In the current scenario of medicinal chemistry, quinoline plays a pivotal role in the design of new heterocyclic compounds with several pharmacological properties, so the search for new synthetic methodologies and their application in drug discovery has been widely studied. So far, many procedures have been performed for the preparation of quinoline scaffolds, among which Friedländer quinoline synthesis plays an important role in obtaining these heterocycles. The Friedländer reaction involves condensation between 2‐aminobenzaldehydes and keto‐compounds. The quinoline nucleus, once obtained through the Friedländer synthesis, has been extensively modified so that these derivatives can exhibit a large number of biological activities such as anticancer, antimalarial, antimicrobial, antifungal, antituberculosis, and antileishmanial properties. In this work, the focus is on the applicability of the Friedländer reaction in the synthesis of various types of bioactive heterocyclic quinoline compounds, which to date has not been reported in the context of medicinal chemistry. The main part of this review selectively focuses on research from 2010 to date and will present highlights of the Friedländer quinoline synthesis procedures and findings to address biological and pharmacological activities.

Friedlӓnder's synthesis of quinolines as a pivotal step in the development of bioactive heterocyclic derivatives in the current era of medicinal chemistry

Design, synthesis and biological evaluation of novel isoniazid hybrids

Microwave‐assisted synthesis of 2‐styrylquinoline‐4‐carboxylic acid derivatives to improve the toxic effect against Leishmania (Leishmania) amazonensis

A 2,4-diarylquinoline derivative, 2-(4-chlorophenyl)-4-(3,4-dimethoxyphenyl)-6-methoxy-3-methylquinoline, was synthesized in a conventional two-step procedure from p-anisidine, p-chlorobenzaldehyde and methyl isoeugenol as available starting reagents through a sequence of BF3·OEt2-catalyzed Povarov cycloaddition reaction/oxidative dehydrogenation aromatization processes under microwave irradiation conditions in the presence of a green oxidative I2-DMSO system. The structure of the compound was fully characterized by FT-IR, 1H and 13C-NMR, ESI-MS, and elemental analysis. Its physicochemical parameters (Lipinski’s descriptors) were also calculated using the Molinspiration Cheminformatics software. The diarylquinoline molecule obtained is an interesting model with increased lipophilicity and thus permeability, an important descriptor for quinoline-based drug design. Such types of derivatives are known for their anticancer, antitubercular, antifungal, and antiviral activities.

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2-(4-Chlorophenyl)-4-(3,4-dimethoxy-phenyl)-6-methoxy-3-methylquinoline

Tuberculosis was discovered more than a century ago, and it is still a disease that presents difficulties in its treatment due to the appearance of new resistant strains. To design new antituberculosis agents with a quinoline structure, our group developed three-dimensional structure-activity relationship (3D-QSAR) models, based on Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA). Statistically robust models (q2>0.6; r2ncv>0.8; r2pred>0.7) and with good external predictability were obtained. We found that positions 2, 3, and 4 of the quinoline nucleus are directly related to the modulation of the growth inhibitory activity of Mycobacterium tuberculosis H37Rv. To validate the models, we synthesized twelve quinolines through the Friëdlander reaction and three indolinones. The synthesized compounds were evaluated in the growth inhibition of resistant H37Rv tuberculosis strains (rpoBS450L, katGdel, and gyrAD94K) and in nontuberculous strains (M. avium and M. abscessus). We found that the compound (Z)-4-((2-oxoindolin-3-ylidene)amino)-N-(thiazol-2-yl)benzenesulfonamide was active in all resistant strains; the compound 2-(1H-indol-3-yl)-4-methylquinoline was active on M. avium; and the compound 10-methyl-11H-indeno[1,2-b]quinoline was active on M. abscessus. These models are useful for the discovery of new compounds with inhibitory properties of M. tuberculosis H37Rv, and with potential applications in resistant and nontuberculous strains. 

María Victoria Peláez

Papers

Synthesis, anti-tuberculosis activity and QSAR study of 2,4-diarylquinolines and analogous polycyclic derivatives