Current progress toward synthetic routes and medicinal significance of quinoline

Quinoline motifs are essential in several pharmacological active heterocyclic compounds due to their various applications in medicinal and industrial chemistry. Furthermore, there are greater societal expectations in the current scenario that synthetic and medicinal chemists should produce greener and more sustainable chemical processes. Therefore, this mini-review article highlights the traditional and green synthetic approaches of quinoline and its analogs, including multicomponent one-pot reactions and solvent-free reaction conditions utilizing microwave and ultraviolet irradiation-promoted synthesis using eco-friendly and safe reusable catalysts, in addition to discussing the medicinal importance of quinoline derivatives such as anticancer, antioxidant, anti-inflammatory, antimalarial, anti-SARS-CoV-2, and antituberculosis activities within the period from 2011 till 2021. Therefore, the quinoline scaffolds signify a unique class of pharmacophores present in various therapeutic agents.


Introduction
Quinoline is a nitrogen-based heterocyclic aromatic compound with systematic IUPAC name as benzo[b]pyridine or 1-aza-naphthalene with the C 9 H 7 N chemical formula.It exhibits chemical reactivity similar to the benzene and pyridine ring system as it undergoes nucleophilic and electrophilic substitution reactions [1].
Owing to this wide range of applications, quinoline chemistry has attained the synthetic and medicinal chemists' efforts; therefore, many studies discussed synthetic protocols succeeding quinoline and its analogs, such as conventional methods, but these pathways suffer from non-environmental reagents, generating a significant quantity of waste, long reaction times, and objectionable byproducts which lead to undesirable yields [30]; so, the scientific communities urgently needed to create green and more feasible chemical reactions utilizing unconventional reaction media, energy sources, and safe catalysts to synthesize quinoline derivatives [31].
Based on our interests and efforts in the green synthetic organic and medicinal chemistry research field [32][33][34][35][36][37], in the present mini-review, we exhibit an overview of the classical and novel strategies for various quinoline compounds production, including multicomponent one-pot reactions, electrophilic annulation, oxidative and radical-promoted cyclization, cascade reactions, solvent-free reaction conditions under microwave and ultraviolet irradiation-promoted synthesis using eco-friendly and safe reusable catalysts in addition to explaining their various pharmacological properties including anticancer, antioxidant, anti-inflammatory, antimalarial, anti-SARS-CoV-2, and antituberculosis activities within the period from 2011 till 2021.

Traditional synthetic routes of quinolines
Traditional methods are summarized in Fig. 2. Ferdinand Runge was the first researcher to isolate quinoline from coal tar in 1834.Since then, the primary source of industrial quinoline remains coal tar.Up to this time, the preparation of quinoline and its derivatives has fascinated many researchers.Quinoline production has been described in numerous traditional reactions such as the Skraup method that involved the heating of aromatic amine with glycerol in sulfuric acid, which acted as a dehydrating agent that converted glycerol to acrolein, and PhNO 2 and oxidizing agent, which finally converted 1,2-dihydroquinoline into quinoline [38].
The Friedländer condensation of 2-aminoarylaldehyde with α-carbonyl molecule bearing a reactive a-methylene group in the presence of sodium ethoxide (10 mol%) as a catalyst has been developed to produce different polysubstituted quinolines.The tetrahydroacridine derivatives and 11H-indeno [1,2-b]quinolines achieved good yields ranging from 51 to 93%.Friedländer reactions were performed in entirely anhydrous ethanol with sodium ethoxide under reflux for about 2-3 h [39].2-Aminoarylketones underwent condensation with α-methylene ketones in the presence of 10 mol% poly(ethylene glycol) (PEG)-supported sulfonic acid under moderate reaction conditions to generate good yields of polysubstituted quinolines.A catalytic amount of PEG-supported sulfonic acid was used to perform the Friedlaender condensation of 2-aminoacetophenone with ethyl acetoacetate to obtain ethyl 2,4-dimethylquinoline-3-carboxylate at room temperature in various solvents such as CH 3 OH, Et 2 O, CH 3 CN, and CH 2 Cl 2 .It was reported that the best results were achieved when the reaction was carried out in CH 2 Cl 2 at reflux room temperature for 40 min in the presence of 10 mol% PEG-supported sulfonic acids, resulting in a 96% yield [40]. Cu−mesoporous organic nanorod was employed to synthesize quinoline via the Frieldländer method.The catalyst successfully catalyzes the one-pot sequential multi-step oxidative dehydrogenative coupling of 2-aminobenzyl alcohol with various aromatic ketones to give high yields of quinolines up to 97% [41].Doebner reaction produced quinoline derivatives through two mechanisms.The first was an aldol condensation between the aldehyde and pyruvic acid to give a β,γ-unsaturated α-keto acid, which subsequently underwent a Michael addition with aniline, and the second mechanism involved the formation of a Schiff's base from the 1,2-addition of the aniline to aromatic aldehyde which was subjected to Mannich reaction with pyruvic acid.Doebner-von Miller mechanism involved the condensation of aniline derivatives with an α,β-unsaturated ketones, and then, the fragmentation to the corresponding imine occurred.The fragments were recondensed to the conjugated imine followed by nucleophilic addition to another aniline molecule [42]; the Pfitzinger reaction, which entails condensation in an alkaline medium of an isatin and a ketone with the general Fig. 1 Examples of natural products and approved drugs with a quinoline ring system formula RCOCH 2 R', was employed throughout to create these quinoline derivatives [43,44].Riehm, Combes, Povarov hour methods synthesized quinoline derivatives [45][46][47][48].Gould-jacobs reaction, which is a method for the synthesis of 4-hydroxyquinolines via the condensation of aniline with alkoxy methylene malonic ester by cyclization and subsequent decarboxylation and this protocol was developed by using new techniques such as microwave [49] as indicated in (Fig. 2), There are many proven protocols for the production of the quinoline group, which can be widely Lewis acids-catalyzed synthesis of quinoline 1-(2,4-Dimethylquinoline-3-yl) ethenone 1 was produced when 1-(2-aminophenyl) ethenone reacted with pentane-2,4-dione using 4-toluenesulfonic acid (TsOH.H 2 O), magnesium chloride (MgCl 2 .6H 2 O), or cupric nitrate (Cu (NO 3 ) 2 .3H 2 O) as a catalyst at 80 °C (Scheme 1) [50] in fair yield.The treatment of anthranil with 1,3-diphenylpropane-1,3-dione resulted in quinoline cyclization producing 2-Phenyl-3-benzoylquinoline 2 (Scheme 2) [51].The reaction of aniline and polyhydric alcohols or monohydric alcohols had quinoline 3-5 (Scheme 3) [52].Quinoline 6 was created by Friedlander reaction in solvent-free conditions between 2-amino aryl ketones and ketones at 84-85 °C in good yield (Scheme 4) [53].
The condensation of p-nitroaniline synthesized Nitroquinoline derivatives 9, benzaldehyde derivatives, and phenylacetylene under air atmosphere, room temperature, and constant stirring using anhydrous acetonitrile as solvent.NbCl 5 was used in the proportion of 50% for each mole of benzaldehyde derivative used.Reduction of the nitro group in the nitroquinoline derivatives was conducted with hydrazine monohydrate in the presence of 10% Pd/C (Scheme 7) [56].

Synthesis of functionalized quinoline
The synthesis of quinoline by quinoline N-oxide Consequently, there is a substantial supply of new methods to synthesize structurally and mechanically complex quinolines efficiently.In this context, the existing activities of organic production rely more on the direct functionalization of the quinoline scaffold than on the development of this center from the methods of cyclocondensation or cyclization.Easy quinoline N-oxides have populations more significant as an ideal substrate to change this N-heterocycle because of the capacity of the N-oxide moiety to act as a directing group to conduct and regulate the region-selectivity of the C-H functional groups, being widely available or readily manufactured at multi-gram scale in the lab.Use of reactions between quinoline N-oxides and various acrylates with N-oxide alkenylation, high quinoline production was developed 10 (Scheme 8) [57].Over microwave irradiation at 120 °C, quinoline N-oxide and p-methoxybenzene diazonium tetrafluoroborate in acetonitrile contribute to producing a C2-aminated quinoline 11 (Scheme 9) [58].Olefination of 2-methyl substituted quinoline N-oxide with ethyl acrylate in the involvement of Cu(OAc) 2 at 90 °C generated high yielded quinoline derivatives (12, 13) (Scheme 10) [59].

Synthesis of quinolines using a non-metal catalyst
Quinoline derivatives 15 were produced in the presence of iodine by the reaction of amino acids and aniline derivatives (Scheme 12) [61].

Synthesis of functionalized quinolines under solvent-free conditions
The cyclo condensation reaction between 2-aminoarylketones and α-aroyl ketene dithioacetals was performed under solvent-free conditions using indium chloride (InCl 3 ) as a catalyst to produce a decent yield of quinolines 17 (Scheme 14) [63].

Synthesis of quinoline using photocatalysis
The transformation of m-nitrotoluene soluble in ethanol was studied as a first-time model reaction to define the ability of newly synthesized molecules.Irradiation (λ > 320 nm) of the reaction mixture below 25 °C in the presence of acidmodified mesoporous TiO 2 -SiO 2 molecules resulted in the creation of 2,7-dimethyl quinoline 18 (Scheme 15) [64].

Photocatalytic radical transformation reaction toward the synthesis of quinoline
The reaction of β-aryl propionitrile derivatives with aryl lithiums and water produced 1,3-diphenylpropan-1-imines, which were treated with N-iodosuccinimide via iminyl radical-mediated cyclization under transition metal-free condition with a tungsten lamp irradiation to attain 2-aryl quinoline 21 in a good yield (Scheme 18) [66].
The treatment of N-tosylamide derivatives of (aza)-Morita-Baylis-Hillman adducts with the photocatalyst Ru(bpy) 3 Cl 2 using blue light photoredox-catalyzed single electron transfer conditions at room temperature resulted in the production of quinoline derivatives 26 and 27 (Scheme 21) [69].

Synthesis of quinoline by microwave irradiation
Microwave irradiation exhibits electric and magnetic fields, but the starting materials are controlled only by the electric field.As a result, [70].
Reactions under solvent conditions Zhang et al. established a new green method for the preparation of pyrroloquinolinediones 28 and quinolinedicarboxylates 29 by reacting 2-azido benzaldehydes with N-maleimide and dimethyl fumarate, respectively, via a one-pot synthesis reaction including denitrogenation of azide, benzisoxazole formation, aza-Diels-Alder cycloaddition, and dehydrative aromatization in acetonitrile as a solvent under microwave heating at 115 °C for 35 min (Scheme 22) [71].
Poly-functionalized dihydroquinoline derivatives 34 were synthesized through the reaction of aldehydes and aryl ethylidene malononitriles (2 equiv) via an intermolecular cyclization process under microwave irradiation in ethylene glycol and NaOH as a base (Scheme 25) [74].
Under solvent-free conditions and using microwave irradiation at 80 °C, the condensation reaction between acyl anilines and pentane-2,4-dione (10 equiv) was achieved in the presence of barium or calcium imidazoliumdicarboxylate (10 mol%) as a heterogeneous catalyst to afford quinoline derivatives 42 with a decent yield (Scheme 30) [79].

Computer prediction of biological activity of quinoline
A drug-like organic molecule, whose molecular mass ranges from 50 to 1250 Da, can have its likely biological activity profile estimated using computer tools like the PASS and Swiss ADME web resources based on its structural formula.The estimation is based on examining the structure-activity relationships for a large training set that includes pharmaceutical agents, chemical probes, compounds for which specific toxicity data is known, drug substances, drug candidates in various clinical and preclinical research stages, and drug substances.Using the Pass Web resource for prediction of biological activity of quinoline PASS Online, a free online resource, is given.With an average accuracy above 95%, this resource (http://www.way2drug.com/passonline) is made to predict the biological activity spectra of organic compounds based on their structural formulas for more than 4000 categories of biological activity.A study of the structure-activity relationships in the training set, which contains data on the composition and biological function of more than 300,000 organic compounds, served as the foundation for the prediction [81].

Drug-likeness and oral bioavailability analysis of quinoline nucleus using Swiss ADME web resources
Table 1S shows biological activity spectrum predictions obtained using the Pass Program for the quinoline nucleus; it gives the prediction score for biological properties on the ratio of probability to be active (Pa)' and 'probability of being inactive (Pi).'A higher Pa means the biological property has more probability for a compound.., while Table 2S shows possible adverse & toxic effects of quinoline nucleus calculated through the PASS webserver.

Biological activity of quinoline derivatives
Almost heterocyclic compounds such as coumarin, indole, pyridone, quinoline, tetrazole, pyrimidine, thiazole, purine, imidazole, flavones, and others have already been employed as a tool for drug discovery research and development.For example, the quinoline ring is an attractive scaffold with many essential properties, mainly anticancer, antioxidant, antimicrobial, anti-inflammatory, and antituberculosis.
Özcan et al. [84] prepared quinoline derivatives (Fig. 6) and tested their anticancer potencies.The newly synthesized compounds' activities were determined in the cervical (HeLa), rat brain tumor (C6), and colon (HT29) cancer cell lines according to the MTT, sulforhodamine B, and bromodeoxyuridine cell proliferation ELISA assays using 5fluoro uracil as a reference.This study's results show that the compound 5,7-dibromo-8-hydroxyquinoline 50 is the most hopeful anticancer against the HeLa, HT29, and C6 cell lines with IC 50 ranging from 3.7 to 16.3 µM.

Antimalarial and anti-SARS-CoV-2 activity
Chloroquine 62 contributes to chloroquine phosphate 63 (Fig. 8), a promising medication for malaria and SARS-CoV-2 diseases.In 1950, hydroxychloroquine 64 (Fig. 9) was derived from chloroquine 62 and gave better safety features besides a similar action mechanism to chloroquine [87].In addition, chloroquine has a small molecular size and lipophilic properties, so chloroquine can diffuse through erythrocyte and parasite membranes and inhibit DNA and RNA synthesis.Furthermore, hydroxychloroquine can inhibit SARS-CoV-2 replication [88].
On February 17, 2020, the Chinese State Council announced chloroquine phosphate 63 as an effective SARS-CoV-2 treatment based on clinical trials at a different clinic center in China [89].Chloroquine 62 prevents in vitro SARS-CoV-2 infection at low concentrations on micromolar scale with a maximum effective concentration (EC 50 )

Antituberculosis activity
Thakare et al. [92] prepared several quinoline-substituted benzyl groups 70-74 (Fig. 11) containing pyrazole and triazole moiety.They tested their in vitro activity as antituberculosis agents against M. tuberculosis H37Ra strains using rifampicin as a reference.The results revealed that most new compounds displayed excellently to moderate Activity against M. tuberculosis H37Ra with 34.10-54.60%inhibition.Based on the results outcomes from the study, it

Conclusion and future perspectives
Based on a great interest in quinoline compounds chemistry and its medicinal applications, it is clear that quinoline and its derivatives interact with diverse biological targets like proteins, receptors, and enzymes, which could pave the way for finding novel medication candidates to overcome recent world health problems such as the present COVID-19 crisis.
In this regard, we have briefed traditional and novel synthetic methods for accessing quinoline and its congeners, including green multicomponent one-pot synthesis, cascade reactions, and solvent-free reaction conditions besides a microwave ultraviolet irradiation-promoted synthesis using reusable and recyclable green catalysts.All these aspects are highly significant to the achievement of these pharmacologically active heterocycles; on these bases, we have summarized the current progress and recent studies of the biological importance of different quinoline derivatives, mainly anticancer, anti-inflammatory, antioxidant, antituberculosis, antimalarial, and anti-SARS-CoV-2.
The significant markers of advances in this sector are signs of quinoline core compounds entering the preclinical stages and clinical usages.Therefore, the researchers are still using synthetic approaches to prepare and improve bioactive quinoline derivatives utilizing classical methods and novel developed reaction procedures.These protocols will significantly impact the quick construction of molecular libraries and the cohort of structure-activity relationship studies.So we predict that more signs of progress will be made in the synthetic process with these findings.
Regarding the scope of topics covered in this minireview, we expect that the combined approach of the conventional methods with green synthetic procedures will find widespread applications and continue to capture great interest and developments in the eco-friendly, fast, and economical synthetic methods of quinoline motifs.Finally, we hope the subjects mentioned above of quinoline scaffolds will lead the researchers to develop and find novel and efficient therapeutic products.

Scheme 18
Scheme 18 Synthesis of 2-aryl quinolines 21 from β-arylpropionitriles with aryl lithiums and NIS Analysis of the pharmacokinetic properties of the potential drug is essential in the early stage of drug discovery.According to Lipinski and his team (Lipinski CA.Lead, and drug-like compounds: the rule-of-five revolution.Drug Discov Today.2004; 1:337-341), drug-like quinoline must obey the rule of five (RO5), i.e., molecular weight (M.W.) ≤ 500 Da, number of hydrogen bond donor ≤ 5, number of hydrogen bond acceptor ≤ 10, as shown in Fig.3[80].

Scheme 28 and 39 Scheme 29
Scheme 28 Synthesis of quinoline and bis-quinoline derivatives 38 and 39