Quinolones as prospective drugs: Their syntheses and biological applications

doi:10.1016/bs.aihch.2020.08.001

Advances in Heterocyclic Chemistry

Volume 135, 2021, Pages 147-196

https://doi.org/10.1016/bs.aihch.2020.08.001 Get rights and content

Abstract

Quinolones continue to receive significant attention owing to their diverse range of biological activities. They provide an important scaffold in anticancer, antibacterial and antiviral drug research. Some chemical syntheses, and biological activities of quinolone derivatives are reviewed.

Introduction

Quinolines I–III belong to the benzo-pyridine family, they are naturally plant-derived, and a wide variety of their derivatives can be synthesized.¹^, ² The quinolone (oxo-quinoline) ring system is one of the most ubiquitous heterocycles in drug research.³ Quinolone derivatives have been utilized extensively in medicinal chemistry due to its privileged structure that shows various pharmacological activities such as anti-bacterial,⁴ anti-tubercular,⁵ anti-malarial,⁶ anti-HIV,⁷ anti-HCV,⁸ antitumor,⁹ anti-cancer¹⁰ and many other biological activities (Fig. 1).11, 12, 13

Cancer, the second leading cause of mortality after cardiovascular diseases globally, has many anatomic and molecular subtypes.¹⁴ It has been estimated by the World Health Organization (WHO) that around 14 million cases and 9 million cancer-related deaths (1 in 6 deaths is due to cancer) occur annually. The total annual economic cost of cancer was estimated at approximately $1.16 trillion in the last decade.¹⁵ The most common types are leukemia, lung, breast, colorectal, prostate, stomach and skin cancers, while lung, colorectal, stomach, liver and breast cancers are the most common causes of cancer death.¹⁶ The increasing threat of drug resistance makes the anti-cancer agents currently used less and less effective.¹⁷ Many anti-cancer candidates with diverse novel structures are under clinical evaluations, but they are still insufficient.¹⁸^,¹⁹ In order to prevent or treat this fatal disease, it is imperative to develop anti-cancer drugs with higher efficiency.

Quinolones are one of the most commonly prescribed classes of antibacterial in the world and they are used to treat a variety of bacterial infections in humans.²⁰^, ²¹ Because of the worldwide use (and sometimes overuse) of these drugs, the number of quinolone-resistant bacterial strains has been growing steadily since the 1990s, as is the case with other antibacterial agents.²² Since the appearance of bacterial and fungal resistance towards the known chemotherapeutic agents; the discovery of new chemotherapeutic molecules constitutes a real challenge.²³ Consequently, new potent chemo-therapeutic agents are needed, and if possible, with new modes of action.²⁴^,²⁵

Section snippets

Synthesis of 4-hydroxy-2(1H)-quinolone I

4-Hydroxy-2(1H)-quinolone (2,4-quinolone, I) can theoretically exist in five possible tautomeric forms Ia-e (Fig. 2). However, in a practical sense, the tautomerism is confined to forms Ic-e. These three possible prototropic transformations have been examined by various chemical reactivity, thermochemical, spectral and computational methods.²⁴ Recently, X-ray structure analyses of numerous compounds of that class have shown that structure Ie is the most common form.²⁶^,²⁷

Many synthetic routes to

Biological activities of 4-hydroxyquinoline-2-ones I and quinoline-2-one II

Quinolones are one of the most promising and vigorously pursued heterocycles in contemporary anti-infective chemotherapy exhibiting broad spectrum and potent activity.⁷⁴ Their derivatives have a relatively simple molecular nucleus, which is amenable to many structural modifications. Quinolone derivatives have found use in effective treatment of various infectious diseases.⁷⁵ Some simple 4-hydroxyquinolin-2-ones I (Fig. 3) are found in nature. Compound 4-hydroxyquinolone II itself, was isolated

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A novel Cu-catalyzed tandem C–N and C–C bond-formation reaction has been developed to furnish 2-substituted-4-(1H)-quinolones. 4-(1H)-quinolones play an important role in medicinal chemistry. Many 2-aryl(alkyl)-4(1H)-quinolones are found to exhibit diverse biological properties. While traditional methods have inherent issues [like starting materials with incompatible functional groups (NH₂ and keto groups)], many modern methods either require activated starting materials (like Ynones) or employ expensive metals (Pd, Rh, Au, etc.) involving carbonylation using CO or metal complexes. Our protocol presents an environmentally friendly one-step method for the construction of these useful 2-substituted-4-(1H)-quinolones from easily available aryl boronic acid (or pinacolate ester) and nitriles as new raw materials, using a cheap Cu-catalyst and O₂ (air) as a green oxidant. We further extended its application to the synthesis of various natural products, including the first formal total synthesis of punarnavine. A plausible mechanism involving an aryl nitrilium ion (formed due to the intermolecular C–N bond-forming coupling between aryl boron species and the nitrile group) followed by tandem intramolecular C–C bond formation has been proposed.
Novel diphenyltin(IV) complexes with carboxylato N-functionalized 2-quinolone ligands: Synthesis, characterization and in vitro anticancer studies
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Three new diphenyltin(IV) complexes, bis(3-(4-methyl-2-oxoquinolinyl-1(2H)-yl)propanoato)diphenyltin(IV) (1), bis(2-(4-methyl-2-oxoquinolin-1(2H)-yl)ethanoato)diphenyltin(IV) (2), and bis(2-(4-hydroxy-2-oxoquinolin-1(2H)-yl)ethanoato)diphenyltin(IV) (3), were synthesized and characterized by elemental microanalysis, FT-IR spectroscopy, and multinuclear (¹H, ¹³C and ¹¹⁹Sn) NMR spectroscopy. Crystal structure of ligand precursor, 2-(4-methyl-2-oxoquinolinyl-1-(2H)-yl)acetic acid (HL2), has been determined by X-ray diffraction studies. Asymmetric bidentate coordination of the carboxylato ligands and skew trapezoidal structures are assumed for the synthesized complexes. In vitro anticancer activity of the synthesized diphenyltin(IV) complexes was evaluated against three human: MCF-7 (breast adenocarcinoma), A375 (melanoma), HCT116 (colorectal carcinoma), and three mouse tumor cell lines: 4T1 (breast carcinoma), B16 (melanoma), CT26 (colon carcinoma) using MTT and CV assays. The IC₅₀ values fall in the range from 0.1 to 3.7 μM. Flow cytometric analysis and fluorescent microscopy suggest that complex 1 induces caspase-dependent apoptosis followed with strong blockade of cell division in HCT116 cells. Since complex 1 showed ROS/RNS scavenging potential mentioned cytotoxicity was not connected with oxidative stress.
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Design, synthesis and antimicrobial activity of novel quinoline-2-one hybrids as promising DNA gyrase and topoisomerase IV inhibitors
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A new series of quinoline-2-one Schiff-base hybrids has been designed and synthesized. Their structure has been established using 1H NMR, 13C NMR, and mass as well as elemental analyses. All compounds were screened for antimicrobial activity and the minimum inhibitory concentration was determined. Compound 6c, one of the most potent compounds achieving (MIC of 0.075, 0.018, 0.018 µg/ml) against B. subtilis, E. coli and S. aureus, respectively, comparable to ciprofloxacin. Moreover, in vitro E. coli topoisomerase IV and DNA gyrase inhibitory activity have been also assigned. 6c showed IC₅₀ of 280± 30 nM, 17.50 ± 1.50 µM against reference Novobiocin with 170 ± 20 nM and 11± 2 µM, respectively.
Tautomerism and antioxidant power of sulfur-benzo[h]quinoline: DFT and molecular docking studies
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Citation Excerpt :
Consistently, the discovery of antioxidants is an intensive research area. Quinoline derivatives have recently gained specific attention due to their prospective usage in medicinal chemistry as skeletal components or significant pharmacophoric moieties, particularly when using their antioxidant properties [6,7]. Sulfur-benzo[h]quinoline (QH) is a quinoline analogue with significant antioxidant action (Fig. 1) [8].
In this work, a systematic quantum chemical investigation of antiradical activity of sulfur-benzo[h]quinolone was performed in physiological environments. DFT analysis revealed that sulfur-benzo[h]quinolone exhibits strongly solvent-dependent tautomerism. The reactions of the tautomeric and different acid-base species toward hydroperoxyl (HOO) radical were considered following the formal hydrogen atom transfer (FHT) mechanism and the single electron transfer (SET) mechanism. It was found that the antioxidant activity of NH form in lipid medium is higher than that of the reference antioxidants Trolox and ascorbic acid with the rate constant k = 3.2 × 10⁵ M⁻¹s⁻¹. Molecular docking analysis illustrated that sulfur-benzo[h]quinolone is also a potential inhibitor of the pro-oxidant action of cytochrome P450, myeloperoxidase, NADPH oxidase, and xanthine oxidase enzymes.
Antimicrobial modification of polypropylene films by photograft and layered double hydroxides assembly
2022, Reactive and Functional Polymers
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Among the AMD intercalated into LDH, sodium benzoate (Na-Bz) is an AMD with a wide industrial use for the preservation of food and pharmaceuticals due to its broad-spectrum AM activity against bacteria and fungi [35,36]. On the other hand, nalidixic acid (HNaI) is a synthetic quinolone that generates a specific inhibition of bacterial DNA gyrase and presents AM activity on microorganisms such as S. aureus, E.coli and Morganella morganii, among others [27,37]. HNaI has been used for the prophylaxis and the treatment of infections both in humans and animals, but its use has declined due to the high concentrations necessary to reach AM activity and its short shelf life, due to its photosensitivity [36].
Providing antimicrobial (AM) properties to polypropylene (PP) films is an appealing strategy for food packaging and biomedical areas. In this study, PP-based platforms with AM activity were obtained by the incorporation of layered double hydroxides (LDH) nanoparticles, intercalated with antimicrobial drugs (AMD), either nalidixate (Nal⁻) or benzoate (Bz⁻), to polyacrylate (PAA)-photografted PP films (PP-g-PAA/LDH-AMD). The assembly mechanism was explored, and the composition, morphological and interfacial properties of the obtained platforms were determined. Finally, the AM activity was assayed against Staphylococcus aureus and Escherichia coli strains. LDH-AMD were successfully incorporated to the platforms by electrostatic interactions with the carboxylate groups of the photografted PAA chains and they were mainly located in the outer region of the PAA layer. This incorporation was first produced at grooves and pits of this surface layer, and then spread by aggregation of the incoming LDH-AMD particles, which increased the surface roughness of PP-g-PAA/LDH-AMD platforms. These showed significant AM activity due to their roughness, the high surface AMD concentration and the positive charge of LDH-AMD particles. Thus, Nal-incorporating platforms presented a high bactericidal effect on the proliferation of both bacterial strains. On the other hand, Bz-loaded platform slightly delayed the bacterial growth of S. aureus.

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Chapter Three - Quinolones as prospective drugs: Their syntheses and biological applications

Abstract

Introduction

Section snippets

Synthesis of 4-hydroxy-2(1H)-quinolone I

Biological activities of 4-hydroxyquinoline-2-ones I and quinoline-2-one II

Eur. J. Med. Chem.

Arab. J. Chem.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Tetrahedron

Bioorg. Med. Chem. Lett.

Adv. Synth. Catal.

Org. Lett.

Int. J. Antimicrob. Agents

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

J. Heterocyclic Chem.

J. Heterocyclic Chem.

Eur. J. Med. Chem.

Bioorg. Chem.

J. Mol. Struct.

Bioorg. Chem.

Bioorg. Chem.

Phytochemistry

ACS Sustainable Chem. Eng.

Clin. Infect. Dis.

Genome Inform.

Drugs

Mini-Rev. Med. Chem.

Antimicrob. Agents Chemother.

Curr. Med. Chem.

Chem. Pharm. Bull.

World J. Pharm. Pharm. Sci.

J. Pharm. Pharm. Sci.

DICP Ann. Pharmacother.

Cancers

Cancer J. Clin.

Int. J. Cancer

Adv. Pharm. Bull.

Clin. Transl. Med.

Inorg. Chem.

Proc. Nat. Acad. Sci. U. S. A.

J. Antimicrob. Chemother.

Cureus

Biochemistry

Heterocycles

Tautomerism of Heterocycles

Chem. Pap.

Monatsh. Chem.

Bull. Korean Chem. Soc.

Synth. Commun.

Mol. Diversity

Name Reactions: A Collection Of Detailed Reaction Mechanisms;[More Than 300 Reactions]

Comprehensive Organic Name Reactions