Biological and In silico
 Evaluation of Quinolinedione and Naphthoquinone Derivatives as Potent Antibacterial Agents

Egu, Samuel Attah; Ibezim, Akachukwu; Onoabedje, Efeturi A.; Okoro, Uchechukwu C.

doi:10.1002/slct.201700692

Cited by 11 publications

(8 citation statements)

References 20 publications

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“…Likewise, imidazoles and the 2,4,5 –trisubstituted imidazole derivatives were regarded as versatile and promising antimicrobials as well as sensitizers of MDR pathogens 55 – 57 . Quinolinedione derivatives were also reported as potent antimicrobial agents against Gram negative and positive bacteria 58 . Though compounds belonging to same chemical groups were reported with antimicrobial activity against several pathogenic bacteria including E .…”

Section: Discussionmentioning

confidence: 99%

Novel small molecules affecting cell membrane as potential therapeutics for avian pathogenic Escherichia coli

Kathayat

Helmy

Deblais

et al. 2018

Sci Rep

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Avian pathogenic Escherichia coli (APEC), a most common bacterial pathogen of poultry, causes multiple extra-intestinal diseases in poultry which results in significant economic losses to the poultry industry worldwide. In addition, APEC are a subgroup of extra-intestinal pathogenic E. coli (ExPEC), and APEC contaminated poultry products are a potential source of foodborne ExPEC infections to humans and transfer of antimicrobial resistant genes. The emergence of multi-drug resistant APEC strains and the limited efficacy of vaccines necessitate novel APEC control approaches. Here, we screened a small molecule (SM) library and identified 11 SMs bactericidal to APEC. The identified SMs were effective against multiple APEC serotypes, biofilm embedded APEC, antimicrobials resistant APECs, and other pathogenic E. coli strains. Microscopy revealed that these SMs affect the APEC cell membrane. Exposure of SMs to APEC revealed no resistance. Most SMs showed low toxicity towards chicken and human cells and reduced the intracellular APEC load. Treatment with most SMs extended the wax moth larval survival and reduced the intra-larval APEC load. Our studies could facilitate the development of antimicrobial therapeutics for the effective management of APEC infections in poultry as well as other E. coli related foodborne zoonosis, including APEC related ExPEC infections in humans.

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Section: Discussionmentioning

confidence: 99%

Novel small molecules affecting cell membrane as potential therapeutics for avian pathogenic Escherichia coli

Kathayat

Helmy

Deblais

et al. 2018

Sci Rep

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“…It also stops acetylcholine-induced vasorelaxation (Johnson and Wick, 2006). The worry intrinsic ability of micro-organism to acquire resistance or insensitivity to otherwise potent antimicrobial agents has necessitated the continued discovery of new chemotherapeutic drugs (Egu et al, 2017). Therefore, quinoline-5,8-dione an established antimicrobial lead, had undergone various transformations with a view to obtaining an improved drugs (Monika et al, 2017).…”

mentioning

confidence: 99%

Double Alkynylation of Quinoline-5,8-diones and their In-silico and Antimicrobial Studies

Ezeokonkwo¹,

Ja²,

Okafor³

et al. 2018

Journal of Applied Sciences and Environmental Management

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A double alkynylation of quinoline-5,8-dione to furnished bis-alkynylquinoline-5,8-dione in good yields and their in silico and antimicrobial studies is described. This was achieved by cross-coupling of 6,7dibromoquinoline-5,8-dione with various terminal alkynes in the presence of bis(triphenylphosphine) palladium(II) chloride as a pre-catalyst and tetrabutyl ammonium fluoride trihydrate. The structures of the synthesised compounds were confirmed by UV/Visible, Fourier Transform-Infrared and 1 H and 13 C-NMR spectral data. The synthesised compounds exhibited good activity against Escherichia Coli 1, Escherichia Coli 12, Klebsiella Pneumonia, Pseudomonas aeroginosa and Staphylococcus aureus compare to the gentamycin and ampicillin. Molecular docking simulation study of the binding interactions of compounds with receptors disclosed significant binding affinity for P. aeruginosa LpxC than the E. coli glutaredoxin.

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“…Recently, a library of aryl-and aniline-substituted QQs were tested for their ability to inhibit the growth of both the Gram positive and Gram negative bacteria, S. aureus and E. coli, respectively. 150 For both bacterial species, aniline-substituted QQs exhibited higher inhibitory activity compared to QQs functionalised with aryl substituents. Of particular relevance to this project is the anti-mycobacterial activity of quinones.…”

Section: Figure 32mentioning

confidence: 96%

“…146 Indeed, many quinone-based drugs exhibit their therapeutic activity by accepting electrons from NADH and generating harmful levels of ROS. 144,[148][149][150][151] 𝑄 + 𝑁𝐴𝐷𝐻 + 𝐻 + → 𝑄𝐻 2 + 𝑁𝐴𝐷 + (1)…”

Section: Introductionmentioning

confidence: 99%

The Synthesis and Evaluation of Heterocycles as Anti-Tuberculosis Agents

Santoso¹

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Tuberculosis (TB) is the leading cause of death from a single infectious agent, Mycobacterium tuberculosis (Mtb), worldwide. Currently, the efficacy of TB treatment regimens has declined due to the rise in antibacterial resistance and the shortage of new TB drugs. Thus, much effort has been spent in anti-tuberculosis drug development and in identifying new therapeutic targets against Mtb. One such target is NADH dehydrogenase-II (NDH-II), an essential enzyme in the mycobacterial electron transport chain that is not present in mammalian cells. In this thesis, four classes of heterocyclic compounds that have the potential to target NDH-II and their evaluation as anti-tubercular agents, are described. An overview of TB drug development and NDH-II as a promising target for TB drugs are described in Chapter 1. In Chapters 2 and 3, the potential of anti-tubercular drugs based on the quinolinequinone (QQ) scaffold is described. QQs have previously shown promise as TB drugs by activating NDH-II to overproduce harmful reactive oxygen species leading to bacterial cell death. Chapter 2 describes the total synthesis of the QQ natural products ascidiathiazone A and ascidiathiazone B, and derivatives thereof, using a synthetic route that allows for high divergency and the efficient synthesis of the natural products and their intermediates. To this end, the first total synthesis of ascidiathiazone B is reported, as is the identification of ascidiathiazone A as a promising anti-tuberculosis drug with an MIC of 1.6 μM against Mtb. Insight into the ability of a representative quinone, 7-chloro-6-chloroethylamino-2-methyl-QQ, to increase NDH-II activity is also described. In Chapter 3, the syntheses of thirty-two simplified QQs with different functional groups at the 6- and 7-positions of the QQ scaffold are described. These compounds were screened against Mtb, with the lead compound from this library, 7-chloro-6-propargylamino-QQ, exhibiting an MIC of 8 μM against Mtb. Structure-activity data revealed diminished biological activity for QQs bearing tertiary amines, as compared to those with secondary amines, suggesting that the presence of a hydrogen bond donor at the 6- and 7-positions of QQs may play a critical role in antimycobacterial activity. In Chapter 4, the synthesis and anti-mycobacterial activity of chromonyl-pyrimidines is presented. Chromonyl-pyrimidines have a structural resemblance to quinolinyl pyrimidines, a class of known NDH-II inhibitors and anti-TB agents. Chromones have shown promise as TB drugs, though they have not yet been reported to bind NDH-II. Despite this, chromonyl-pyrimidines contain a ketone functionality that may be able to bind the quinone binding site. For the first eleven-member library of chromonyl pyrimidines synthesised, all but two of the compounds exhibited inhibitory activity against Mtb, however, the growth inhibition was modest (MIC = 36-684 M). Accordingly, a second generation of chromonyl pyrimidines was synthesised, which included six compounds with improved potency against Mtb – all with an MIC value of 12.5 μM. The activity of these chromonyl pyrimidines was attributed to the presence of aromatic rings both on the pyrimidine and the chromone scaffolds, though changes to the electronic properties of the aryl groups, i.e. the incorporations of electron-withdrawing and electron-donating groups, did not affect inhibitory activity. Finally, in Chapter 5, a library of phthalazinones and pyrimidinyl-phthalazinones with anti-tubercular activity is described. While phthalazinones have not yet been extensively explored as anti-mycobacterial agents, the phthalazinone scaffold has the potential to act as an uncoupler. Uncouplers are typically weak acids or bases that act on the electron transport chain by dissipating the proton motive force and ultimately preventing the generation of ATP. In Mtb, this uncoupling process is detrimental and leads to cell death. Phthalazinones are weakly basic and, due to their bicyclic ketone-bearing motif, has the potential to bind NDH-II at the proposed Q-site. Accordingly, a series of phthalazinones was synthesised to investigate their anti-tubercular activity and uncoupling activity. From the library of phthalazinones, N-tert-butyl- and nitro-substituted phthalazinones elicited high inhibitory activity, both with an MIC value of 3 μM. Of particular note among the pyrimidinyl-phthalazinones was the 4-fluorophenyl-pyrimidinyl-N-heptyl phthalazinone, which showed high potency against Mtb with an MIC of 1.6 μM. Further biological studies showed that some phthalazinones increased the rate of NADH oxidation in mycobacteria, which could be a result of uncoupling activity, while a number of pyrimidinyl-phthalazinones decreased NADH oxidation rates. These mechanistic results indicated that the two classes of compounds may have different modes of inhibition.

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Biological and In silico Evaluation of Quinolinedione and Naphthoquinone Derivatives as Potent Antibacterial Agents

Cited by 11 publications

References 20 publications

Novel small molecules affecting cell membrane as potential therapeutics for avian pathogenic Escherichia coli

Novel small molecules affecting cell membrane as potential therapeutics for avian pathogenic Escherichia coli

Double Alkynylation of Quinoline-5,8-diones and their <i>In-silico</i> and Antimicrobial Studies

The Synthesis and Evaluation of Heterocycles as Anti-Tuberculosis Agents

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