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The recent formulation, production, and ongoing administration of vaccines represent a starting point in the battle against SARS-CoV-2, but they cannot be the only aid available. In this regard, the use of drugs capable to mitigate and fight the virus is a crucial aspect of the pharmacological strategy. Among the plethora of approved drugs, a consistent element is a heterocyclic framework inside its skeleton. Heterocycles have played a pivotal role for decades in the pharmaceutical industry due to their high bioactivity derived from anticancer, antiviral, and anti-inflammatory capabilities. In this context, the development of new performing and sustainable synthetic strategies to obtain heterocyclic molecules has become a key focus of scientists.
Heterocyclic compounds have versatile applications across many chemistry fields. N, S, and O are the most common heteroatoms, and their corresponding heterocycles can be found as the main structural units in synthetic pharmaceuticals and agrochemicals, as well as widely present in nature in plant alkaloids, nucleic acids, anthocyanins, and flavones . Drugs containing a heterocyclic moiety inside their structure show antitumor, anti-inflammatory, antifungal, antidepressant, anti-HIV, antimalarial, and antiviral properties . In particular, the latter three properties are central in the fight against SARS-CoV-2 . Over the years, due to the importance of these small molecules, synthetic organic chemists have focused their efforts on the development of synthetic protocols which are more and more efficient, atom-economical, and environmentally friendly. Metal-catalyzed protocols, involving all metals from transition to rare-earth metals, have attracted the attention of chemists as compared to other synthetic methodologies because they directly employ easily available substrates to build multi-substituted complex molecules under mild conditions. Metal-catalyzed heterocyclization starting from acyclic precursors is considered a very performant tool in drug synthesis . In this review, we focus our attention on metal-catalyzed heterocyclization methodologies for achieving pivotal scaffolds associated with molecules showing anti-COVID-19 properties.
2. Chloroquine and Hydroxychloroquine
Quinoline Synthesis: Metal-Promoted Annulation
Metal-Promoted Heterocyclization to Achieve Polysubstituted Indoles
5. Quercetin and Luteolin
Metal-Catalyzed O-Heterocyclization to Flavonoids
6. SARS-CoV-2 3CL Protease Target Drugs
The SARS-CoV-2 3C-like protease is the main protease present in the virus, and it is crucial in the translation process from polyproteins to viral RNA . It was demonstrated that the catalytic domain (Cys-145 and His-41) is particularly conserved, which makes the 3CL protease an attractive target for broad-spectrum anti-coronavirus therapies and drug discovery . The SARS-CoV-2 main protease and spike protein are essential for the transmission of the virus and the severity of the infection in the host. Suppressing one or both biological targets can address the concerns linked to transmission, whereby acute COVID-19 symptoms can be drastically minimized . Potential 3CL protease inhibitors reported in the literature have been screened to test their efficacy. Among the prospective bioactive molecules targeting this protein, ritonavir in combination with lopinavir and N-decorated isatins has shown promising results in the fight against SARS-CoV-2 .
The entry is from 10.3390/molecules26092620
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