Novel 4-aminoquinolines: Synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase, antitubercular activity, SAR, and preclinical evaluation

Paz, Josiane Delgado; Sperotto, Nathalia Denise de Moura; Ramos, Alessandro Silva; Pissinate, Kenia; Rodrigues-Junior, Valnês S.; Abbadi, Bruno Lopes; Borsoi, Ana Flávia; Rambo, Raoní Scheibler; Minotto, Ana Carolina Corso; Dadda, Adílio da Silva; Galina, Luiza; Hopf, Fernanda Souza Macchi; Muniz, Mauro Neves; Martinelli, Leonardo K.; Roth, Candida Deves; Silva, Rodrigo Braccini Madeira; Perelló, Marcia Alberton; Czeczot, Alexia de Matos; Neves, Christiano Ev; Duarte, Lovaine Silva; Leyser, Mariana; Oliveira, Sı́lvia Dias de; Bizarro, Cristiano Valim; Machado, Pablo; Basso, Luiz Augusto

doi:10.1016/j.ejmech.2022.114908

Cited by 13 publications

(3 citation statements)

References 41 publications

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“…In Vivo Model of TB Infection. The evaluation of pharmacological activity of 5-Fluoro-1H-indole hydrochloride was performed in accordance with a previously reported methodology, 34 with some modifications. One isolated colony of the laboratorial H37Rv strain was cultured in 5 mL of 7H9 medium supplemented with ADC, 0.05% (v/v) Tween-80, and 0.02% (v/v) of glycerol until reaching the mid log phase.…”

Section: -Fi Salt Preparationmentioning

confidence: 99%

5-Fluoroindole Reduces the Bacterial Burden in a Murine Model of Mycobacterium tuberculosis Infection

Neves,

Paz,

Abbadi

et al. 2024

ACS Omega

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Tuberculosis is a disease caused by a single pathogen that leads to a death toll estimated to be more than a million per year. Mycobacterium tuberculosis (Mtb), which affects mainly the lungs, spreads by airborne transmission when infectious respiratory particles from an infected human enter the respiratory tract of another person. Despite diagnosis and treatment being well established, the rise of cases of patients infected with Mtb strains with multidrug resistance to the antibiotics used in the regimen against the disease is alarming. Indole used as a core molecule has been described as a promising structure to treat several diseases. 5-Fluoroindole (5-FI) compound, evaluated in the free base and in the hydrochloride (5-FI.HCl) forms, inhibited the growth of pansensitive Mtb H37Rv strain in the same range (4.7−29.1 μM) of clinical isolates that have resistance to at least two first-line drugs. Although 5-FI showed no cytotoxicity in Vero and HepG2 cells, high permeability (2.4.10 −6 cm/s) in the PAMPA assay, and high metabolic stability (Cl int 9.0 mL/min/kg) in rat liver microsomes, limited solubility at plasmatic and intestinal pH values prompted formation and employment of its salt form (5-FI.HCl). Although the 5-FI.HCl compound showed increased solubility at pH values of 7.4 and 9.1 and increased stability in aqueous solutions, data for intrinsic clearance (Cl int = 48 mL/min/kg) and a half-life (t 1/2 = 12 min) showed decreased metabolic stability. As 5-FI.HCl showed both good absorption and ability to reach the systemic circulation of animals without the need to use vehicles containing cosolvents or surfactants, it was chosen to evaluate its effectiveness in the model of tuberculosis in mice. The in vivo results showed the concentration of the compound in plasma increasing within 30 min in the systemic circulation and the capacity of reducing the Mtb burden in the lungs at the concentration of 200 μmol/kg after 21 days of infection, with no toxicity in mice.

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Section: -Fi Salt Preparationmentioning

confidence: 99%

5-Fluoroindole Reduces the Bacterial Burden in a Murine Model of Mycobacterium tuberculosis Infection

Neves,

Paz,

Abbadi

et al. 2024

ACS Omega

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“…While LBVS holds great promise, challenges remain in accurately predicting compound activity and optimizing lead compounds. Additionally, the integration of experimental validation remains crucial to confirm the efficacy of computationally identified candidates [13]. Future directions in LBVS for malaria drug discovery include the refinement of algorithms, the incorporation of structural biology data, and the pursuit of multi-targeted drug development strategies.…”

Section: Literature Reviewmentioning

confidence: 99%

Ligand Based Virtual Screening Testing and Analysis for Plasmodium Falciparum

Sanjeev Sharma

2023

IJSREM

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Malaria, caused by the parasite Plasmodium falciparum, continues to pose a significant global health challenge, with drug resistance and limited treatment options exacerbating the problem. Ligand-Based Virtual Screening (LBVS) has emerged as a promising computational tool for identifying potential drug candidates. This research focuses on the application of LBVS to target essential proteins within Plasmodium falciparum and identify small molecules with inhibitory potential. A diverse dataset of ligands and advanced computational algorithms were employed to predict binding affinities and screen compounds for potential antimalarial activity. LBVS is a computational method used to identify potential drug candidates by screening large databases of molecules for those that have a high similarity to known active molecules. This is done by calculating the shape and chemical properties of the molecules and comparing them to the known active molecules. Malaria is a mosquito-borne disease caused by the parasite Plasmodium falciparum. It isa major public health problem, especially in tropical and subtropical regions. LBVS can be used to accelerate the drug discovery process by identifying potential drug candidatesmore quickly and efficiently. Keywords: LBVS, Plasmodium Falciparum, DHFR, Anti-malarial compound, Protein target.

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“…The in silico pharmacokinetics and hepatotoxicity experiments predicted that the derivatives of isonicotinic acid were with better oral bioavailability and lesser hepatoxicity than isoniazid [27]. A novel ligand screening approach identified 4-aminoquinolines as a potential inhibitor (87 fold) of NADH-dependent enoyl-acyl carrier protein reductase (MtInhA) and an effective growth inhibitor against H37Rv (32 fold inhibition) with no genotoxicity and acute systemic toxicity in a murine model of TB [28].…”

Section: Alpha Mycolic Acid Inhibitorsmentioning

confidence: 99%

Protein targets in Mycobacterium tuberculosis and their inhibitors for therapeutic implications: A narrative review

Souparnika

Nagarajan

Natarajan

2023

International Journal of Biological Macromolecules

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Novel 4-aminoquinolines: Synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase, antitubercular activity, SAR, and preclinical evaluation

Cited by 13 publications

References 41 publications

5-Fluoroindole Reduces the Bacterial Burden in a Murine Model of Mycobacterium tuberculosis Infection

5-Fluoroindole Reduces the Bacterial Burden in a Murine Model of Mycobacterium tuberculosis Infection

Ligand Based Virtual Screening Testing and Analysis for Plasmodium Falciparum

Protein targets in Mycobacterium tuberculosis and their inhibitors for therapeutic implications: A narrative review

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