Synthesis, crystal structure and biological evaluation of substituted quinazolinone benzoates as novel antituberculosis agents targeting acetohydroxyacid synthase

Lu, Wei; Baig, Irshad Ahmed; Sun, Huijie; Cui, C. Q.; Guo, Rui; Jung, In-Pil; Wang, Di; Ming, Dong; Yoon, Moon‐Young; Wang, Jianguo

doi:10.1016/j.ejmech.2015.03.014

Cited by 55 publications

(23 citation statements)

References 24 publications

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“…40,53 Molecular docking experiments revealed that most of these inhibitors likely bind outside of the active site, 53 in agreement with what was previously reported for SU herbicides. 40,43,47,53 …”

Section: Ilvb/n Acetolactate (Acetohydroxyacid) Synthasesupporting

confidence: 88%

“…39 Amino acid substitutions of conserved residues located in the immediate proximity of Glu85, His84, and Gln86 also led to a decrease in AHAS activity, suggesting that these residues are involved in the stabilization of the Glu85 side chain, keeping it interacting with N1′ of the ThDP. 39 Mutagenesis studies of Arg318 led to complete inactivation of the protein, 40 while the substitution of another highly conserved residue, Pro126, demonstrates its importance for ThDP binding. 36 The FAD-binding site in AHAS is located in one monomer and seems not to be implicated in dimer stabilization 41 but is required for structural integrity.…”

Section: Ilvb/n Acetolactate (Acetohydroxyacid) Synthasementioning

confidence: 99%

“…3,40,50-55 Many of these inhibitors are active against both the enzyme and resistant strains, with minimal inhibitory concentration (MIC) values similar to those of the standard antibiotics. 40,53 Molecular docking experiments revealed that most of these inhibitors likely bind outside of the active site, 53 in agreement with what was previously reported for SU herbicides. 40,43,47,53 …”

Section: Ilvb/n Acetolactate (Acetohydroxyacid) Synthasementioning

confidence: 99%

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Bacterial Branched-Chain Amino Acid Biosynthesis: Structures, Mechanisms, and Drugability

2017

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The eight enzymes responsible for the biosynthesis of the three branched-chain amino acids (l-isoleucine, l-leucine, and l-valine) were identified decades ago using classical genetic approaches based on amino acid auxotrophy. This review will highlight the recent progress in the determination of the three-dimensional structures of these enzymes, their chemical mechanisms, and insights into their suitability as targets for the development of antibacterial agents. Given the enormous rise in bacterial drug resistance to every major class of antibacterial compound, there is a clear and present need for the identification of new antibacterial compounds with nonoverlapping targets to currently used antibacterials that target cell wall, protein, mRNA, and DNA synthesis.

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Section: Ilvb/n Acetolactate (Acetohydroxyacid) Synthasesupporting

confidence: 88%

Section: Ilvb/n Acetolactate (Acetohydroxyacid) Synthasementioning

confidence: 99%

Section: Ilvb/n Acetolactate (Acetohydroxyacid) Synthasementioning

confidence: 99%

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Bacterial Branched-Chain Amino Acid Biosynthesis: Structures, Mechanisms, and Drugability

2017

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“…In addition, in vivo pharmacokinetics studies pointed out compound ( 21 ) with C max of 4.9 μM, plasma clearance of 34.4 mL/min/kg and T 1/2 of 0.5 h [38]. A series of quinazolinone derivatives have been reported, showing potent antitubercular activity [39]. Compound ( 22 ) (Figure 8) exhibited MIC 90 of 6.6 μM against several MDR and XDR-TB clinical isolates.…”

Section: Antituberculosis Compoundsmentioning

confidence: 99%

“…Compound ( 22 ) (Figure 8) exhibited MIC 90 of 6.6 μM against several MDR and XDR-TB clinical isolates. In addition, the authors suggested that the Mtb acetohydroxy-acid synthase (AHAS) is the target of these quinazolinone derivatives [39]. AHAS is an enzyme that plays an important role in the branched-chain amino acids (BCAAs) biosynthetic pathway and its inhibition seems to be a potential target for anti-TB drugs [40].…”

Section: Antituberculosis Compoundsmentioning

confidence: 99%

Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds

2017

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Tuberculosis (TB), a disease caused mainly by the Mycobacterium tuberculosis (Mtb), is according to the World Health Organization (WHO) the infectious disease responsible for the highest number of deaths worldwide. The increased number of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, and the ineffectiveness of the current treatment against latent tuberculosis are challenges to be overcome in the coming years. The scenario of drug discovery becomes alarming when it is considered that the number of new drugs does not increase proportionally to the emergence of drug resistance. In this review, we will demonstrate the current advances in antitubercular drug discovery, focusing on the research of compounds with potent antituberculosis activity against MDR-TB strains. Herein, active compounds against MDR-TB with minimum inhibitory concentrations (MICs) less than 11 µM and low toxicity published in the last 4 years in the databases PubMed, Web of Science and Scopus will be presented and discussed.

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Quinazoline‐tethered hydrazone: A versatile scaffold toward dual anti‐TB and EGFR inhibition activities in NSCLC

Emam

Dahal

Singh

et al. 2021

Archiv der Pharmazie

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Globally, lung cancer and tuberculosis are considered to be very serious and complex diseases. Evidence suggests that chronic infection with tuberculosis (TB) can often lead to lung tumors; therefore, developing drugs that target both diseases is of great clinical significance. In our study, we designed and synthesized a suite of 14 new quinazolinones (5a-n) and performed biological investigations of these compounds in Mycobacterium tuberculosis (MTB) and cancer cell lines. In addition, we conducted a molecular modeling study to determine the mechanism of action of these compounds at the molecular level. Compounds that showed anticancer activity in the preliminary screening were further evaluated in three cancer cell lines (A549, Calu-3, and BT-474 cells) and characterized in an epidermal growth factor receptor (EGFR) binding assay. Cytotoxicity in noncancerous lung fibroblast cells was also evaluated to obtain safety data. Our theoretical and experimental studies indicated that our compounds showed a mechanism of action similar to that of erlotinib by inhibiting the EGFR tyrosine kinase. In turn, the antituberculosis activity of these compounds would be produced by the inhibition of enoyl-ACP-reductase. From our findings, we were able to identify two potential lead compounds (5i and 5l) with dual activity and elevated safety toward noncancerous lung fibroblast cells. In addition, our data identified three compounds with excellent anti-TB activities (compounds 5i, 5l, and 5n).

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Synthesis, crystal structure and biological evaluation of substituted quinazolinone benzoates as novel antituberculosis agents targeting acetohydroxyacid synthase

Cited by 55 publications

References 24 publications

Bacterial Branched-Chain Amino Acid Biosynthesis: Structures, Mechanisms, and Drugability

Bacterial Branched-Chain Amino Acid Biosynthesis: Structures, Mechanisms, and Drugability

Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds

Quinazoline‐tethered hydrazone: A versatile scaffold toward dual anti‐TB and EGFR inhibition activities in NSCLC

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