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Medicinal Chemistry of Indole and Quinoline Derivatives: Trends, and Future...
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Medicinal Chemistry of Indole and Quinoline Derivatives: Trends, and Future Directions as Therapeutic Drugs

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 March 2024) | Viewed by 2954

Special Issue Editor

Dr. Florence O. McCarthy

E-Mail Website
Guest Editor
School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, College Road, T12 K8AF Cork, Ireland
Interests: indoles; quinolines; quinones; heterocycles; kinase inhibitors; plant sterols; pharmaceutical discovery and development

Special Issue Information

Dear Colleagues,

Nitrogen-containing heterocycles have made an enormous contribution to medicinal and pharmaceutical chemistry since the identification of alkaloids such as morphine and strychnine. The prevalence and potency of nitrogen-containing natural products that incorporate indole and quinoline (with melatonin, quinine, serotonin and tryptophan as other examples) frame this success.  

The two bicyclic ring systems have provided a rich source of diversity, upon which medicinal and pharmaceutical chemistry has thrived, and multiple examples of therapeutics with real-life benefits exist. Examples on the WHO Essential Medicines List stretch from chloroquine (discovered in 1934) to ciprofloxacin, fluvastatin, indomethacin, mefloquine, ondansetron, primaquine, quinine and sumatriptan. More recently, aripiprazole, tadalafil and ziprasidone are some of the most commonly prescribed medicines and highlight the tangible impact of these heterocycles on people and the treatment of their diseases.  

Medicinal chemistry approaches to find small-molecule lead compounds with pharmacological activity continue to use natural products, synthesis and existing small-molecule drug libraries as sources. The focus of this series of papers is the use of indole and quinoline as therapeutics. 

The journal Pharmaceuticals invites both reviews and original articles which concern the use of indoles and  quinolines in the discovery and development of pharmaceuticals. The scope of the Special Issue will cover, but is not limited to: new synthetic methods in the synthesis of indoles and quinolines, medicinal chemistry and structure–activity studies of indole and quinoline derivatives, natural product discovery involving indoles and quinolines,  indole and quinoline drug repositioning, new combinations of indoles and quinolines, and indoles and quinolines beyond pharmaceutical applications. The collection of manuscripts will be published as a Special Issue of the journal.

Dr. Florence O. McCarthy
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. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

  • indole
  • quinoline
  • heterocycle
  • pharmaceutical discovery and development

Published Papers (3 papers)

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Research

17 pages, 2685 KiB  
Article
Nature-Inspired 1-Phenylpyrrolo[2,1-a]isoquinoline Scaffold for Novel Antiproliferative Agents Circumventing P-Glycoprotein-Dependent Multidrug Resistance
by Alisa A. Nevskaya, Rosa Purgatorio, Tatiana N. Borisova, Alexey V. Varlamov, Lada V. Anikina, Arina Yu. Obydennik, Elena Yu. Nevskaya, Mauro Niso, Nicola A. Colabufo, Antonio Carrieri, Marco Catto, Modesto de Candia, Leonid G. Voskressensky and Cosimo D. Altomare
Pharmaceuticals 2024, 17(4), 539; https://doi.org/10.3390/ph17040539 - 22 Apr 2024
Viewed by 261
Abstract
Previous studies have shown that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in some tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, several novel substituted 1-Ph-DHPIQ derivatives [...] Read more.
Previous studies have shown that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in some tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, several novel substituted 1-Ph-DHPIQ derivatives were synthesized which carry carboxylate groups (COOH, COOEt), nitrile (CN) and Mannich bases (namely, morpholinomethyl derivatives) in the C2 position, as replacements of the already reported aldehyde group. They were evaluated for antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and for the ability of selectively inhibiting P-gp-mediated MDR. Lipophilicity descriptors and molecular docking calculations helped us in rationalizing the structure–activity relationships in the P-gp inhibition potency of the investigated 1-Ph-DHPIQs. As a main outcome, a morpholinomethyl Mannich base (8c) was disclosed which proved to be cytotoxic to all the tested tumor cell lines in the low micromolar range (IC50 < 20 μM) and to inhibit in vitro the efflux pumps P-gp and MRP1 responsible for MDR, with IC50s of 0.45 and 12.1 μM, respectively. Full article
(This article belongs to the Special Issue Medicinal Chemistry of Indole and Quinoline Derivatives: Trends, and Future Directions as Therapeutic Drugs)
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15 pages, 1839 KiB  
Article
The Effective Synthesis of New Benzoquinoline Derivatives as Small Molecules with Anticancer Activity
by Gheorghita Zbancioc, Ionel I. Mangalagiu and Costel Moldoveanu
Pharmaceuticals 2024, 17(1), 52; https://doi.org/10.3390/ph17010052 - 28 Dec 2023
Viewed by 763
Abstract
In this study, some novel benzo[c]quinoline derivatives were synthesized, their structural characteristics were described, and their in vitro anticancer efficacy was investigated. The synthesis involves an initial quaternization of the nitrogen atom from benzo[c]quinoline and then a [3+2] dipolar [...] Read more.
In this study, some novel benzo[c]quinoline derivatives were synthesized, their structural characteristics were described, and their in vitro anticancer efficacy was investigated. The synthesis involves an initial quaternization of the nitrogen atom from benzo[c]quinoline and then a [3+2] dipolar cycloaddition reaction of the in situ formed ylide. The effectiveness of synthesis using traditional thermal heating (TH) compared to microwave (MW) and ultrasound (US) irradiation was investigated in detail. The setup of a reaction under MW or US irradiation offers a number of additional benefits: higher yields, a reduction in the amount of solvent used compared to TH, a reduction in the reaction time from hours to minutes, and a reduction in the amount of energy consumed. The structure of all the obtained compounds was proved by several spectral techniques (FTIR, HRMS, and NMR). All benzo[c]quinoline derivatives (quaternary salts and cycloadducts) along with ten other benzo[f]quinoline derivatives (quaternary salts and cycloadducts), previously obtained, were tested in an in vitro single-dose anticancer experiment. The results demonstrated that the cycloadducts 5a–c and 6a–c exhibit stronger anticancer activity than quaternary salts 3a–c. The most active compound is compound 5a, with anticancer activity on most of the cell lines studied, while the second most active compound is 6c, showing significant lethality for the SR leukemia cell line (17%). Structure-activity relationship (SAR) correlations are also included in the study. Full article
(This article belongs to the Special Issue Medicinal Chemistry of Indole and Quinoline Derivatives: Trends, and Future Directions as Therapeutic Drugs)
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27 pages, 4368 KiB  
Article
Quinoline- and Isoindoline-Integrated Polycyclic Compounds as Antioxidant, and Antidiabetic Agents Targeting the Dual Inhibition of α-Glycosidase and α-Amylase Enzymes
by Mohammed Al-Ghorbani, Osama Alharbi, Abdel-Basit Al-Odayni and Naaser A. Y. Abduh
Pharmaceuticals 2023, 16(9), 1222; https://doi.org/10.3390/ph16091222 - 30 Aug 2023
Cited by 2 | Viewed by 1107
Abstract
Novel analogs of quinoline and isoindoline containing various heterocycles, such as tetrazole, triazole, pyrazole, and pyridine, were synthesized and characterized using FT-IR, NMR, and mass spectroscopy, and their antioxidant and antidiabetic activities were investigated. The previously synthesized compound 1 was utilized in conjugation [...] Read more.
Novel analogs of quinoline and isoindoline containing various heterocycles, such as tetrazole, triazole, pyrazole, and pyridine, were synthesized and characterized using FT-IR, NMR, and mass spectroscopy, and their antioxidant and antidiabetic activities were investigated. The previously synthesized compound 1 was utilized in conjugation with ketone-bearing tetrazole and isoindoline-1,3-dione to synthesize Schiff’s bases 2 and 3. Furthermore, hydrazide 1 was treated with aryledines to provide pyrazoles 4a–c. Compound 5 was obtained by treating 1 with potassium thiocyanate, which was then cyclized in a basic solution to afford triazole 6. On the other hand, pyridine derivatives 7a–d and 8a–d were synthesized using 2-(4-acetylphenyl)isoindoline-1,3-dione via a one-pot condensation reaction with aryl aldehydes and active methylene compounds. From the antioxidant and antidiabetic studies, compound 7d showed significant antioxidant activity with an EC50 = 0.65, 0.52, and 0.93 mM in the free radical scavenging assays (DPPH, ABTS, and superoxide anion radicals). It also displayed noteworthy inhibitory activity against both enzymes α-glycosidase (IC50: 0.07 mM) and α-amylase (0.21 mM) compared to acarbose (0.09 mM α-glycosidase and 0.25 mM for α-amylase), and higher than in the other compounds. During in silico assays, compound 7d exhibited favorable binding affinities towards both α-glycosidase (−10.9 kcal/mol) and α-amylase (−9.0 kcal/mol) compared to acarbose (−8.6 kcal/mol for α-glycosidase and −6.0 kcal/mol for α-amylase). The stability of 7d was demonstrated by molecular dynamics simulations and estimations of the binding free energy throughout the simulation session (100 ns). Full article
(This article belongs to the Special Issue Medicinal Chemistry of Indole and Quinoline Derivatives: Trends, and Future Directions as Therapeutic Drugs)
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