

    Contents lists available at ScienceDirect

    European Journal of Medicinal Chemistry


    journal homepage: www.elsevier.com/locate/ejmech

    Research paper

    Novel 4-aminoquinolines: Synthesis, inhibition of the Mycobacterium


    tuberculosis enoyl-acyl carrier protein reductase, antitubercular activity,
    SAR, and preclinical evaluation
    Josiane Delgado Paz a, b, Nathalia Denise de Moura Sperotto a, Alessandro Silva Ramos a,
    Kenia Pissinate a, Valnês da Silva Rodrigues Junior a, Bruno Lopes Abbadi a, Ana Flávia Borsoi a, c,
    Raoní Scheibler Rambo a, Ana Carolina Corso Minotto a, Adilio da Silva Dadda a, Luiza Galina a, b,
    Fernanda Souza Macchi Hopf a, b, Mauro Neves Muniz a, Leonardo Kras Borges Martinelli a,
    Candida Deves Roth a, Rodrigo Braccini Madeira Silva a, Marcia Alberton Perelló a,
    Alexia de Matos Czeczot a, b, Christiano Ev Neves a, b, Lovaine Silva Duarte a, Mariana Leyser d,
    Sílvia Dias de Oliveira b, d, Cristiano Valim Bizarro a, b, Pablo Machado a, b, c, **,
    Luiz Augusto Basso a, b, c, *
    a
    Instituto Nacional de Ciência e Tecnologia em Tuberculose, Centro de Pesquisas em Biologia Molecular e Funcional, Pontifícia Universidade Católica do Rio Grande do
    Sul, 90616-900, Porto Alegre, Rio Grande do Sul, Brazil
    b
    Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, 90616-900, Porto Alegre, Rio Grande do Sul,
    Brazil
    c
    Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, 90616-900, Porto Alegre, Rio Grande do Sul,
    Brazil
    d
    Laboratório de Imunologia e Microbiologia, Pontifícia Universidade Católica do Rio Grande do Sul, 90616-900, Porto Alegre, Rio Grande do Sul, Brazil

    A R T I C L E I N F O A B S T R A C T

    Keywords: Herein a series of 4-aminoquinolines were synthesized in an attempt to optimize and study the structural features
    Tuberculosis related to LABIO-17 biological activity, a Mycobacterium tuberculosis NADH-dependent enoyl-acyl carrier protein
    Multidrug-resistant strains reductase (MtInhA) inhibitor previously identified by a virtual-ligand-screening approach. Structure-activity
    InhA
    relationships led to novel submicromolar inhibitors of MtInhA and potent antitubercular agents. The lead
    Hit optimization
    In vivo activity
    compound is 87-fold more potent as enzymatic inhibitors and 32-fold more potent against M. tuberculosis H37Rv
    Antitubercular drug candidate strain in comparison with LABIO-17. These molecules were also active against multidrug-resistant strains, devoid
    of apparent toxicity to mammalian cells and showed favorable in vitro ADME profiles. Additionally, these
    compounds were active in an intracellular model of tuberculosis (TB) infection, showed no genotoxicity signals,
    satisfactory absorption parameters and absence of in vivo acute toxicity. Finally, treatment with selected 4-amino­
    quinoline for two weeks produced bacteriostatic effect in a murine model of TB. Taken together, these findings
    indicate that this chemical class may furnish candidates for the future development of drug-sensitive and drug-
    resistant tuberculosis treatments.

    1. Introduction disease has been impacted by COVID-19 pandemic raising to levels seen
    in 2017 and reversing years of progress and achievements in reducing
    Tuberculosis (TB) is a human infectious disease caused mainly by TB disease burden [1]. The number of people newly diagnosed with TB
    Mycobacterium tuberculosis (Mtb). The number of deaths from this declined from 7.1 millions in 2019 to 5.8 millions in 2020 falling short

    * Corresponding author. Av. Ipiranga 6681, TECNOPUC, Prédio 92A, 90619-900, Porto Alegre, RS, Brazil.
    ** Corresponding author. Instituto Nacional de Ciência e Tecnologia em Tuberculose, Centro de Pesquisas em Biologia Molecular e Funcional, Pontifícia Uni­
    versidade Católica do Rio Grande do Sul, 90616-900, Porto Alegre, Rio Grande do Sul, Brazil.
    E-mail addresses: pablo.machado@pucrs.br (P. Machado), luiz.basso@pucrs.br (L.A. Basso).

    https://doi.org/10.1016/j.ejmech.2022.114908
    Received 23 August 2022; Received in revised form 25 October 2022; Accepted 3 November 2022
    Available online 18 November 2022
    0223-5234/© 2022 Elsevier Masson SAS. All rights reserved.

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