Title : Synthesis of chromeno[4,3?b]quinolines through an imine formation/aza-Diels-Alder/aromatization tandem reaction under metal-catalyst and photosensitizer-free conditions and their in vitro antiviral activity
Abstract:
Chromeno[4,3-b]quinolines have emerged as an important class of tetracyclic O- and N-heterocyclic compounds because of their broad biological activities. Particularly, the chromenoquinoline skeleton is found in a variety of potential bioactive entities, such as ?-selective estrogen ligands (ER?), antitumor agents and anti-inflammatory derivatives. Furthermore, due to their fluorescent properties, some chromeno[4,3-b]quinoline analogues have been used in fluorescent probes to study cell permeability and live cell imaging of thiols and amino acids.
Owing to their biological and fluorescent properties, synthetic and medicinal chemists are focusing their efforts in developing easy-to-handle and practical protocols for the synthesis of substituted chromeno[4,3-b]quinolines. Approaches such as the aza-Diels-Alder/aromatization, the tandem aza-Diels-Alder/halogenation and the oxidative arylation/cyclization tandem reactions catalysed by copper catalysts have been reported for the construction of chromenoquinoline derivatives.
Tandem reactions, a well-defined sequential process in which multiple chemical steps occurs one after another, without the need for external intervention for the formation of multiple bonds in a single operation, have become a useful and important strategy to construct complex organic molecules of great interest to scientists in both academia and industry. Besides the undeniable benefits of these protocols: time, effort and cost savings, these processes are often associated with the use of transition metal catalysts, toxic reagents and harsh conditions. Thus, in continuation of our studies on the imine Diels-Alder and the Povarov reactions, we report an improved, non-toxic, transition metal free, I2/DMSO-catalysed tandem reaction between arylamines 1a-q and O-cinnamyloxy salicylaldehydes 2a-b to synthesize 7-aryl-6H-chromeno[4,3-b]quinolines 3a-u (Scheme 1).
All products 8a-u were obtained as stable solids and were fully characterized by IR, mass spectrometry and NMR (1H, 13C) Techniques. Finally, the antiviral profile of the synthetized compounds 3a-u were studied against infected Vero CCL-81 cells with the Zika virus. Compounds were identified as the most promising agents by exhibiting an inhibitory concentration of 77 and 57 PFU/mL, respectively, and with an antiviral activity of 25 µg/mL for both agents, which were substituted with electro-withdrawing groups on the quinoline moiety.
Acknowledgments: We thank the Colombian Institute for Science and Research (COLCIENCIAS) under the project No. 111574455595 contract 648-2017 for the financial support. A.P.G. thanks the fellowship given by Universidad de Antioquia under the contract 20730003-028-2018 and the project 648-2017.
Audience take-away:
- Organic and green chemistry, catalysis, tandem reactions, first steps in drug discovery (Synthesis and preliminary biological evaluation), reaction mechanism
- This work will be of interest to the organic chemistry industry since a series of small molecules with a complex structure were easily prepared through a green, cheap and efficient methodology. The major advantage in comparison with the previous works is avoiding the use of metal and expensive catalysts that would be a big problem in scaling these protocols at industrial scale. Moreover, the synthetized compounds can be used for material science applications, medicinal or biological studies. Finally, the described tandem process involves a series of important chemical transformation in organic chemistry that can be used as an example for middle and advanced chemistry courses.
