Design, synthesis and evaluation of new GEQ derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth

Chollet, Aurélien; Mori, Giorgia; Menendez, Christophe; Rodriguez, Frédéric; Fabing, Isabelle; Pasca, Maria Rosalia; Madacki, Jan; Korduláková, Jana; Constant, Patricia; Quémard, Annaık̈; Bernardes-Génisson, Vânia; Lherbet, Christian; Baltas, Michel

doi:10.1016/j.ejmech.2015.06.035

Cited by 46 publications

(28 citation statements)

References 47 publications

(31 reference statements)

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“…Isoniazid was found to interfere with Nicotinamide adenine dinucleotide (NAD)-utilizing enzymes, primarily the enoyl-ACP reductase encoded by the InhA gene, leading to the arrest of mycolic acid synthesis, which is essential to M. tuberculosis [32, 33]. InhA enzyme was chosen based upon its hydrophobic properties that favorably interact with thioamide or thiourea moieties [25]. …”

Section: Resultsmentioning

confidence: 99%

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Synthesis, docking study and biological evaluation of some new thiourea derivatives bearing benzenesulfonamide moiety

Ghorab

El‐Gaby

Soliman

et al. 2017

Chemistry Central Journal

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BackgroundA series of novel N-(2, 6-dimethoxypyrimidin-4-yl)-4-(3-(aryl)thioureido) benzenesulfonamides 3a–t was synthesized by the addition of N-(2,6-dimethoxypyrimidin-4-yl)-4-isothiocyanatobenzenesulfonamide 2 to the appropriate aromatic amine. The structures of the synthesized compounds were inspired from the second line antituberculosis pro-drugs.ResultsMost of the new compounds were screened for their activity against Mycobacterium tuberculosis. The results of the antimycobacterial assay showed that compound 3i exerted the highest activity (MIC = 3.13 µg/mL), followed by compound 3s (MIC = 6.25 µg/mL).ConclusionThe structure–activity relationship (SAR) analysis revealed that the introduction of the benzo[1,3]dioxol moiety in 3i and the 4-morpholinyl-4-phenyl moiety in 3s has proven to give the most potent compounds in this study. Docking of the promising compounds inside the active site of M. tuberculosis enoyl reductase InhA was performed in order to emphasize the results. The compounds showed a similar orientation to that of GSK 625 inside the active site of 5JFO and bind to Met 98 in a way similar to that of the co-crystallized ligand.

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Section: Resultsmentioning

confidence: 99%

“…The promising compounds 3i and 3s were docked inside the active site of M. tuberculosis enoyl reductase InhA, to predict their possible mode of action. InhA enzyme was chosen as it contains a very hydrophobic site that favorably interacts with thioamide or thiourea moieties [25]. …”

Section: Introductionmentioning

confidence: 99%

Synthesis, docking study and biological evaluation of some new thiourea derivatives bearing benzenesulfonamide moiety

Ghorab

El‐Gaby

Soliman

et al. 2017

Chemistry Central Journal

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“…Esta enzima é essencial para a biossíntese de ácidos micólicos através da via bioquímica de ácido graxo sintase tipo II (FASII) e atua como uma proteína transportadora de grupos acila (ACP) utilizando NADH. 64 67 Recentemente, diversas outras classes de heterociclicos vêm sendo reportadas como potentes inibidores da enzima InhA, como por exemplo derivados tiazólicos identificados por pesquisadores da AstraZeneca. 68 …”

Section: Alvos Envolvidos Com a Biossíntese Da Parede Celularunclassified

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

2017

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POTENTIAL MOLECULAR TARGETS FOR ANTITUBERCULOSIS DRUG DISCOVERY. Tuberculosis (TB) is an infectious disease caused by mycobacteria from the Mycobacterium genus, mainly by Mycobacterium tuberculosis (MTB). The World HealthOrganization (WHO) aims to reduce the number of TB cases worldwide in the coming years. Nevertheless, the increasing number of multidrug-resistant (MDR-TB) and extensive-drug resistance (XDR-TB) strains, and the ineffectiveness of the current treatment in latent tuberculosis are challenges to be overcome. In this review, we will demonstrate the recent advances in the tuberculosis drug discovery, focusing the research of new molecular targets in the Mycobacterium tuberculosis. Among the promising targets described herein, we highlight those, which act in different pathways in the mycobacteria, such as energy metabolism, cell wall biosynthesis, DNA synthesis, iron metabolism and transport through membranes. Furthermore, bioactive compounds discovered using phenotypic assays screening and validated through genetic approaches are also presented.Keywords: medicinal chemistry; tuberculosis; Mycobacterium tuberculosis; molecular targets; new drugs. INTRODUÇÃOA tuberculose (TB) é uma doença infecciosa causada por micobactérias do complexo Mycobacterium, no entanto, a espécie responsável pelo maior número de casos de morbidade e mortalidade é o Mycobacterium tuberculosis (MTB). 1 Ocupando o ranking mundial como a principal causa de mortes causadas por doenças infecciosas, nos últimos anos a tuberculose ultrapassou, em número de casos, a infecção causada pelo vírus da imunodeficiência humana (HIV). 2,3 O último levantamento realizado em 2015 pela Organização Mundial da Saúde (OMS) apontou 9.6 milhões de novos casos no mundo e 1.5 milhões de mortes causadas pela doença. 3 Somado a esses dados, o surgimento e aumento de cepas de M. tuberculosis multirresistente aos fármacos (MDR-TB) e extensivamente resistente aos fármacos (XDR-TB) vêm alarmando as autoridades de todo o mundo. Essas formas de tuberculose apresentam baixas taxas de cura e maiores taxas de mortalidade devido às dificuldades de tratamento. 4 Além disso, já foram relatados na clínica casos de tuberculose totalmente resistente aos fármacos (TDR-TB). 5,6 Ao longo dos últimos anos, é possível constatar algumas evoluções no desenvolvimento de compostos candidatos a fármacos que possam atuar contra a TB. 7 Após um intervalo de mais de 50 anos sem novos medicamentos para o tratamento da TB, a bedaquilina foi aprovada em 2012 pela agência norte-americana U.S. Food and Drug Administration (FDA) para o tratamento de MDR-TB. Atualmente, diversos candidatos a fármacos estão em estudos clínicos, [8][9][10][11][12] 39 Atualmente, diversos métodos e estratégias são utilizados para o desenvolvimento de novos fármacos contra a TB, como por exemplo: 1) abordagens genéticas para identificação de novos alvos; 2) ensaios de triagem em larga escala utilizando a micobactéria como plataforma; 3) ferramentas de biologia estrutural e triagem virtual e; 4) modificações ...

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“…To improve the membrane permeability, Chollet et al have reported the structural modification of the aryl amide‐based new Genz10850 (GEQ) derivatives derived from fluorene moiety (Fig. ).…”

Section: Small‐molecule Inhibitorsmentioning

confidence: 99%

Recent Advances and Structural Features of Enoyl‐ACP Reductase Inhibitors of Mycobacterium tuberculosis

Inturi

Pujar

Purohit

2016

Archiv der Pharmazie

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Mycobacterium tuberculosis enoyl-ACP reductase (InhA) has been validated as a promising target for antitubercular agents. Isoniazid (INH), the most prescribed drug to treat tuberculosis (TB), inhibits a NADH-dependent InhA that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. It is a pro-drug that needs activation to form the inhibitory INH-NAD adduct by KatG coding for catalase-peroxidase. The INH resistance of M. tuberculosis is caused by mutations in KatG, which may lead to multidrug-resistant TB (MDR-TB). Hence, there is a need for new drugs that can combat MDR-TB. The rationale for the development of new drugs to combat MDR-TB strains is the design of InhA inhibitors that can bypass bioactivation by KatG. In the present review, special attention was paid to discuss the chemical nature and recent developments of direct InhA inhibitors. The InhA inhibitors reported here have significant inhibitory effects against Mtb InhA. The diphenyl ether derivatives have shown slow onset, a tight-binding mechanism, and high affinity at the InhA active site. However, some of the diphenyl ethers have significant in vitro efficacy, which fails to transform into in vivo efficacy. Among the InhA inhibitors, 4-hydroxy-2-pyridones have emerged as a new chemical class with significant InhA inhibitory activity and better pharmacokinetic parameters when compared to diphenyl ethers.

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Design, synthesis and evaluation of new GEQ derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth

Cited by 46 publications

References 47 publications

Synthesis, docking study and biological evaluation of some new thiourea derivatives bearing benzenesulfonamide moiety

Synthesis, docking study and biological evaluation of some new thiourea derivatives bearing benzenesulfonamide moiety

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

Recent Advances and Structural Features of Enoyl‐ACP Reductase Inhibitors of Mycobacterium tuberculosis

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