Design, synthesis, and evaluation of new 2-(quinoline-4-yloxy)acetamide-based antituberculosis agents

Borsoi, Ana Flávia; Paz, Josiane Delgado; Abbadi, Bruno Lopes; Macchi, Fernanda Souza; Sperotto, Nathalia Denise de Moura; Pissinate, Kenia; Rambo, Raoní Scheibler; Ramos, Alessandro Silva; Machado, Diana; Viveiros, Miguel; Bizarro, Cristiano Valim; Basso, Luiz Augusto; Machado, Pablo

doi:10.1016/j.ejmech.2020.112179

Cited by 38 publications

(33 citation statements)

References 16 publications

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“…The minimum inhibitory concentration (MIC) for each tested compound was determined by the resazurin reduction microplate assay (REMA), as thoroughly described before [ 43 , 44 ]. Isoniazid (INH, control drug) and compound solutions were solubilized at 1 mg/mL in neat DMSO, followed by dilution in Middlebrook 7H9 broth, supplemented with 10% ADC (albumin, dextrose, and catalase) and 5% DMSO, to a concentration of 50 μg/mL.…”

Section: Methodsmentioning

confidence: 99%

Anti-tubercular profile of new selenium-menadione conjugates against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain and multidrug-resistant clinical isolates

Ribeiro

Marins

Leo

et al. 2021

European Journal of Medicinal Chemistry

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Tuberculosis (TB) is one of the most fatal diseases and is responsible for the infection of millions of people around the world. Most recently, scientific frontiers have been engaged to develop new drugs that can overcome drug-resistant TB. Following this direction, using a designed scaffold based on the combination of two separate pharmacophoric groups, a series of menadione-derived selenoesters was developed with good yields. All products were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv and attractive results were observed, especially for the compounds 8a , 8c and 8f (MICs 2.1, 8.0 and 8.1 μM, respectively). In addition, 8a , 8c and 8f demonstrated potent in vitro activity against multidrug-resistant clinical isolates (CDCT-16 and CDCT-27) with promising MIC values ranging from 0.8 to 3.1 μM. Importantly, compounds 8a and 8c were found to be non-toxic against the Vero cell line. The SI value of 8a (>23.8) was found to be comparable to that of isoniazid (>22.7), which suggests the possibility of carrying out advanced studies on this derivative. Therefore, these menadione-derived selenoesters obtained as hybrid compounds represent promising new anti-tubercular agents to overcome TB multidrug resistance.

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Section: Methodsmentioning

confidence: 99%

Anti-tubercular profile of new selenium-menadione conjugates against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain and multidrug-resistant clinical isolates

Ribeiro

Marins

Leo

et al. 2021

European Journal of Medicinal Chemistry

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“…Nevertheless, they also showed moderate metabolic stability, both in mouse plasma and mouse liver microsomes, attributed in part to the amide group lability [ 69 ]. In an attempt to improve the metabolic profile, recently, Borsoi et al, via molecular simplification of the attached acetamide group, provided molecules that were metabolically more stable than their counterparts, which retained submicromolar activity against MDR- Mtb strains [ 70 ].…”

Section: Classification Of Drugs Targeting Energy-metabolism In mentioning

confidence: 99%

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

et al. 2020

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Tuberculosis remains the world’s top infectious killer: it caused a total of 1.5 million deaths and 10 million people fell ill with TB in 2018. Thanks to TB diagnosis and treatment, mortality has been falling in recent years, with an estimated 58 million saved lives between 2000 and 2018. However, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains is a major concern that might reverse this progress. Therefore, the development of new drugs acting upon novel mechanisms of action is a high priority in the global health agenda. With the approval of bedaquiline, which targets mycobacterial energy production, and delamanid, which targets cell wall synthesis and energy production, the energy-metabolism in Mtb has received much attention in the last decade as a potential target to investigate and develop new antimycobacterial drugs. In this review, we describe potent anti-mycobacterial agents targeting the energy-metabolism at different steps with a special focus on structure-activity relationship (SAR) studies of the most advanced compound classes.

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“…Recently, another group conducted molecular simplification of these compounds yielding more stable and active even towards MDR-TB. The compounds thus generated were active in a macrophage model of TB infection (Borsoi et al, 2020).…”

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confidence: 99%

Terminal Respiratory Oxidases: A Targetables Vulnerability of Mycobacterial Bioenergetics?

Bajeli

Baid

Kaur

et al. 2020

Front. Cell. Infect. Microbiol.

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Recently, ATP synthase inhibitor Bedaquiline was approved for the treatment of multi-drug resistant tuberculosis emphasizing the importance of oxidative phosphorylation for the survival of mycobacteria. ATP synthesis is primarily dependent on the generation of proton motive force through the electron transport chain in mycobacteria. The mycobacterial electron transport chain utilizes two terminal oxidases for the reduction of oxygen, namely the bc1-aa3 supercomplex and the cytochrome bd oxidase. The bc1-aa3 supercomplex is an energy-efficient terminal oxidase that pumps out four vectoral protons, besides consuming four scalar protons during the transfer of electrons from menaquinone to molecular oxygen. In the past few years, several inhibitors of bc1-aa3 supercomplex have been developed, out of which, Q203 belonging to the class of imidazopyridine, has moved to clinical trials. Recently, the crystal structure of the mycobacterial cytochrome bc1-aa3 supercomplex was solved, providing details of the route of transfer of electrons from menaquinone to molecular oxygen. Besides providing insights into the molecular functioning, crystal structure is aiding in the targeted drug development. On the other hand, the second respiratory terminal oxidase of the mycobacterial respiratory chain, cytochrome bd oxidase, does not pump out the vectoral protons and is energetically less efficient. However, it can detoxify the reactive oxygen species and facilitate mycobacterial survival during a multitude of stresses. Quinolone derivatives (CK-2-63) and quinone derivative (Aurachin D) inhibit cytochrome bd oxidase. Notably, ablation of both the two terminal oxidases simultaneously through genetic methods or pharmacological inhibition leads to the rapid death of the mycobacterial cells. Thus, terminal oxidases have emerged as important drug targets. In this review, we have described the current understanding of the functioning of these two oxidases, their physiological relevance to mycobacteria, and their inhibitors. Besides these, we also describe the alternative terminal complexes that are used by mycobacteria to maintain energized membrane during hypoxia and anaerobic conditions.

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Design, synthesis, and evaluation of new 2-(quinoline-4-yloxy)acetamide-based antituberculosis agents

Cited by 38 publications

References 16 publications

Anti-tubercular profile of new selenium-menadione conjugates against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain and multidrug-resistant clinical isolates

Anti-tubercular profile of new selenium-menadione conjugates against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain and multidrug-resistant clinical isolates

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

Terminal Respiratory Oxidases: A Targetables Vulnerability of Mycobacterial Bioenergetics?

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