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Synthesis and Transformations of Bioactive Hydroxyquinolines 2022

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 7101

Special Issue Editor


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Guest Editor
Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Hungary
Interests: indole derivatives; 8-hydroxyquinolines; 4-hydroxyquinoline-2-carboxylic acid (KYNA) derivatives; β-carbolines; drug design and synthesis; ortho-quinone methides; modified Mannich reaction; modified aza-Friedel–Crafts reaction
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Special Issue Information

Dear Colleagues,

We are delighted to announce a call for submissions to a Special Issue of the International Journal of Molecular Sciences on the topic of “Synthesis and Transformations of Bioactive Hydroxyquinolines”.

Privileged structures can bind to a diverse range of targets with high affinities, thus benefitting the discovery of novel bioactive agents. Hydroxyquinoline derivatives represent an important type of such a privileged structure, possessing a rich diversity of biological properties.

One participant of such compounds is 4-hydroxyquinoline-2-carboxylic acid (kynurenic acid or KYNA). It is one of the few endogenous excitatory amino acid receptor blockers, produced via the metabolism of tryptophan (TRP). It is well established that KYNA has high affinity toward NMDA receptors and a high affinity toward positive modulatory binding sites at the AMPA receptor that are assumed to be the reasons for its biological effects.

On the other hand, 8-hydroxyquinoline itself or its derivatives have a broad pharmacological activity and have been exploited in several medicinal applications ranging from anti-neurodegenerative, anti-inflammatory, and antimicrobial to anticancer therapies.

We encourage the submission of both original research articles and topical reviews on all aspects of synthesis and pharmacological studies on hydroxyquinoline derivatives. All submitted articles will undergo peer review.

Prof. Dr. István Szatmári
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hydroxyquinolines
  • 8-quinolinols
  • 4-hydroxyquinoline-2-carboxylic acid (KYNA)
  • bioactive compounds
  • neuroprotection
  • antiproliferative activity

Published Papers (4 papers)

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Research

27 pages, 11014 KiB  
Article
Metal Complexes of a 5-Nitro-8-Hydroxyquinoline-Proline Hybrid with Enhanced Water Solubility Targeting Multidrug Resistant Cancer Cells
by Tamás Pivarcsik, Vivien Pósa, Hilda Kovács, Nóra V. May, Gabriella Spengler, Szonja P. Pósa, Szilárd Tóth, Zeinab Nezafat Yazdi, Csilla Özvegy-Laczka, Imre Ugrai, István Szatmári, Gergely Szakács and Éva A. Enyedy
Int. J. Mol. Sci. 2023, 24(1), 593; https://doi.org/10.3390/ijms24010593 - 29 Dec 2022
Cited by 5 | Viewed by 2477
Abstract
Multidrug resistance (MDR) in cancer is one of the major obstacles of chemotherapy. We have recently identified a series of 8-hydroxyquinoline Mannich base derivatives with MDR-selective toxicity, however with limited solubility. In this work, a novel 5-nitro-8-hydroxyquinoline-proline hybrid and its Rh(η5-C [...] Read more.
Multidrug resistance (MDR) in cancer is one of the major obstacles of chemotherapy. We have recently identified a series of 8-hydroxyquinoline Mannich base derivatives with MDR-selective toxicity, however with limited solubility. In this work, a novel 5-nitro-8-hydroxyquinoline-proline hybrid and its Rh(η5-C5Me5) and Ru(η6-p-cymene) complexes with excellent aqueous solubility were developed, characterized, and tested against sensitive and MDR cells. Complex formation of the ligand with essential metal ions was also investigated using UV-visible, circular dichroism, 1H NMR (Zn(II)), and electron paramagnetic resonance (Cu(II)) spectroscopic methods. Formation of mono and bis complexes was found in all cases with versatile coordination modes, while tris complexes were also formed with Fe(II) and Fe(III) ions, revealing the metal binding affinity of the ligand at pH 7.4: Cu(II) > Zn(II) > Fe(II) > Fe(III). The ligand and its Rh(III) complex displayed enhanced cytotoxicity against the resistant MES-SA/Dx5 and Colo320 human cancer cell lines compared to their chemosensitive counterparts. Both organometallic complexes possess high stability in solution, however the Ru(II) complex has lower chloride ion affinity and slower ligand exchange processes, along with the readiness to lose the arene ring that is likely connected to its inactivity. Full article
(This article belongs to the Special Issue Synthesis and Transformations of Bioactive Hydroxyquinolines 2022)
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13 pages, 2108 KiB  
Article
Fine-Tuned Reactivity of N-Containing Naphthol Analogues
by Oszkár Csuvik, Petra Barta, Antal Csámpai and István Szatmári
Int. J. Mol. Sci. 2022, 23(20), 12329; https://doi.org/10.3390/ijms232012329 - 15 Oct 2022
Viewed by 1349
Abstract
6-Hydroxyquinoline and 3-hydroxyisoquinoline as N-containing naphthol analogues were tested in modified Mannich reactions (mMr’s). In the case of 6-hydroxyquinoline, the outcomes of the attempted Mannich reactions were strongly influenced by the amine components. Aminoalkylation of this substrate with reagents 1-naphthaldehyde [...] Read more.
6-Hydroxyquinoline and 3-hydroxyisoquinoline as N-containing naphthol analogues were tested in modified Mannich reactions (mMr’s). In the case of 6-hydroxyquinoline, the outcomes of the attempted Mannich reactions were strongly influenced by the amine components. Aminoalkylation of this substrate with reagents 1-naphthaldehyde and N-benzylmethylamine led to the isolation of a diol regarded as a stabilised water adduct of an ortho-quinone methide (o-QM), of which formation can be ascribed to the presence of a hydroxide ion in a relatively higher concentration generated by the bulky and basic amine component with decreased nucleophilicity. The classical Mannich base was isolated as a single product when the amine component was replaced for morpholine, featuring nucleophilicity rather than basic character under the applied reaction conditions. Starting from the isomer substrate 3-hydroxyisoquinoline, independently on the nucleophile (methanol or morpholine) besides the formation of the classical Mannich base, the nucleophilic attack at position one of the heterocyclic substrate was also observed. The DFT analysis of the acceptor molecular orbitals of the potential electrophilic components and the thermodynamics of the assumed-possible transformations demonstrated that this regioselective addition is a feasible process on the investigated heterocyclic skeleton. DFT modelling studies also suggest that besides the steric bulk, the orbital-controlled electronic properties of the aryl group, originating from the aldehyde components, have a strong influence on the ratios and the NMR-monitored interconversions of the C-1-substituted 3-hydroxyisoquinolines and the classical Mannich bases formed in multistep reaction sequences. On the basis of the DFT analysis of the thermodynamics of alternative pathways, a reaction mechanism was proposed for the rationalization of these characteristic substrate-controlled interconversions. Full article
(This article belongs to the Special Issue Synthesis and Transformations of Bioactive Hydroxyquinolines 2022)
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17 pages, 1923 KiB  
Article
Synthesis of 4-Hydroxyquinolines as Potential Cytotoxic Agents
by Oszkár Csuvik, Nikoletta Szemerédi, Gabriella Spengler and István Szatmári
Int. J. Mol. Sci. 2022, 23(17), 9688; https://doi.org/10.3390/ijms23179688 - 26 Aug 2022
Cited by 1 | Viewed by 1594
Abstract
The synthesis of alkyl 2-(4-hydroxyquinolin-2-yl) acetates and 1-phenyl-4-(phenylamino)pyridine-2,6(1H,3H)-dione was optimised. Starting from 4-hydroxyquinolines (4HQs), aminomethylation was carried out via the modified Mannich reaction (mMr) applying formaldehyde and piperidine, but a second paraformaldehyde molecule was incorporated into the [...] Read more.
The synthesis of alkyl 2-(4-hydroxyquinolin-2-yl) acetates and 1-phenyl-4-(phenylamino)pyridine-2,6(1H,3H)-dione was optimised. Starting from 4-hydroxyquinolines (4HQs), aminomethylation was carried out via the modified Mannich reaction (mMr) applying formaldehyde and piperidine, but a second paraformaldehyde molecule was incorporated into the Mannich product. The reaction also afforded the formation of bisquinoline derivatives. A new 1H-azeto [1,2-a]quinoline derivative was synthesised in two different ways; namely starting from the aminomethylated product or from the ester-hydrolysed 4HQ. When the aldehyde component was replaced with aromatic aldehydes, Knoevenagel condensation took place affording the formation of the corresponding benzylidene derivatives, with the concomitant generation of bisquinolines. The reactivity of salicylaldehyde and hydroxynaphthaldehydes was tested; under these conditions, partially saturated lactones were formed through spontaneous ring closure. The activity of the derivatives was assessed using doxorubicin-sensitive and -resistant colon adenocarcinoma cell lines and normal human fibroblasts. Some derivatives possessed selective toxicity towards resistant cancer cells compared to doxorubicin-sensitive cancer cells and normal fibroblasts. Cytotoxic activity of the benzylidene derivatives and the corresponding Hammett–Brown substituent were correlated. Full article
(This article belongs to the Special Issue Synthesis and Transformations of Bioactive Hydroxyquinolines 2022)
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13 pages, 1540 KiB  
Article
Synthesis of Indole-Coupled KYNA Derivatives via C–N Bond Cleavage of Mannich Bases
by Bálint Lőrinczi, Péter Simon and István Szatmári
Int. J. Mol. Sci. 2022, 23(13), 7152; https://doi.org/10.3390/ijms23137152 - 28 Jun 2022
Viewed by 1259
Abstract
KYNAs, a compound with endogenous neuroprotective functions and an indole that is a building block of many biologically active compounds, such as a variety of neurotransmitters, are reacted in a transformation building upon Mannich bases. The reaction yields triarylmethane derivatives containing two biologically [...] Read more.
KYNAs, a compound with endogenous neuroprotective functions and an indole that is a building block of many biologically active compounds, such as a variety of neurotransmitters, are reacted in a transformation building upon Mannich bases. The reaction yields triarylmethane derivatives containing two biologically potent skeletons, and it may contribute to the synthesis of new, specialised neuroprotective compounds. The synthesis has been investigated via two procedures and the results were compared to those of previous studies. A possible alternative reaction route through acid catalysis has been established. Full article
(This article belongs to the Special Issue Synthesis and Transformations of Bioactive Hydroxyquinolines 2022)
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Scheme 1

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