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a) Common approaches for 8-hydroxyquinoline synthesis. b) Microwave-enhanced Friedländer reaction from readily available starting materials. c) Illustration of both free-floating planktonic cells and surface-attached bacterial biofilms.
Source publication
Herein, we disclose the development of a catalyst- and protecting-group-free microwave-enhanced Friedländer synthesis which permits the single-step, convergent assembly of diverse 8-hydroxyquinolines with greatly improved reaction yields over traditional oil bath heating (increased from 34% to 72%). This rapid synthesis permitted the discovery of n...
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Highly transparent ultrathin films (UTFs) were fabricated via layer-by-layer assembly of 110-Phenanthroline monohydrate (Phen)–8-hydroxyquinoline (Hq)–Al³⁺(Phen–Hq–Al), polyvinyl alchol(PVA) and Mg–Al-layered double hydroxide (LDH)nanosheets. UV–visible absorption and fluorescence spectroscopy showed regular growth of UTFs increasing the numbers of...
Citations
... It corresponded to the formula of C 11 H 9 NO 2 , and was presumed to be 2-Acetyl-quinoline-8-ol, as seen in Supplementary Materials Figure S4. This heterocyclic structure is an important bioactive molecule [58]. In particular, 8-hydroxyquinolines have been widely used in therapeutics, demonstrating an array of medicinal applications (e.g., antibacterial, anti-cancer, anti-neurodegenerative, antiviral) [21]. ...
... It corresponded to the formula of C11H9NO2, and was presumed to be 2-Acetyl-quinoline-8-ol, as seen in Supplementary Materials Figure S4. This heterocyclic structure is an important bioactive molecule [58]. In particular, 8-hydroxyquinolines have been widely used in therapeutics, demonstrating an array of medicinal applications (e.g., antibacterial, anti-cancer, anti-neurodegenerative, antiviral) [21]. ...
A method was developed to identify and trace the geographic sources of Erigeron breviscapus using high-resolution mass spectrometry and chemometrics. The representative samples were collected from the geographic area of Honghe Dengzhanhua and other areas in Yunnan province and Guizhou province. The data points could be determined well using the PCA and PLS-DA diagram. A total of 46 characteristic compounds were identified from Honghe Dengzhanhua and within Guizhou province, but 37 compounds were different from Honghe Dengzhanhua and other counties in Yunnan province. Two biomarkers were found from three regions. Their structures were inferred as 8-amino-7-oxononanoic acid and 8-hydroxyquinoline, and they had the same molecular composition. This may suggest that a possible synthesis pathway can be proven in the future.
... As shown in Figure 16, derivatives containing a phenyl or pyrimidinyl ring linked directly to position 2 (16a−b) have shown antibacterial activity ranging from good to weak (MIC values of 0.39 to >100 μM). 92 Nevertheless, the introduction of a spacer between position 2 and the aryl group (16c−h) has increased the antibacterial activity, and also led to an antibiofilm effect in general. Compound 16g has shown antibiofilm activity against all studied strains, with MBEC values of 93.8, 5.9, and 1.0 μM against MRSA, MRSE, and VRE, respectively, in addition to presenting low hemolytic effect against human red blood cells at 200 μM. ...
... Despite this, some works have synthesized derivatives with substituents at position 3, introduced during the condensation of the 8HQ core. 86,91,92 Compounds containing an ester or ketones at position 3 (21a−c, Figure 24) were evaluated against yeasts. In general, these compounds were not active against C. albicans, and they have presented selectivity against C. neoformans, with MIC values in the low micromolar range. ...
... The substitution of position 3 by a carboxylic acid (21f) or amides (21g−i) reduced the antibacterial activity. 91,92 In general, alkyl chains (22a−b) or a benzyl group (22c) at position 3 have maintained the antibacterial effect against MRSE (MIC range: 0.59−3.13 μM), being less favorable for the activity against MRSA (MIC range: 3.13−50 μM) and VRE (MIC range: 4.69−18.8 ...
... One major group of biofilm inhibitors, inspired by scaffolds found in natural products with reported activity, are a diverse range of heterocyclic containing families, which include indoles [64][65][66][67][68][69][70][71], 2-aminoimidazoles [72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89], phenazines [90][91][92][93][94][95][96][97][98], and quinolines [99][100][101][102][103][104][105][106]. These lead molecules are the results of significant medicinal chemistry effort to improve potency and other drug-like properties. ...
Biofilms, the predominant growth mode of microorganisms, pose a significant risk to human health. The protective biofilm matrix, typically composed of exopolysaccharides, proteins, nucleic acids, and lipids, combined with biofilm-grown bacteria’s heterogenous physiology, leads to enhanced fitness and tolerance to traditional methods for treatment. There is a need to identify biofilm inhibitors using diverse approaches and targeting different stages of biofilm formation. This review discusses discovery strategies that successfully identified a wide range of inhibitors and the processes used to characterize their inhibition mechanism and further improvement. Additionally, we examine the structure–activity relationship (SAR) for some of these inhibitors to optimize inhibitor activity.
... type strains (Fig. 1). The library of halogenated phenazine and quinoline compounds and the NH125 analogue were created by using a previously efficacious compound as a base structure and modifying different chemical groups at targeted sites to produce a library of more potent phenazine, quinoline, and NH125 analogues [30][31][32]. Nitroxoline, a compound approved for treating urinary tract infections outside of the U.S., was added to the testing as it has a similar structure to the compounds in the library. Triclosan was included as an agent known to be effective Resistance breakpoints for enrofloxacin (≥ 2 μg/mL), erythromycin (≥ 1 μg/mL), tilmicosin (≥ 32 μg/mL), tylosin (≥ 4 μg/mL) and clindamycin (≥ 0.5 μg/mL) used from Tatay-Dualde [7]. ...
... For M. pulmonis, compounds 10, 11, 12 and 14 also had efficacious MICs compared to sister quinolines 15 and 20. In previous studies evaluating halogenated quinoline libraries against MRSA and MRSE, compounds 15 and 20 demonstrated 1.5 and 4-fold higher MICs to MRSA, and compound 20 had a 6-fold higher MIC to MRSE compared to compound 14 [30,31]. Thus, it appears this might be reflective of potency seen against other gram-positive organisms, albeit compound 20 had more frequent, efficacious MICs overall against the veterinary mycoplasmas. ...
... In terms of preliminary safety testing, in-vitro work showed that compounds 14 and 20 produced scant hemolysis at doses of 200 μM (≤ 1%), but compound 15 caused hemolysis in 18.8% of red blood cells at 200 μM [30,31]. Thus far, the majority of halogenated phenazine compounds have showed no cytotoxicity against HeLa cells at concentrations of 100 μM [41]. ...
Background:
Mycoplasmas primarily cause respiratory or urogenital tract infections impacting avian, bovine, canine, caprine, murine, and reptilian hosts. In animal husbandry, mycoplasmas cause reduced feed-conversion, decreased egg production, arthritis, hypogalactia or agalactia, increased condemnations, culling, and mortality in some cases. Antibiotics reduce transmission and mitigate clinical signs; however, concerning levels of antibiotic resistance in Mycoplasma gallisepticum and M. capricolum isolates exist. To address these issues, we evaluated the minimum inhibitory concentrations (MICs) of halogenated phenazine and quinoline compounds, an N-arylated NH125 analogue, and triclosan against six representative veterinary mycoplasmas via microbroth or agar dilution methods. Thereafter, we evaluated the minimum bactericidal concentration (MBC) of efficacious drugs.
Results:
We identified several compounds with MICs ≤25 μM against M. pulmonis (n = 5), M. capricolum (n = 4), M. gallisepticum (n = 3), M. alligatoris (n = 3), M. agassizii (n = 2), and M. canis (n = 1). An N-arylated NH125 analogue, compound 21, served as the most efficacious, having a MIC ≤25 μM against all mycoplasmas tested, followed by two quinolines, nitroxoline (compound 12) and compound 20, which were effective against four and three mycoplasma type strains, respectively. Nitroxoline exhibited bactericidal activity among all susceptible mycoplasmas, and compound 21 exhibited bactericidal activity when the MBC was able to be determined.
Conclusions:
These findings highlight a number of promising agents from novel drug classes with potential applications to treat veterinary mycoplasma infections and present the opportunity to evaluate preliminary pharmacokinetic indices using M. pulmonis in rodents as an animal model of human infection.
... They have other potential applications in materials science and supramolecular chemistry (Normah et al, 2011;Tlahuext et al, 2011). Complexes of different metals with 8-hydroxyquinoline (HQ) or its derivatives have involved significant care having biological activities and capable use in organic light-emitting diodes (OLEDs), optical detecting, and so on (Song et al, 2015;Garrison et al, 2017). Specific attention has been located in supramolecular coordination compounds based on 8-hydroxyquinoline derivatives (Balasubramani et al, 2010;. ...
... 8-hydroxyquinoline (HQ) is a well-studied, privileged structure, with activity against a wide range of cell types (Prachayasittikul, Prachayasittikul, Ruchirawat, & Prachayasittikul, 2013;Song, Xu, Chen, Zhan, & Liu, 2015), including anticancer activity (Barilli et al., 2014;Bhat, Shim, Zhang, Chong, & Liu, 2012;Chang, Chen, Wang, Tzeng, & Chen, 2010;Feng et al., 2015;Li et al., 2016;Moret et al., 2009;Mrozek-Wilczkiewicz et al., 2015;Sosi c et al., 2013;Spaczy nska, Tabak, Malarz, & Musiol, 2014), antifungal activity (Cieslik et al., 2012;Musiol et al., 2006), and antibacterial activity (Warner, Musto, Turesky, & Soloway, 1975). The HQ are active against several bacterial species including Staphylococcus aureus and Staphylococcus epidermidis (Abouelhassan et al., 2014(Abouelhassan et al., , 2015Basak et al., 2016;Garrison et al., 2017;Lam et al., 2014), Enterococcus faecium (Basak et al., 2016;Garrison et al., 2017), Burkholderia pseudomallei (Wangtrakuldee et al., 2013), Neisseria gonorrhoeae, (Lawung et al., 2018), Listeria monocytogenes (Cherdtrakulkiat et al., 2016), and Mycobacterium avium (Hongmanee, Rukseree, Buabut, Somsri, & Palittapongarnpim, 2007;Kos et al., 2015). In addition, activity of the HQ compounds against replicating and nonreplicating Mycobacterium tuberculosis has been demonstrated in medium containing copper and in infected guinea pigs (Ananthan et al., 2009;Darby & Nathan, 2010;Hongmanee et al., 2007;Shah et al., 2016;Tison, 1952;Urbanski, Slopek, & Venulet, 1951). ...
... 8-hydroxyquinoline (HQ) is a well-studied, privileged structure, with activity against a wide range of cell types (Prachayasittikul, Prachayasittikul, Ruchirawat, & Prachayasittikul, 2013;Song, Xu, Chen, Zhan, & Liu, 2015), including anticancer activity (Barilli et al., 2014;Bhat, Shim, Zhang, Chong, & Liu, 2012;Chang, Chen, Wang, Tzeng, & Chen, 2010;Feng et al., 2015;Li et al., 2016;Moret et al., 2009;Mrozek-Wilczkiewicz et al., 2015;Sosi c et al., 2013;Spaczy nska, Tabak, Malarz, & Musiol, 2014), antifungal activity (Cieslik et al., 2012;Musiol et al., 2006), and antibacterial activity (Warner, Musto, Turesky, & Soloway, 1975). The HQ are active against several bacterial species including Staphylococcus aureus and Staphylococcus epidermidis (Abouelhassan et al., 2014(Abouelhassan et al., , 2015Basak et al., 2016;Garrison et al., 2017;Lam et al., 2014), Enterococcus faecium (Basak et al., 2016;Garrison et al., 2017), Burkholderia pseudomallei (Wangtrakuldee et al., 2013), Neisseria gonorrhoeae, (Lawung et al., 2018), Listeria monocytogenes (Cherdtrakulkiat et al., 2016), and Mycobacterium avium (Hongmanee, Rukseree, Buabut, Somsri, & Palittapongarnpim, 2007;Kos et al., 2015). In addition, activity of the HQ compounds against replicating and nonreplicating Mycobacterium tuberculosis has been demonstrated in medium containing copper and in infected guinea pigs (Ananthan et al., 2009;Darby & Nathan, 2010;Hongmanee et al., 2007;Shah et al., 2016;Tison, 1952;Urbanski, Slopek, & Venulet, 1951). ...
There is an urgent need for new treatments effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. The 8‐hydroxyquinoline series is a privileged scaffold with anticancer, antifungal, and antibacterial activities. We conducted a structure–activity relationship study of the series regarding its antitubercular activity using 26 analogs. The 8‐hydroxyquinolines showed good activity against M. tuberculosis, with minimum inhibitory concentrations (MIC90) of <5 μM for some analogs. Small substitutions at C5 resulted in the most potent activity. Substitutions at C2 generally decreased potency, although a sub‐family of 2‐styryl‐substituted analogs retained activity. Representative compounds demonstrated bactericidal activity against replicating M. tuberculosis with >4 log kill at 10× MIC over 14 days. The majority of the compounds demonstrated cytotoxicity (IC50 of <100 μM). Further development of this series as antitubercular agents should address the cytotoxicity liability. However, the 8‐hydroxyquinoline series represents a useful tool for chemical genomics to identify novel targets in M. tuberculosis.
... In order to expand our existing arsenal of antibiotics, we evaluated the MICs of 22 halogenated phenazine, quinoline, and NH125 analogues ( Fig. 1) and triclosan against the following human mycoplasmas: M. genitalium, M. hominis, M. pneumoniae, and Ureaplasma spp. These analogue libraries were synthesized by substituting various halogen or methyl groups at critical positions along the base structure of a previously efficacious, representative compound for each class (70)(71)(72). This led to an expanded library of halogenated phenazine, quinoline, and NH125 analogues that had, in some cases, MICs comparable to or more efficacious than those of leading antimicrobials used to treat methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant S. epidermidis (MRSE), and vancomycin-resistant Enterococcus faecium (VRE) (70)(71)(72). ...
... These analogue libraries were synthesized by substituting various halogen or methyl groups at critical positions along the base structure of a previously efficacious, representative compound for each class (70)(71)(72). This led to an expanded library of halogenated phenazine, quinoline, and NH125 analogues that had, in some cases, MICs comparable to or more efficacious than those of leading antimicrobials used to treat methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant S. epidermidis (MRSE), and vancomycin-resistant Enterococcus faecium (VRE) (70)(71)(72). Mechanistically, past investigations have accumulated evidence suggesting that the NH125 analogues exert their effects through bacterial membrane destruction (73), whereas the quinolines and halogenated phenazine compounds appear to work through a non-membrane-destroying, metal(II)-dependent mechanism (70,(74)(75)(76). As mycoplasmas lack a cell wall, which leaves an exposed cell membrane, we hypothesize that NH125 analogues will result in low MICs against human mycoplasmas. ...
Escalating levels of antibiotic resistance in mycoplasmas, particularly macrolide resistance in Mycoplasma pneumoniae and M. genitalium , have narrowed our antibiotic arsenal. Further, mycoplasmas lack a cell wall and do not synthesize folic acid, rendering common antibiotics such as beta-lactams, vancomycin, sulfonamides and trimethoprim of no value. To address this shortage, we screened nitroxoline, triclosan, and a library of 20 novel, halogenated phenazine, quinoline, and NH125 analogues against Ureaplasma spp. and M. hominis clinical isolates from urine. We tested a subset of these compounds (n = 9) against four mycoplasma type strains ( M. pneumoniae , M. genitalium , M. hominis and U. urealyticum ) using a validated microbroth or agar dilution method. Among 72 Ureaplasma spp. clinical isolates, nitroxoline proved most effective (MIC 90 : 6.25 µM), followed by an N -arylated NH125 analogue (MIC 90 : 12.5 µM). NH125 and its analogue had significantly higher MICs against U. urealyticum versus U. parvum isolates, whereas nitroxoline did not. Nitroxoline exhibited bactericidal activity against U. parvum isolates, but bacteriostatic activity against the majority of U. urealyticum isolates. Among the type strains, the compounds had the greatest activity against M. pneumoniae and M. genitalium with 8 (80%) and 5 (71.4%) demonstrating MICs ≤12.5 µM, respectively. Triclosan also exhibited lower MICs against M. pneumoniae and M. genitalium . Overall, we identified a promising range of quinoline and NH125 compounds that showed effectiveness against M. pneumoniae and M. genitalium and found that nitroxoline, approved to treat urinary tract infections outside the US and an N -arylated NH125 analogue demonstrated low MICs against Ureaplasma spp. isolates.
... They have other potential applications in materials science and supramolecular chemistry (Normah et al, 2011;Tlahuext et al, 2011). Complexes of different metals with 8-hydroxyquinoline (HQ) or its derivatives have involved significant care having biological activities and capable use in organic light-emitting diodes (OLEDs), optical detecting, and so on (Song et al, 2015;Garrison et al, 2017). Specific attention has been located in supramolecular coordination compounds based on 8-hydroxyquinoline derivatives (Balasubramani et al, 2010;. ...
The preparation, spectroscopic characterisation of complexes derived from the mixed ligands with Cd II , Zn II and Co II metal ions with Schiff base, Dithiocarbamates (DTCs) and 8-Hydroxyquinoline are reported. The compounds that prepared have been defined via; chloride content, F.T-IR, UV-Vis 1 H-NMR spectroscopy and C.H.N.S, as well as conductance and magnetic susceptibility.All data which collected from such methods specified complexes with 6 coordinates in solution and solid states. The biologicalactivity that is related to all the prepared compounds which were screened for their antimicrobial activitiesagainst (G + and (G-)). The data that collected from biological activity indicate that complexes will have extra activity against such tested bacteria in comparison to that in free ligands.
... The class of the 8-hydroxyquinolines represents another class of biofilm-eradicating agents structurally related to the phenazine derivatives. It was indeed demonstrated that the phenolic oxygen and the vicinal nitrogen atom coordinate metal(II) cations [189]. ...
Biofilm formation significantly contributes to microbial survival in hostile environments and it is currently considered a key virulence factor for pathogens responsible for serious chronic infections. In the last decade many efforts have been made to identify new agents able to modulate bacterial biofilm life cycle, and many compounds have shown interesting activities in inhibiting biofilm formation or in dispersing pre-formed biofilms. However, only a few of these compounds were tested using in vivo models for their clinical significance. Contrary to conventional antibiotics, most of the anti-biofilm compounds act as anti-virulence agents as they do not affect bacterial growth. In this review we selected the most relevant literature of the last decade, focusing on the development of synthetic small molecules able to prevent bacterial biofilm formation or to eradicate pre-existing biofilms of clinically relevant Gram-positive and Gram-negative pathogens. In addition, we provide a comprehensive list of the possible targets to counteract biofilm formation and development, as well as a detailed discussion the advantages and disadvantages of the different current biofilm-targeting strategies.
... [25] Subsequent examples were utilized mostly in total synthesis. [26][27][28][29][30] In the recent decade, growing interest in PG-free synthesis has been observed ( Figure 3). The synthesis of sulfonamides startingf rom sulfonyl fluorides is an economic approachc ompared to the use of the corresponding sulfonyl chlorides and thus comes closer to an "ideals ynthesis" concept. ...
The cover picture shows a view of downtown Kyiv, the capital of Ukraine. There is a constellation of a novel scaffold for protecting‐free group synthesis of aliphatic sulfonamides in the sky. Cyclic aliphatic aminosulfonyl fluorides were developed as alternatives to unstable aminosulfonyl chlorides by scientists from Enamine (http://www.enamine.net) and ChemSpace (http://www.chem‐space.com). More information can be found in the Full Paper by Y. S. Moroz, P. K. Mykhailiuk, et al. (DOI: 10.1002/chem.201801140).
