ABSTRACT
Reactions for the palladium-catalyzed intramolecular cyclization of the o-bromoindole and the o-bromo-N-methyl-indole derivatives in the presence and absence of base (Cs2CO3) were explored through DFT calculations. For the base-free reactions, the palladium atom firstly interacts with the aromatic rings of the indole molecule to yield a stable adduct. Once this adduct has been formed, reaction proceeds readily to the oxidative addition intermediate that arises from the insertion of the metal atom into the C-Br bond of the organic fragment. Further steps leading to the paullone (or dimethyl paullone) product, mainly those involving the metalation and deprotonation of the inserted intermediate, are not energetically viable for these reactions. When the effect of the base on the metalation-deprotonation steps is modeled by replacing the bromide ion with CO32- in the metal-inserted structure, a feasible pathway connecting the oxidative addition intermediate with the paullone-type product was located for each of the investigated reactions. The results emerging from this study suggest that palladium can insert into the C-Br bond of the indole derivatives to yield the oxidative addition intermediate (without participation of the base). However, the metalation and deprotonation steps that evolve to the paullone-type product take place via a concerted action involving both the metal and the base. Metalation and deprotonation steps that evolve to the paullone-type product take place via a concerted action involving both the metal and the base.
ABSTRACT
The virus SARS CoV-2, which causes the respiratory infection COVID-19, continues its spread across the world and to date has caused more than a million deaths. Although COVID-19 vaccine development appears to be progressing rapidly, scientists continue the search for different therapeutic options to treat this new illness. In this work, we synthesized five new 1-aryl-5-(3-azidopropyl)indol-4-ones and showed them to be potential inhibitors of the SARS CoV-2 main protease (3CLpro). The compounds were obtained in good overall yields and molecular docking indicated favorable binding with 3CLpro. In silico ADME/Tox profile of the new compounds were calculated using the SwissADME and pkCSM-pharmacokinetics web tools, and indicated adequate values of absorption, distribution and excretion, features related to bioavailability. Moreover, low values of toxicity were indicated for these compounds. And drug-likeness levels of the compounds were also predicted according to the Lipinski and Veber rules.
Subject(s)
Antiviral Agents/metabolism , Azides/metabolism , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/metabolism , Indoles/metabolism , SARS-CoV-2/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Azides/chemical synthesis , Azides/pharmacokinetics , Catalytic Domain , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/pharmacokinetics , Indoles/chemical synthesis , Indoles/pharmacokinetics , Internet , Molecular Docking Simulation , Protein BindingABSTRACT
We report the regio- and stereoselective synthesis of a novel cis-C(3)N-C(4)X-C(6)N series (X=O, S, and C(2)) from cyclic ketones. The cytotoxic activity of the new compounds was studied in five cell lines; the observed activities were in accordance with the concept of bioisosteric replacement.
