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Advances on Quinoline Derivatives: A Review of Synthesis and

Biological Activities

Emmanuel Chinedu Nnadi

2,4

, Vivian Ifeoma Okonkwo

, Chidinma Eucharia Ikwelle

, Faith Temitope

Elijah

, Anulika Ruphina Phil-Mba

, Vivian Chinenye Odo

, Blessing Ginika Eke

Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka, Nigeria

Department of Science Laboratory Technology, University of Nigeria, Nsukka, Nigeria

Department of Pharmacy, University of Nigeria, Nsukka, Nigeria

Department of Chemistry, University of Iowa, USA

DOI: https://doi.org/10.51244/IJRSI.2025.120800228

Received: 25 Aug 2025; Accepted: 01 Sep 2025; Published: 25 September 2025

ABSTRACT

Quinoline compounds and their derivatives have a vast distribution in nature coupled with their immense

therapeutic potential. Due to the unfading therapeutic benefits of these compounds over the years, a lot of

researchers are exploring the synthesis of various derivatives of quinoline which are screened for different

therapeutic activities including, anti-malarial, anti-microbial, anti-inflammatory, anti-convulsant, anti-cancer

anti-mycobacterial, cardio-protective, neuroprotective activity etc. This review highlights various advances in

the synthetic routes and methodology for some quinoline derivatives including Friedlander modified metal-

catalyzed reactions, Photo-induced oxidative annulation reaction, Microwave-assisted doebner reaction and

their biological properties.

Key Words: Quinolines, Derivatives, Synthetic routes, biological properties

INTRODUCTION

Quinolines are important class of organic compounds characterized with the basic skeleton C

N and belong

to the class of Organic compounds of the hetero aromatic series which are characterized by a double-ring

structure composed of compounds of benzene and a nucleus pyridine ring fused at two adjacent carbon atoms

as seen in fig. (1) which makes it offer enough opportunities for substitution. Quinolines are also considered to

be heterocyclic analogues of naphthalene (1-azanaphthalene) [1-6].

Fig 1: Structure of Quinoline

Quinolines can be derived from natural sources such as flowering plants, animals, microorganisms and coal tar

which is the primary source of quinoline; they occur in different natural products (Cinchona Alkaloids) and

pharmacological active substances displaying a broad range of biological activity [7-8]. The versatility of the

quinoline derivatives has caught the attention of researchers for several decades, owing to their vast

distribution in nature and immense therapeutic potential. The interest of this compound class does not appear

to fade [9-11]. Compounds containing quinoline and quinoxaline nucleus have been reported to have various

pharmacological activities such as anti-malarial, anti-microbial, anti-inflammatory, anti-convulsant, anticancer,

anti-mycobacterial, cardio-protective, neuroprotective activity, etc. [12-15]. Due to their broad range of

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bioactivity, quinolines and their derivatives are known as privileged structures in drug discovery programs [16-

19].

In addition to the medicinal applications, quinolines have been employed in the study of bio-organic and bio-

organometallic processes, formation of conjugated molecules and polymers that can be combined to enhance

electronic and opto-electronic or non-linear optical properties with excellent mechanical properties [20-24]. In

agriculture, quinolines and their derivatives have been largely beneficial in fighting pests and fungi that attack

plants, farm produce and livestock [25-27].

The structure determination and structure activity relationship (SAR) studies of these compounds have also

resulted in the discovery of newer antimalarial drugs like chloroquine, primaquine and mefloquine [28-32].

Quinoline on its own has few applications but is considered a privileged molecule because its derivatives have

a vast area of application in Medicinal chemistry [33-35]. Due to their wide spectrum of bioactivities, the

scientific communities are continuously looking for more efficient synthetic routes to form quinoline

derivatives by improving on the existing routes through optimization of reactions [36-40].

A good number of synthetic processes have been developed for various quinoline derivatives including

transition metal catalysts, Brønsted acid/base catalysts and non-catalyst synthesis. The well-known synthetic

techniques include but are not limited to Friedländer, Pfitzinger, Povarov, Skraup, Doebner and Conrad–

Limpach–Knorr synthesis [41-44].

Recently, synthesis of quinoline derivatives through multi-component reactions (MCRs) has emerged as an

efficient and versatile strategy in organic synthesis giving room for synthesizing complex molecular structures

in a single step [45-49].

This review focuses on Friedlander Modified Metal-Catalyzed Reactions, Photo-Induced Oxidative Annulation

Reaction and Microwave-Assisted Doebner Reaction as these are environmentally friendly synthetic methods

[50].

Synthetic Approaches Of Quinoline And Its Derivatives

Several approaches have been reported for quinoline synthesis. Some of the oldest and prevalent approaches

are Skraup, Doebner-von Miller, Conrad-Limpach-Knorr, Povarov, Riehm, Gould-Jacobs and Combes

reactions, which primarily employed aniline as a common reactant in the presence of strong acids, high

temperatures, and organic solvents (Fig. 2). However, even though these techniques are quite successful, they

are often criticized for their environmental impact since they produce a lot of waste that needs to be disposed

of and require a lot of effort to separate the output. In recent years, significant advances have been made in the

development of more efficient, environment-friendly, and sustainable methods of synthesizing quinoline. This

section reviews recent advancements in quinoline synthesis, emphasizing its reaction pathways.

Fig. 2: Traditional methods of synthesizing Quinoline derivatives [51]

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Friedlander Modified Metal-Catalyzed Reactions

The Friedlander reaction has been one of the traditional methods with a larger number of modifications to

cleaner versions because it is one of the most simple and practical ways to develop quinoline compounds [52].

In 2022, Xiu Wang et al., reported a Ruthenium-catalyzed aza-Michael addition and intramolecular annulation

of enaminones with anthranils to access substituted quinolines (Scheme 1) [53]. The catalytic process began

with the treatment of compound 3 with [(p-cymene)RuCl

]

, which resulted in the formation of intermediate 6.

Then, intermediate 6 passes through an aza-Micheal addition-type C-N coupling with anthranil to obtain

intermediate 7 and the ruthenium catalyst was released to participate in the next cycle. An intermolecular

cyclization process was carried out by intermediate 8 to give rise to intermediate 9, which undergoes the

process of dehydration and deamination to give the final product 5.

Scheme 1: Synthesis of 3-substituted quinolines by ruthenium-catalyzed annulation of enaminones with

anthranils

Zou et al., in 2024, reported a copper(I)-catalyzed [4 + 1 + 1] annulation strategy using anthranils and

ammonium salts to access 2,3-diaroylquinolines under mild condition (Scheme 2) [54]. Using only CuCl as the

catalyst and molecular oxygen as the terminal oxidant, this transformation showed some noteworthy benefits,

such as excellent product yield, wide substrate compatibility, and easily accessible starting materials. An

efficient and practical approach to constructing these valuable heterocyclic scaffolds was provided using this

methodology, which were otherwise challenging to synthesize using other conventional pathways.

Scheme 2: copper(I)-catalyzed [4 + 1 + 1] annulation to synthesize 2,3-diaroylquinolines

Photo-Induced Oxidative Annulation Reaction

Huang et al., 2020 reported sodium sulfinates as a green inorganic sulfur source to synthesize quinoline

derivatives [55]. Scheme 3 outlines the plausible mechanism which led to the formation of 3-

sulfonylquinolines involving N-propargylanilines and sodium sulfinates. Under blue LED irradiation, the

photocatalyst, Eosin Y transits to its excited state, which was subsequently deductively quenched by the

sulfinyl anion, yielding Eosin Y

·−

and an oxygen-centered radical 16 that resonated with a sulfonyl radical 17.

The addition of 15 to 13 gave new radical intermediate 18, followed by an intramolecular radical cyclization to

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form the cyclized radical intermediate 19. The t-BuO· radical generated from the single electron transfer

process between TBPB and Eosin Y

·−

abstracted a hydrogen atom from 19 to afford the 1,2-dihydroquinoline

20 and t-BuOH. Intermediate 19 was oxidized to the corresponding cyclohexadienyl cation 20, which was

transferred to 21 after deprotonation. Finally, an aromatization process of 21 was executed smoothly to

construct the target product 15.

Scheme 3: Visible-light promoted metal-free synthesis of 3-sulfonylquinolines

An efficient and sustainable approach for the synthesis of polysubstituted quinolines through the

electrocyclization of 2-vinylarylimines which was visible-light-excited to give 9,10-phenanthrenequinone

(PQ*) was developed by Talvitie et al., in 2022 (Scheme 4) [56]. The process involved the use of MgCO

as an

additive in DCM and after being excited to its triple state, PQ* induced a single-electron transfer (SET) from

2-vinylarylimine 22. This reaction generated a radical cation 24 that cyclized to a dihydroquinoline cation

radical 25. Then, the radical anion removed an acidic proton, providing an intermediate 26. Finally, the process

of hydrogen-atom (HAT) formed the quinoline product 23, and 9,10-phenanthrenequinone was regenerated by

molecular oxygen.

Scheme 4: Phenanthrenequinone-sensitized photocatalytic synthesis of polysubstituted quinolines from 2-

vinylarylimines

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Microwave-Assisted Doebner Reaction

Transition-metals are interesting catalysts in quinoline synthesis showing several advantages when compared

with traditional non-catalytic methods [57-58]. However, metal catalyzed reactions could be disadvantageous

in the preparation of pharmaceutical products due to potential metal residues in the final products.

Consequently, other approaches have been explored by researchers, one of them is the replacement of

transition-metal catalysts with less toxic and more environmentally friendly organocatalysts [59-60].

Patel et al., 2020 reported a one-pot three component synthesis of 4-carboxyquinoline derivatives using p-

toluensulfonic acid (TsOH) catalyst under MW irradiation [61]. Optimal conditions were achieved with 10 mol%

TsOH and 300W MW for 3–4 min. Mechanistically, the imine was formed between aniline and aldehyde and

CSA acted as a promoter of the subsequent [4 + 2] cycloaddition with the alkyne. The results obtained in the

work concluded that imines with electron donating groups and arylalkynes with electron withdrawing groups

favored the synthesis of 4-arylated quinolines.

Scheme 5: Doebner reaction catalyzed by TsOH under microwave irradiation [61]

The lack of sustainable and less toxic methods for the synthesis of quinolines encouraged Faraz et al. to

develop a new eco-friendly and transition metal-free method by using TsOH.H

O as catalyst [62]. 4-

Arylquinolines were obtained in a three-component one-pot synthesis using arylamines, arylacetylenes and

dimethylsulfoxide (DMSO), in the presence of 20 mol% of TsOH.H

O. A variety of differently substituted

arylacetylenes were tested under the optimal conditions. It was observed that all reactions underwent well with

good to high yields of the final products (78 - 91 %), independently of their substituent.

Scheme 6: Reaction of substituted anilines, arylacetylenes and DMSO catalyzed by TsOH

Biological Activities Of Quinoline

Antimicrobial Activity

Rao et al., (2024) reported a one-pot synthesis, characterization, and antimicrobial activity of novel Quinolines.

A reaction mixture of 5,5-dimethylcyclohexane-1,3-dione 35, aromatic substituted benzaldehyde 36, and N-

phenylacetamide hydrate 37 was heated in 50mL of ethanol for 8 hours and monitored using TLC for

completion. Upon completion, the crude products were recrystallized using ethanol to obtain the target product

38 (Scheme 7) [63].

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Scheme 7: Synthetic route of quinoline derivatives.

The synthesized compounds were screened against Aspergillus niger, Aspergillus flavus, Aspergillus fumigatus,

and Candida albicans as fungal strains and Enterobacter cloacae, Staphylococcus haemolyticus, Bacillus

cereus, and Staphylococcus aureus as bacterial strains for their antimicrobial activity using the disc diffusion

assay. The results showed that compound 38d exhibited the lowest inhibition among all bacterial strains (Table

1), while compounds 38a, 38b, 38c, and 38e exhibited the highest inhibition for all strains when compared to

the reference drug, ciprofloxacin. Against the fungal strains, compound 38a exhibited the lowest activity,

while compounds 38d and 38e exhibited the maximum antifungal activity against all strains when compared to

fluconazole.

Table 1: Antibacterial activity of quinoline derivatives (38a-e)

No.

Bacterial

Zone of inhibition in mm

38a

38b

38c

38d

38e

Control (Dimethyl sulphoxide)

Enterobacter cloacae

Staphylococus Haemolytics

Bacillus cereus

Staphylococcus aureus

Ref: Ciprofloxacin

Recently, more quinoline derivatives were synthesized by Prashanth, et al., in 2025, they reported the multi-

step synthesis of 2-(quinolin-8-yloxy) acetate analogs (43a-j) by the esterification of quinolin-8-ol derivatives

(39a-j) with ethyl chloroacetate in the presence of potassium carbonate and dry acetone as solvent. This

afforded 2-(quinolin-8-yloxy) acetic acid ethyl esters (40a-j), which on further refluxing with sodium

hydroxide in ethanol yielded 2-(quinolin-8-yloxy) acetic acids (41a–j) [64]. Subsequently, compounds 41a-j

were further coupled with 1,2-diaminobenzene using TBTU (o-(benzotriazol-1-yl)- N,N,N',N'-tetramethyl

aminium tetrafluoroborate in the presence of dichloromethane as solvent and lutidine as base, to afford 2-[2-

(quinolin-8-yloxy) aceto] amino anilines (42a-j). On cyclization of compounds 42a-j with acetic acid, the

target products (43a-j) were obtained.

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Scheme 8: Synthesis of 8-((1H-benzo[d]imidazol-2-yl)methoxy) quinoline analogs (43a-j)

The synthesized compounds were subjected to antibacterial activity using five gram-positive bacterial

strains (Methicillin-resistant Staphylococcus aureus, Staphylococcus simulans, Staphylococcus epidermidis,

Staphylococcus aureus, and Enterococcus faecalis) and five gram-negative strains (Klebsiella pneumoniae,

Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, and Salmonella typhi). Results showed that

eight of the derivatives are active with inhibition zones against both gram-positive and gram-negative bacteria

(8-31 mm), comparable to those of vancomycin and ciprofloxacin which were positive controls and DMSO as

negative control. Compound 43i showed better activity against all gram-positive and four gram-negative

bacteria. Compounds 43e, 43g, and 43i inhibited gram-negative bacteria E. coli and P. aeruginosa better than

others, while compounds 43f, 43d, and 43j showed good inhibition activity against S. aureus and S.

aureus MRSA.

Ghorab et al., (2023) reported a one-pot synthesis of some novel 7-methoxyquinoline derivatives bearing a

sulfonamide moiety(46a-f) with antimicrobial activity. They achieved this by reacting to 4-chloro-7-

methoxyquinoline (44) with a series of sulfonamides (45a-f) in the presence of DMF. The reaction mixture

was refluxed for 2 hours to afford the target derivatives (46a-f) (Scheme 32) [65].

Scheme 9: Synthesis of novel 7-methoxyquinoline derivatives bearing sulfonamide moiety

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The synthesized compounds (46a-e) were screened for their antimicrobial potential against E. coli, P.

aeruginosa, S. aureus, B. subtilis, C. albicans, and C. neoformans and compared with a reference standard

drug, amoxicillin/clavulanic acid. The results revealed that compound 46f, bearing sulfamethazine, had the

highest effect on most of the tested bacterial and fungal strains when compared to the other derivatives.

Compounds 46c and 46d displayed moderate antimicrobial activity against the test bacteria and fungi.

Zieba et al., (2024) reported the synthesis, anticancer, and antimicrobial activities of quinoline-5-sulfonamide

derivatives(49a-f). The synthesis began with the treatment of 8-hydroxyquinoline (47) with chlorosulfonic acid

under stirring at room temperature for 3 hours to give 8-hydroxyquinoline-5-sulfonyl chloride (48). The

compound was further reacted with different amines containing an acetylene moiety in the presence of

acetonitrile, and the mixture was stirred for 2 hours at room temperature to afford the target products, 8-

hydroxyquinoline-5-sulfonamides (49a-f) (Scheme 10) [66].

Scheme 10: Synthesis of 8-hydroxyquinoline-5-sulfonamide derivatives

The synthesized compounds (49a-f) were screened for their antimicrobial activity against Staphylococcus

aureus and Enterococcus faecalis and for their anticancer activity against human amelanotic melanoma cells

(C-32), human breast adenocarcinoma cells (MDA-MB-231), and human lung adenocarcinoma cells (A549).

The results of the anticancer activity and the results showed that compound 49c had the highest activity against

human amelanotic melanoma cells (C-32), human breast adenocarcinoma cells (MDA-MB-231), and human

lung adenocarcinoma cells (A549) when compared to the reference standard drugs cisplatin. Compound 49a,

49b, 49d, 49e, and 49f displayed moderate anticancer activity against the three cancer cell lines. All the novel

derivatives (49a-f) demonstrated good antimicrobial activities against the tested bacterial strain,

Staphylococcus aureus and Enterococcus faecalis when compared to the reference standard drugs and

doxorubicin.

Saifi et al., (2025) reported the synthesis and antibacterial activities of novel quinoline-sulfonamide

derivatives. In this synthesis, 4,7-dichloroquinoline (50) was condensed with p-phenylenediamine (51) and m-

phenylenediamine (52) in the presence of the catalyst p-TSA and ethanol and heated for 3 hours to afford N-

(7-chloroquinolin-4-yl)-benzene-1,4-diamine (53) and N-(7-chloroquinolin-4-yl)-benzene-1,3-diamine (54).

Both compounds (53 and 54) were further reacted with different substituted benzenesulfonyl chlorides in the

presence of DMF and TEA, and the reaction mixtures were stirred at room temperature to 60°C for 12-16

hours to yield the target derivatives (55a-l) (Scheme 11) [67].

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Scheme 11: Synthesis of novel quinoline-sulfonamide derivatives

The synthesized compounds (55a-i) were evaluated for their antimicrobial activity against Gram-positive

bacterial strains, specifically E. faecalis, and Gram-negative strains, E. coli, P. aeruginosa, and S. typhi, and

compared with a reference standard drug, ciprofloxacin. The results revealed that compound 55c had the

highest inhibition property. The other compounds displayed moderate to low inhibition activity.

El-Shershaby et al., (2020) reported the synthesis and in vitro antimicrobial evaluation of novel quinoline

derivatives (60a-k). They began the synthesis with the treatment of p-methyacetanilide (56) with

dimethylformamide (DMF) and phosphorus oxychloride. The reaction mixture was then stirred at 0°C for 2

hours to yield quinoline-3-carbaldehyde derivatives (57). The quinoline-3-carbaldehyde derivatives (57) were

treated with hydroxylamine hydrochloride at 70°C for 2 hours to produce 2-chloro-6-methylquinoline-3-

carbonitrile (58). The compound (58) was further reacted with thiourea to yield 6-methyl-2-

mercaptoquinoline-3-carbonitrile (59). Finally, 6-methyl-2-mercaptoquinoline-3-carbonitrile (59) was treated

with various ester derivatives in the presence of potassium carbonate to neutralize the effects of the HCl side

product to yield the target products (60a-k) (Scheme 12) [68].

Scheme 12: Synthesis of new quinolines derivatives

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The synthesized compounds (60a-k) were evaluated for their antimicrobial activity against a range of

pathogenic microbes, including Gram-positive bacteria (Streptococcus pneumoniae and Bacillus subtilis),

Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus

fumigatus, Syncephalastrumracemosum, Geotrichumcandidum, and Candida albicans). The compounds that

demonstrated the best activity were subjected to further biological studies to determine their minimum

inhibitory concentrations (MICs) against the selected pathogens. Additionally, the in vitro activity against E.

coli DNA gyrase was assessed to determine whether their antimicrobial action is mediated through the

inhibition of this enzyme. The result showed that 60c, 60f, 60g, and 60i exhibit relatively potent antimicrobial

activity with MIC values ranging from 0.66 to 5.29 μg/mL. Compound 60c showed broad-spectrum

antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values between 0.66

and 3.98 μg/mL.

Singh et al., (2024) reported the design, synthesis and antimicrobial activity of novel quinoline derivatives

(65a-e). They achieve this by reacting to aromatic amine (61) with acetoacetate (62) in the presence of H

as a catalyst. The reaction mixture was stirred at 140-150℃ for 3-4 hours to give 6-amino-4-methyl-1H-

quinoline-2-one (63). The compound (63) was further reacted with benzenesulphonyl chloride/benzoyl

chloride (64a-e) in the presence of DCM and stirred overnight at room temperature to afford the target

products (65a-e) (Scheme 13) [69].

Scheme 13: Synthesis of new quinoline derivatives

These new synthesized compounds (65a-e) were evaluated for their in vitro antibacterial and antifungal

activity. Antibacterial screening of all compounds showed excellent MIC value (MIC, 50 -3.12μg/mL) against

bacteria strains such as Bacillus cerus, Staphylococcus, Psedomonasand Escherichia coli. Compound 65b and

65e showed better activity. Furthermore, antifungal screening against fungal strains such as A. flavus, A. niger,

F. oxysporum, and C. albicans also revealed that all compounds were potentially active, and compound 65e

being most potent.

Al-Matarneh et al., (2024) reported the synthesis of iodo-quinoline derivatives(69a-j) and their antimicrobial

activity. In this reaction, iodo-aniline (66) and pyruvic acid (67) were reacted with various aldehydes (68a-j) in

the presence of acetic acid and TFA under reflux for 12 hours. The crude products were then recrystallized

using dichloromethane and ethanol to obtain the target products (69a-j) (Scheme 14) [70].

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Scheme 14: Synthesis of Iodo-quinoline derivatives

The synthesized compounds (69a-j) were evaluated for their in vitro antimicrobial activity against S.

epidermidis, K. pneumonia and C. parapsilos and the result suggested that the new derivatives are interesting

scaffolds for the development of novel antimicrobial agents.

Antitubercular Activity

Abdelrahman et al., in 2022 reported the multiple-step synthesis, characterization, and antitubercular activity

of quinoline-isatin conjugates. The reaction began with the condensation of 3-chloroaniline 70a and 4-

chloroaniline 70b with diethyl ethoxymethylene malonate to yield ethyl anilinomethylene malonate 71a-b, and

on cyclization with diphenyl ether, it yielded ethyl esters of 4-hydroxyquinoline-3-carboxylic acids 72a-b. On

further reaction with hydrazine hydrate in the presence of ethanol, acid hydrazides 73a-b were obtained. To

afford the target products 75a-b and 77a-b, the hydrazine derivatives (13a-b) were further condensed with

various 5-substituted isatins (74a-d) or N-substituted isatins (76a-d) in glacial acetic acid [71].

Scheme 15: Synthetic routes for Quinoline-isatin conjugates 74a-b and 76a-b

They further investigated the anti-tubercular activity of the novel target compounds against RCMB 010126 M.

tuberculosis, the MDR strain (FJ05120), and the XDR strain (FJ05195) using isoniazid as a reference. The

result showed that the derivatives have potent to moderate anti-M. tuberculosis activity, with the MICs ranging

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between 0.06 and 7.81 g/mL, except for 75c and 77d with MICs of 31.25 and 15.63µg/mL, respectively.

Compound 77b showed a 100-fold increase in activity in terms of growth inhibition towards M. tuberculosis

with a MIC of 0.06g/mL, and compound 77h showed excellent anti-mycobacterial action with a MIC value of

0.12µg/mL that equals the MIC for the reference drug, isoniazid.

Against both MDR and XDR M. tuberculosis strains, derivatives 77b and 77h showed excellent antitubercular

activity with MIC values of 0.24µg/mL and 0.98µg/mL for MDR and 1.95µg/mL, 3.9µg/mL for XDR,

respectively. Compounds 75a, 75b, 77a, 77c, 77e, and 77f showed good activity against the MDR strain with

MIC values of 3.9, 3.9, 7.81, 3.9, 7.81, and 7.81µg/mL while compounds 75a, 75b, 75c, and 75f showed

moderate activity against the XDR strain with a MIC range from 7.81 to 15.63µg/mL.

Antimalarial Activity

Lagdhir et al., (2021) reported the design and synthesis of new quinoline hybrid (84a-l) derivatives with

antimalarial properties. The synthesis began with the treatment of acetanilide (78) with POCl

in the presence

of DMF. The reaction mixture was stirred at 80°C for 6 hours to obtain 2-chloroquinoline-3-carbaldehyde (79).

This compound (79) was then reacted with tert-butyl piperazine-1-carboxylate (80) and heated at 110°C for 5

hours, resulting in tert-butyl 4-(3-formylquinolin-2-yl) piperazine-1-carboxylate (81). This was followed by

reacting compound (81) with amines (82a-l) in the presence of acetic acid and NaCNBH

and the mixture was

stirred at room temperature for 2 hours, yielding tert-butyl 4-(3-phenylamino) methyl(quinoline-2-yl)

piperazine-1-carboxylate derivatives (83a-l). Finally, the target products (84a-l) were obtained by treating

these compounds (83a-i) with 1,4-dioxane and stirring at room temperature for 2 hours [72].

Scheme 16: Synthesis of new quinoline hybrid

All synthesized compounds (84a-l) were screened for in vitro antimalarial activity against the Plasmodium

falciparum 3D7 chloroquine-sensitive strain, and their activity was compared to that of a reference standard

drug, Quinine/Chloroquine. The results indicatede that compounds (84a-l) exhibited moderate antimalarial

activity.

Touré et al., (2024) reported the synthesis and in vitro/in silico evaluation of the antimalarial activity of

potential amino-quinoline derivatives. They achieve this by reacting to 4,7-dichloroquinoline (85) with various

amines (86a-d) in the presence of absolute ethanol. The mixture was stirred under reflux at room temperature

for 4 hours to obtain 4-arylamino-7-chloroquinoline (87a-d). The compounds (87a-d) were further reacted

with substituted brominated benzyl derivatives (88a-p) in the presence of MeCN/DMF or DIPEA/K

and

stirred for 5-24 hours at 100℃ to afford the target products, N-aryl-N-benzylamino-7-chloroquinoline (89a-t)

[73].

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Scheme 17: Synthesis of N-aryl-N-benzylamino-7-chloroquinoline

The synthesized compounds (89a-t) were evaluated to have their antimalarial efficacy against chloroquine-

sensitive (Pf3D7) and chloroquine-resistant (PfW2) Plasmodium falciparum strains. The result showed that

compound 89i and 89c have promising efficacy against the Pf3D7 strain with IC

values of 0.25 μM and 0.54

μM, respectively, while compound 89l demonstrated significant activity against the PfW2 strain with an IC

of 5.82 μM.

Choudhary et al., (2024) reported the synthesis of novel anti-plasmodial quinoline-furanone hybrids (96a-h,

97a-h, 98a-h, 99a-h) through a multi-step process. Initially, succinic anhydride (90) was reacted with various

aromatic compounds (2-methoxy-naphthalene, diphenyl ether, diphenylmethane, and methoxy methyl

benzene) (91a-d) in the presence of anhydrous aluminum chloride and dry nitrobenzene. The mixture was

heated and stirred at room temperature for 2-3 hours to yield β-aryl propionic acid (92a-d). In a separate step,

acetophenone (93a-h) was treated with hydroxylamine hydrochloride, sodium acetate, ethanol, and sufficient

water. The reaction mixture was refluxed in a water bath for 3-6 hours at 100°C to obtain 4-substituted-1-

phenylethanone oxime (94a-h). This intermediate was then treated with DMF and phosphorus oxychloride

under stirring for 16 hours at 50-60°C to give substituted 2-chloroquinoline-3-carbaldehydes (95a-h). Finally,

β-aryl propionic acid (92a-d) was reacted with aromatic aldehydes (95a-h) in the presence of acetic anhydride

and triethylamine and the reaction mixture was heated for 5 minutes under anhydrous conditions to yield the

target products 3-{(2-chloro-6-substituted-quinolin-3-yl)methylene}-5-(aryl-2-yl)-furan-2(3H)-one (96a-h,

97a-h, 98a-h, 99a-h) [74].

Scheme 18: Synthesis of quinoline-furanone hybrids

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The synthesized compounds (96a-h, 97a-h, 98a-h, 99a-h) were studied for their antimalarial properties against

the resistant strain of Plasmodium through Schizont Maturation Inhibition assays. Among the compounds

tested, 96g and 97e demonstrated the best activity, with IC

values like chloroquine (CQ), and 96g exhibited

superior LDH inhibition compared to CQ. Compounds 96f, 98a, and 98f showed IC

values comparable to CQ

and moderate LDH inhibition. Structure-activity relationship (SAR) analysis revealed that halogen

substitutions, particularly Br and Cl, enhanced antimalarial activity, while strong electron-withdrawing (–NO

)

or -donating (–OH) groups led to diminished activity. Additionally, bulkier aromatic substitutions were

favored for antimalarial activity and LDH inhibition. The investigation successfully found potent anti-

plasmodial quinoline–furanone hybrids, demonstrating promising prospects for combating malaria.

Anticancer Activity

Zaraei et al., (2022) reported the design and synthesis of novel quinoline derivatives (110m-P) exhibiting

potent anticancer activity. The synthesis began with the reduction of the nitro group in 4-(benzyloxy)-5-

methoxy-2-nitrobenzaldehyde (100) to its corresponding amino derivative (101) using iron and hydrochloric

acid. In a separate reaction, 4-nitrophenol (102) was reacted with chloroacetone (103) in the presence of

potassium carbonate. The reaction mixture was refluxed for 5 hours to yield 1-(4-nitrophenoxy) propan-2-one

(104). This was followed by a Friedländer cyclization reaction between the o-aminobenzaldehyde derivative

(101) and 1-(4-nitrophenoxy) propan-2-one (104) in refluxing ethanol, using piperidine as a catalyst, to

produce the 3-(4-nitrophenoxy) quinoline intermediate (105). The subsequent step involved acid-catalyzed

benzyl ether deprotection using a hydrochloric acid and acetic acid, yielding the 7-quinolinol intermediate

(106). The hydroxy group in the compound (106) was then reacted with (2-chloroethyl) dimethylamine or 4-

(2-chloroethyl) morpholine (107a-b) in the presence of potassium carbonate. The reaction mixture was stirred

overnight to obtain the nitro intermediate (108a-b), which was later converted to the corresponding aniline

derivatives (109a-b) under a hydrogen atmosphere using Pd/C as a catalyst at room temperature. Finally,

compounds (109a-b) were reacted with aryl isocyanate to produce the target diarylurea-containing compounds

(110a-l). Additionally, they reacted with appropriately substituted benzoic acid derivatives using 1-

hydroxybenzotriazole (HOBt), EDCI, and TEA to yield the target diarylamide-containing compounds (110m-

P) (Scheme 19) [75].

Scheme 19: Synthesis of new quinoline derivatives

The synthesized compounds (110a-p) were screened for their anticancer activities, and the results showed that

compounds 110j-l had the highest mean inhibition percentage values over the 60-cell line panel at 10 µM with

broad-spectrum antiproliferative activity. Subsequently, compounds 110j-l were subjected to a dose-response

study to measure their GI50 and total growth inhibition (TGI) values against the cell lines. Three of the tested

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molecules exerted higher potency against most of the cell lines than the reference drug, sorafenib. Compound

110l indicated higher potency than sorafenib against the tested cancer cell lines. Compounds 110j-l

demonstrated promising selectivity against cancer cells rather than normal cells. Moreover, compound 110l

induced apoptosis and necrosis in the RPMI-8226 cell line in a dose-dependent manner.

Khodair et al., (2024) reported the synthesis and anticancer activity of novel benzo[h]quinoline

derivatives(116a-d). The compounds were synthesized by reacting α-naphthylamine (111) with an appropriate

aldehyde (112a-d) and malononitrile (113) in the presence ofethanol, and a catalytic amount of potassium

trioxocarbonate (IV). The mixture was refluxed at room temperature for 24 hours to obtain amino-

benzo[h]quinoline-3-carbonitriles (114a-d). The compounds (114a-d) were further treated with formic acid

and a few drops of HCl, then refluxed for 30 minutes to yield compounds (115a-d). In a separation reaction,

amino-benzo[h]quinoline-3-carbonitriles (114a-d) were treated with acetic anhydride and a few drops of HCl,

then refluxed for 30 hours to yield the target compounds (116a-d) (Scheme 20) [76].

Scheme 20: Synthesis of novel Benzo [h] quinoline Derivatives

They evaluated the synthesized compounds (114a-d, 115a-d & 116a-d) for their anticancer activities. Among

all tested compounds compound 114b and compound 116c exhibited the strongest activity, especially against

melanoma compared to the standard imatinib.

Srinivasa et al., (2024) reported the synthesis and anticancer activity of novel benzimidazole containing

quinoline hybrids (127a-f). Isatin (117) was reacted with 3,5-difluoroacetophenone (118) in the presence of

potassium hydroxide and ethanol. The reaction mixture was heated under reflux for 4 hours to obtain 2-aryl-

quinoline-4-carboxylic acid (119). In a separate reaction, ethyl 4-chloro-3-nitrobenzoate (120) was reacted

with a substituted amine (121) in the presence of THF and triethylamine, and the reaction mixture was stirred

overnight at room temperature to afford ethyl 4-(alkylamino)-3-nitrobenzoate (122). This was followed by

treating ethyl 4-(alkylamino)-3-nitrobenzoate (122) with 5-bromothiophene in the presence of sodium

dithionite, DMSO, and the reaction mixture was stirred at 90°C for 3 hours to yield ethyl 2-(5-bromothiophen-

2-yl)-1-alkyl-1H-benzo[d]imidazole-5-carboxylate (123). The compound (123) was then reacted with

hydrazine hydrate in ethanol and refluxed on an oil bath for 10 hours to yield 2-(5-bromothiophen-2-yl)-1-

alkyl-1H-benzo[d]imidazole-5-carbohydrazide (124). Finally, compound (124) was reacted with quinoline-4-

carboxaldehyde (125) in the presence of glacial acetic acid, and the reaction mixture was stirred and refluxed

for about 3 hours to afford 2-(5-bromothiophen-2-yl)-1-alkyl-N-[quinoline-4-ylmethylene]-1H-

benzo[d]imidazole-5-carbohydrazide (126a-c).In a separate reaction, compound (124) was reacted with 2-aryl-

quinoline-4-carboxylic acid (119) in the presence of THF, TBTU, and TEA, and stirred for about 30 minutes to

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afford 2- (5-bromothiophen-2-yl) -1-alkyl-1H-benzo [d] imidazole -5-carbohydrazide-2-(3,5-fluorophenyl)

quinoline-4-carboxylate (127a-f) (Scheme 21) [77].

Scheme 21: Synthesis of benzimidazole-quinoline hybrids

The novel derivatives (126a-c & 127a-f) were screened (in-silico and in-vitro) for their anti-cancer activities

(human melanoma cell line (A375) and human breast cancer cell line (MDA-MB-231) and compared with a

reference standard drug, cisplatin. The result showed that compounds 126a, 127a and 127b have significant

cytotoxicity against these human cancer cell lines (melanoma and breast cancer) and can be potential anti-

cancer molecules.

Shaldam et al., (2021) reported the synthesis of novel quinoline-based sulfonamides (138a-d, 139a-d, and

140a-e) as anticancer agents. The synthesis began with the treatment of malonic acid (128) with acetic

anhydride in the presence of acetone and concentrated H

. The reaction mixture was stirred at room

temperature to yield 2,2-dimethyl-1,3-dioxane-4,6-dione (129). The compound was then heated with triethyl

orthoformate under reflux for 3 hours to give 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (130).

Compound (130) was further reacted with substituted anilines (131a-d) in the presence of DMF under reflux

for 2 hours to afford 5-(phenylaminomethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (132a-d). This was

followed by cyclization of compounds (132a-d) via microwave irradiation at 250 ℃ for 10-15 minutes to

produce 4-hydroxyquinolines (133a-d). Compounds (133a-d) were further converted to the corresponding 4-

chloroquinoline derivatives (134a-d) by heating with excess phosphorus oxychloride for 4 hours. Finally, 4-

chloroquinoline derivatives (134a-d) reacted with different aminobenzenesulfonamide derivatives (135, 136,

and 137a-d) in the presence of a catalytic amount of HCl under reflux to yield the corresponding target

derivatives (138a-d, 139a-d, and 140a-e) (Scheme 22) [78].

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Scheme 22: Synthesis of novel quinoline-based sulfonamide

The synthesized compounds (138a-d, 139a-e and 140a-d) were screened for their CA inhibitory action against

hCA I, II, IX, and XII, and the results showed that 191a-c had the best inhibitory activity against both cancer-

related isoforms hCA IX (Kis = 25.8, 5.5, and 18.6 nM) and hCA XII (Kis = 9.8, 13.2, and 8.7 nM),

respectively.

Marciniec et al., (2023) reported the design, synthesis, and anticancer activity of quinoline-8-sulphonamide

derivatives (145a-b). They achieved this by the reaction of propargylamine or N-methylpropargylamine (141a-

b) with 8-quinolinesulfonyl chloride (142) in the presence of triethylamine and chloroform. The reaction

mixture was stirred at room temperature for 2 hours to give 8-N-substituted (prop-2-ynyl) quinoline

sulfonamide (143a-b). The compound (144a-b) was further reacted with 4-azido-7-chloroquinoline (145) in

the presence of sodium ascorbate, CuSO

·5H

O, and DMF, and the reaction mixture was stirred overnight at

room temperature to afford the target derivatives (146a-b) (Scheme 23) [79].

Scheme 23: Synthesis of quinoline-8-sulphonamide derivatives

The synthesized compounds (145a-b) were studied for their anticancer properties using in silico and in vitro

assays. The results from the in silico studies revealed that compound 145a is a potent modulator of muscle

isoform 2 of pyruvate kinase. The in vitro experiment confirmed the ability of compound 145a to reduce the

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intracellular pyruvate level in A549 lung cancer cells, with a simultaneous impact on cancer cell viability and

cell-cycle phase distribution.

Anti-Inflammatory Activity

Ghanim et al., (2022) reported the design and synthesis of an ibuprofen-quinoline conjugate (153a-d and

154a-d) with potential anti-inflammatory activity. They reacted substituted aniline (146a-d) with ethyl 4,4,4-

trifluoro-3-oxobutanoate (147) in the presence of polyphosphoric acid. The reaction mixture was stirred at

150°C for 2 hours, forming 6-substituted-2-(trifluoromethyl)quinoline-4(1H)-ones (148a-d). These compounds

(148a-d) were then treated with dibromoalkane (149) in the presence of anhydrous potassium trioxocarbonate

(IV) and DMF and stirred for 6-8 hours at room temperature to yield 6-substituted-2-

(trifluoromethyl)quinoline derivatives (150a-d & 151a-d). Subsequently, the bromo-derivatives (150a-d &

151a-d) reacted with ibuprofen (152), which was dissolved in DMF and anhydrous potassium trioxocarbonate

(IV) and the reaction mixture was subjected to microwave irradiation (20 W) at 70°C for 2 hours to afford the

target products (153a-d and 154a-d) (scheme 24) [80].

Scheme 24: Synthesis of ibuprofen-quinoline conjugate

The synthesized conjugates (153a-d and 154a-d) were screened for their anti-inflammatory and ulcerogenic

properties. The results showed that several conjugates exhibited significant anti-inflammatory properties in the

carrageenan-induced rat paw edema test without demonstrating any ulcerogenic liability. Compounds 153a,

153b, and 153c displayed potent anti-inflammatory properties comparable to those of their precursor,

ibuprofen. Moreover, conjugates 153b and 153c did not exhibit ulcerogenic liability. The most promising anti-

inflammatory agents were evaluated in vitro as COX-1/COX-2 inhibitors, and the results revealed considerable

selectivity toward COX-2 compared to ibuprofen.

Silva et al., (2024) reported the synthesis, in vitro, and in silico anti-inflammatory activity of new

thiazolidinedione-quinoline derivatives (161a-c). They achieved this synthesis by reacting to 2-chloroacetic

acid (155) with thiourea (156) in an aqueous medium under reflux and agitation at 90°C for 24 hours to yield

thiazolidine-3,4-dione (157). The compound (157) was further reacted with substituted benzaldehyde (158) in

the presence of acetic acid and ammonium acetate. The reaction mixture was heated at 110°C for 5-8 hours to

obtain 5-aryl-2,4-thiazolidinedione (159). Finally, the target products (161a-c) were obtained by reacting 5-

aryl-2,4-thiazolidinedione (159) with 2-chloromethyl-quinoline (160) in the presence of sodium hydroxide and

ethanol at 70°C under reflux and stirring (scheme 25) [81].

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Scheme 25: Synthesis of new thiazolidinedione-quinoline derivatives

The synthesized compounds (161a-c) were screened for their anti-inflammatory activities using various assays,

including cell viability testing (MTT), ELISA for IFN-γ and TNF-α, adipogenic differentiation, and molecular

docking with PPARγ and COX-2 targets. The results showed that they exhibited a significant, dose-dependent

decrease in IFN-γ and TNF-α concentrations. At a concentration of 50 μM, the compounds (161a-c)

significantly reduced IL-6 expression. Furthermore, the compounds demonstrated lipid accumulation with

significant differences between the untreated and negative control groups, indicating relevant agonist action on

the PPARγ receptor. Molecular docking revealed that all synthesized compounds (161a-c) exhibited good

affinity for PPARγ and COX-2, with binding energies approaching -10,000 kcal/mol.

Villarrel-Vicente et al., (2024) reported the synthesis of new 2-prenylated quinolines (167) as potential anti-

inflammatory drugs. The synthesis began with the treatment of 5-hydroxy-2-nitrobenzaldehyde (162a-b) with

benzyl chloride in a basic medium, followed by refluxing for 4 hours to yield 5-benzyloxy-2-

nitrobenzaldehyde. Subsequent reduction of the ortho-nitrobenzaldehyde with iron powder in aqueous HCl and

ethanol, refluxed for 30 minutes, gave the intermediate compound (163). The quinoline nucleus (164) was then

formed through a Friedländer reaction, involving the condensation of the ortho-aminobenzaldehyde

intermediate (163) with ethyl levulinate in the presence of pyrrolidine as catalyst under refluxed for 4 hours to

give quinoline ester (164). The resulting quinoline ester (164) was further reduced using DIBAL-H in

dichloromethane to obtain aldehyde (165). Finally, introduction of the prenylated hydrocarbon side chain (166)

was achieved through an efficient Grignard reaction with isopropenylmagnesium bromide, and this reaction

was followed by Johnson-Claisen rearrangement with triethyl orthoacetate and catalytic amounts of isobutyric

acid, yielding the target product 2-prenylated quinoline (167) (scheme 26) [82].

Scheme 26: Synthesis of 2-prenylated quinoline

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They screened the synthesized compound 167 for its anti-inflammatory properties, and the result showed that

compound 167 has anti-inflammatory effects on macrophages by reducing LPS-induced expression of

both MCP-1 and IL-6.

Antioxidant Activity

Zeleke et al., (2020) reported the synthesis and antioxidant activities of some novel quinoline derivatives

(172a-d). They achieve this by the reaction of aniline (168) and acetic anhydride (169) in the presence of zinc

powder and acetic acid under reflux for 1 hour to give acetanilide (170). The compound (170) was then treated

by heating with N,N-dimethylformamide and phosphorus oxychloride at a temperature of 85-90 ℃ for 22

hours to give 2-chloroquinoline-3-carbaldehyde (171).The derivatives of 2-chloroquinoline-3-

carbaldehydederivatives (172a-d) were obtained by reacting 2-chloroquinoline-3-carbaldehyde (171) with

alcohol, potassium carbonate, N,N-dimethylformamide, and potassium thiocyanate under reflux for 5 hours

(Scheme 27) [83].

Scheme 27: 2-chloroquinoline-3-carbaldehydederivatives

The radical scavenging activity of these compounds (172a-d) was evaluated using 1,1-diphenyl-2-picryl

hydrazyl (DPPH), and all of them displayed moderate antioxidant activity,with compound 172c exhibiting the

strongest activity.

Abdi et al., (2021) reported the synthesis and evaluation of novel chloroquinoline analogs. 3-chloroaniline

(173) was reacted with acetic anhydride (174) in the presence of zinc powder and acetic acid. The mixture was

boiled under reflux using a water condenser for 2 hours to give 3-chloroacetanilide (175). The compound (175)

was then treated by heating with N,N-dimethylformamide and phosphorus oxychloride at a temperature of

100-105 ℃ for 22 hours to give 2,7-dichloroquinoline-3-carbaldehyde 176). Finally, the derivatives of 2,7-

dichloroquinoline-3-carbaldehyde (177a-d) were obtained by treating 2,7-dichloroquinoline-3-carbaldehyde

(176) with alcohol, potassium carbonate, and N,N-dimethylformamide under reflux for 4 hours to yield

compound (177c-d), while compound 177a was obtained by treating 2,7-dichloroquinoline-3-carbaldehyde

with phosphorus oxychloride and sodium azide under reflux for 6 hours, and upon further treatment of

compound 177a with acetic acid and tetraoxosulfate (VI) acid under reflux for 3 hours, 177b was formed

(Scheme 28) [84].

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The synthesis compounds (177a-d) were evaluated for their antioxidant activityusing 1,1-diphenyl-2-

picrylhydrazyl (DPPH), and compounds 177a and 177b displayed the strongest antioxidant activity with IC

of 2.17 and 0.31 µg/mL relative to ascorbic acid (2.41 µg/mL), respectively.

Asran et al., (2023) reported the synthesis and antioxidant activity of some benzoquinoline-based heterocycles

derived from 2-((3-chlorobenzo[f]quinoline-2-yl)methylene)hydrazine-1-carbothioamide (183). The synthesis

was achieved by reacting 3-chlorobenzo[f]quinoline-2-carbaldehyde (178) with thiosemicarbazide (179) in the

presence of absolute ethanol and glacial acetic acid under reflux for 3 hours. The resulting solid crude

compound was recrystallized from an ethanol/dioxane mixture (2:1) to yield 2-((3-chlorobenzo[f]quinolin-2-

yl)methylene) hydrazine-1-carbothioamide (180). The new derivatives (183a-d) were subsequently obtained

by treating the compound (180) with various reagents, including acetic anhydride under reflux for 6 hours, a

mixture of chloroacetyl chloride, dioxane, and triethylamine at ambient temperature for 5 hours, a mixture of

chloroacetyl chloride, dioxane, and anhydrous sodium acetate under reflux for 6 hours, a mixture of 2-bromo-

1-(3-nitrophenyl)ethan-1-one (181), dioxane, and anhydrous sodium acetate under reflux for 5 hours, and a

mixture of 2-chloro-N-phenylacetamide (182), dioxane, and sodium acetate under reflux for 6 hours, yielding

compounds 183a, 183b, 183c, 183d, and 183e, respectively [85].

Scheme 19: Synthesis of Benzoquinoline‑Based Heterocycles Derivatives

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The synthesized compounds 183a-e were examined for antioxidant activity according to phosphomolybdenum

method using ascorbic acid as standard. The results showed that the compounds have good antioxidant

activity. Compounds 183d and 183e displayed the highest potent levels of activity.

CONCLUSION

Over the years, many researchers have synthesized quinoline and its derivatives via various methodologies.

This review focuses on the recent advancements in quinoline synthesis and their biological activities.

Quinoline derivatives are versatile heterocyclic compounds that possess a wide range of biological activities,

such as anticancer, antimycobacterial, antimicrobial, anticonvulsant, anti-inflammatory, and cardiovascular

activities. This work illustrates different synthetic methods of quinoline derivatives, such as Friedlander-

modified metal-catalyzed reactions, photo-induced oxidative annulation reactions, and microwave-assisted

Doebner reactions. The therapeutic potential of quinoline derivatives has drawn increasing attention from

researchers in the fields of medicinal chemistry, pharmacy, and biochemistry. This review aims to provide

useful insights for researchers seeking to advance the development of quinoline derivatives with enhanced

biological activities via environmentally benign methods.

Conflicts of Interest: The Authors declare no potential conflict of interest concerning the contents, authorship,

and/or publication of this article.

Authors Contributions: All authors have equal contributions in the preparation of the manuscript and

compilation.

Source of Support: Nil

Funding: The authors declared that this study has received no financial support.

Informed Consent Statement: Not applicable.

Data Availability Statement: The data supporting this paper is available in the cited references.

Ethical Approvals: Not applicable

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