Quinoline Heterocycles: Synthesis and Bioactivity

Among heterocyclic compounds, quinoline is a privileged scaffold that appears as an important construction motif for the development of new drugs. Quinoline nucleus is endowed with a variety of therapeutic activities, and new quinolone derivatives are known to be biologically active compounds possessing several pharmacological activities. Many new therapeutic agents have been developed by using quinoline nucleus. Hence, quinoline and its derivatives form an important class of heterocyclic compounds for the new drug development. Numerous synthetic routes have been developed for the synthesis of quinoline and its derivatives due to its wide range of biological and pharmacological activities. The article covers the synthesis as well as biological activities of quinoline derivatives such as antimalarial, anticancer, antibacterial, anthelmintic, antiviral, antifungal, antiinflammatory, analgesic, cardiovascular, central nervous system, hypoglycemic, and miscellaneous activities.


Introduction
Quinoline 1 or 1-azanaphthalene or benzo [b]pyridine is an aromatic nitrogencontaining heterocyclic compound having a molecular formula of C 9 H 7 N, and the molecular weight is 129. 16. Being a weak tertiary base, it forms salts with acids and exhibits reactions similar to benzene and pyridine. It participates in both electrophilic and nucleophilic substitution reactions.
Quinoline moiety commonly exists in various natural compounds (Cinchona alkaloids), and pharmacological studies have shown that the quinolone ring system is present in many compounds exhibiting a broad range of biological activities. Quinoline has been found to have antibacterial, antifungal, antimalarial, anthelmintic, anticonvulsant, cardiotonic, anti-inflammatory, and analgesic activities.

Synthesis
In the literature, a number of established protocols have been reported for the synthesis of quinoline ring, which can be altered to produce a number of differently substituted quinolines. The quinoline ring has been generally synthesized by various conventional named reactions such as Skraup, Doebner-Von Miller, Pfitzinger, Friedlander, Conrad-Limpach, and Combes synthesis (Figure 1) [1].
Apart from the conventional methods, a vast number of synthetic routes have been developed for the synthesis of quinoline and quinoline derivatives. Chen    2,4-Diphenyl-2-methyl-1,2-dihydroquinoline, 4 has been prepared by the condensation followed by cyclization of aniline and acetophenone. The reaction proceeds with the help of a zeolite catalyst, E 4a [5].
By stirring 2-aminoaryl ketones and various α-methylene ketones in the presence of dodecylphosphonic acid (DPA) catalyst in water or solvent-free conditions, poly-substituted quinolones, 6 have been synthesized [7]. Two molecules of o-haloacetophenones condensed with urea or primary amines yielded certain halogen-substituted quinolones, 13. The halogen-substituted quinolines were formed through the cleavage of C(sp 2 )-halogen and α-C(sp 3 )-H bonds and the formation of new bonds in a selective manner [14].
A one-pot reaction of 2-aminoaryl ketones with certain arylacetylenes results in the formation of 2,4-disubstituted quinolones, 14. The reaction was performed in a green synthetic route using potassium dodecatugstocobaltate trihydrate (K 5 CoW 12 O 40 .3H 2 O) as a recyclable and eco-friendly catalyst under microwave and solvent-free conditions [15]. DOI: http://dx.doi.org/10.5772/intechopen. 81239 Kowsari et al. synthesized certain quinolones, 15 by reacting isatin with aryl methyl ketones in the presence of basic ionic liquids in water [16]. The reaction was conducted under ultrasound green synthetic conditions. The main advantages of this procedure are (i) a green method, (ii) milder and shorter reaction time, and (iii) higher yields and selectivity without a transition metal catalyst.

Antimalarial
Quinolines are known for their excellent antimalarial properties. Raynes et al. developed bisquinolines, 19, 20 that exhibit antimalarial activity against chloroquine-resistant and chloroquine-sensitive parasites [20]. Derivatives of ferrochloroquine, 21 were also found to possess antimalarial activity [21]. In these derivatives, the carbon skeleton of chloroquine is replaced by ferrocene group. Modapa et al.

Antitumor
Some amido-anilinoquinolines, 46 were synthesized by Scott et al. that act as antitumor agents by inhibiting CSF-1R kinase [41]. Certain derivatives of 4-hydroxyquinolines, 47 were synthesized by Mai et al. that showed histone acetyltransferase (HAT) inhibitory activity [42]. A few 3-cyanoquinolines, 48 were developed by Miller et al. as inhibitors of growth factor receptors (IGF-1R) for treating cancer [43]. 4-Anilinoquinolines, 49 were synthesized by Assefa et al. which were found to contain tyrosine kinase inhibitors [44]. Quinoline carboxylic acids, 50 have been synthesized by Chen et al. that act as antitumor compounds by inhibiting insulin-like growth factors [45]. A few c-Met kinase inhibitory quinolones, 51 were developed by Wang et al. with IC 50 < 1 nM. These derivatives were found to show the inhibition of c-Met phosphorylation in c-Met-dependent cell lines [46]. Marganakop et al. developed few 6,7,8-substituted thiosemicarbazones of 2-chloro-3-formyl-quinoline derivatives, 52 which exhibit excellent anticancer activities [47]. Recently, some quinoline derivatives, 53 were synthesized as novel Raf kinase inhibitors with potent and selective antitumor activities. These derivatives were synthesized by modifying the structure of sorafenib [48].

Antiviral
Several mono-and poly-substituted quinolones,

Cardiovascular activity
Srimal et al. demonstrated the hypotensive activity of centhaquin, 72, and it was found to show the property of reducing the blood pressure in cat in a dose-dependent manner [57]. Quinoline-4-carboxylic acids, 73 have been synthesized by Lloyd et al. that are angiotensin II receptor antagonists and thereby act as hypotensive agents [58]. Certain biarylether amide quinolones, 74 have been developed by Bernotas et al. which act as liver X receptor agonists and are useful in the situation of dyslipidemia [59]. Phenyl acetic acid-based quinolones, 75 have been developed by Hu et al. which act as agonists at liver X receptors and found to have good binding affinity for LXRb and LXRa receptors [60]. A few 4-thiophenyl quinolones, 76 have been developed by Cai et al. that are HMG-CoA reductase inhibitors and useful as hypocholesterolemic agents [61]. Tetrahydroquinolines, 77 which inhibit the cholesteryl ester transfer protein have been synthesized by Rano et al. [62]. Certain tetrahydroquinolinamines, 78 have been developed by Ramos et al. which are found to inhibit platelet aggregation [63] [65].

Conclusion
Since quinoline and its derivatives are known for their wide spectrum of pharmacological activities, a number of synthetic methods have been developed from time to time for their synthesis by conventional, homogeneous, and heterogeneous acid-catalyzed methods; rare-earth-catalyzed, transition metal-catalyzed, radicalcatalyzed, microwave-assisted, ultrasound-promoted, or solvent-free conditions, and many more. This book chapter will be very useful to the researcher working in © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. this field, and it would help them to develop new synthetic methods for the potent quinoline derivatives with good or enhanced biological activities for the future.