Design and structural optimization of novel 2H-benzo[h]chromene derivatives that target AcrB and reverse bacterial multidrug resistance

Wang, Yinhu; Alenazy, Rawaf; Gu, Xinjie; Polyak, Steven W.; Zhang, Panpan; Sykes, Matthew J.; Zhang, Na; Venter, Henrietta; Ma, Shutao

doi:10.1016/j.ejmech.2020.113049

Cited by 23 publications

(17 citation statements)

References 38 publications

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“…The rise of multidrug resistance (MDR) of bacteria is a worldwide health problem, as hundreds of thousands of people die every year from bacterial infections. If actions are not taken, it is estimated that in less than 30 years, MDR bacteria will cause more deaths than cancer [1,2].…”

Section: Introductionmentioning

confidence: 99%

Quinazoline Derivatives Designed as Efflux Pump Inhibitors: Molecular Modeling and Spectroscopic Studies

et al. 2021

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Multidrug resistance of bacteria is a worrying concern in the therapeutic field and an alternative method to combat it is designing new efflux pump inhibitors (EPIs). This article presents a molecular study of two quinazoline derivatives, labelled BG1189 and BG1190, proposed as EPIs. In silico approach investigates the pharmacodynamic and pharmacokinetic profile of BG1189 and BG1190 quinazolines. Molecular docking and predicted ADMET features suggest that BG1189 and BG1190 may represent attractive candidates as antimicrobial drugs. UV-Vis absorption spectroscopy was employed to study the time stability of quinazoline solutions in water or in dimethyl sulfoxide (DMSO), in constant environmental conditions, and to determine the influence of usual storage temperature, normal room lighting and laser radiation (photostability) on samples stability. The effects of irradiation on BG1189 and BG1190 molecules were also assessed through Fourier-transform infrared (FTIR) spectroscopy. FTIR spectra showed that laser radiation breaks some chemical bonds affecting the substituents and the quinazoline radical of the compounds.

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Section: Introductionmentioning

confidence: 99%

Quinazoline Derivatives Designed as Efflux Pump Inhibitors: Molecular Modeling and Spectroscopic Studies

et al. 2021

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“…Chromene and benzochromene derivatives represent an important class of oxygencontaining heterocyclic compounds. They exhibit a wide range of biological activities, such as antimicrobial [1][2][3][4], anti-influenza virus [5] anti-proliferative [6][7][8], anti-inflammatory, analgesic, and selective COX-2 inhibitory activities [9] and effects. Also, the small molecules of benzochromene derivatives apply their anticancer activities by binding to DNA, thereby damaging DNA structure, changing the replication of double helix DNA, hindering the division of cancer cells, and binding to DNA through covalent and/or noncovalent interactions [8,10].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Cytotoxic Activity, Crystal Structure, DFT Studies and Molecular Docking of 3-Amino-1-(2,5-dichlorophenyl)-8-methoxy-1H-benzo[f]chromene-2-carbonitrile

et al. 2021

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The target compound 3-amino-1-(2,5-d ichlorophenyl)-8-methoxy-1H-benzo[f]- chromene-2-carbonitrile (4) was synthesized via a reaction of 6-methoxynaphthalen-2-ol (1), 2,5-dichlorobenzaldehyde (2), and malononitrile (3) in ethanolic piperidine solution under microwave irradiation. The newly synthesized β-enaminonitrile was characterized by FT-IR, 1H NMR, 13C NMR, mass spectroscopy, elemental analysis and X-ray diffraction data. Its cytotoxic activity was evaluated against three different human cancer cell lines MDA-MB-231, A549, and MIA PaCa-2 in comparison to the positive controls etoposide and camptothecin employing the XTT cell viability assay. The analysis of the Hirshfeld surface was utilized to visualize the reliability of the crystal package. The obtained results confirmed that the tested molecule revealed promising cytotoxic activities against the three cancer cell lines. Furthermore, theoretical calculations (DFT) were carried out with the Becke3-Lee-Yang-parr (B3LYP) level using 6-311++G(d,p) basis. The optimization geometry for molecular structures was in agreement with the X-ray structure data. The HOMO-LUMO energy gap of the studied system was discussed. The intermolecular-interactions were studied through analysis of the topological-electron-density(r) using the QTAIM and NCI methods. The novel compound exhibited favorable ADMET properties and its molecular modeling analysis showed strong interaction with DNA methyltransferase 1.

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“…There have been three mechanisms of resistance against quinolones, including mutations of topoisomerases, decreased membrane permeability, and active drug efflux. − Hence, it is urgent to develop new candidates with low drug resistance trends. This study used reference drug norfloxacin as a positive control to test the drug resistance of S. A.…”

Section: Results and Discussionmentioning

confidence: 99%

New Efforts toward Aminothiazolylquinolones with Multitargeting Antibacterial Potential

Zhang

Battini

et al. 2023

J. Agric. Food Chem.

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New antibacterial 3-(aminothiazolyl)quinolones (ATQs) were designed and efficiently synthesized to counteract the growing multidrug resistance in animal husbandry. Bioactive assays manifested that N,N-dicyclohexylaminocarbonyl ATQ 10e and methyl ATQ 17a, respectively, showed better antibacterial behavior against Staphylococcus aureus ATCC 29213 and Pseudomonas aeruginosa than reference drug norfloxacin. Notably, highly active ATQ 17a with low hemolysis, negligible mammalian cytotoxicity, and good pharmacokinetic properties displayed low trends to induce resistance and synergistic combinations with norfloxacin. Preliminary mechanism exploration implied that representative ATQ 17a could inhibit the formation of biofilms and destroy bacterial membrane integrity, further binding to intracellular DNA and DNA gyrase to hinder bacterial DNA replication. ATQ 17a could also induce the production of excess reactive oxygen species and reduce bacterial metabolism to accelerate bacterial death. These results provided a promise for 3-(aminothiazolyl)quinolones as new potential multitargeting antibacterial agents to treat bacterial infection of animals.

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Design and structural optimization of novel 2H-benzo[h]chromene derivatives that target AcrB and reverse bacterial multidrug resistance

Cited by 23 publications

References 38 publications

Quinazoline Derivatives Designed as Efflux Pump Inhibitors: Molecular Modeling and Spectroscopic Studies

Quinazoline Derivatives Designed as Efflux Pump Inhibitors: Molecular Modeling and Spectroscopic Studies

Synthesis, Cytotoxic Activity, Crystal Structure, DFT Studies and Molecular Docking of 3-Amino-1-(2,5-dichlorophenyl)-8-methoxy-1H-benzo[f]chromene-2-carbonitrile

New Efforts toward Aminothiazolylquinolones with Multitargeting Antibacterial Potential

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