Rational modifications, synthesis and biological evaluation of new potential antivirals for RSV designed to target the M2-1 protein

Abstract

Marcella 2020. Rational modifications, synthesis and biological evaluation of new potential antivirals for RSV designed to target the M2-1 protein. Highlights• Rational modifications on a zinc-ejecting anti-RSV scaffold.• Synthesis of novel analogues to explore antiviral SARs.• New inhibitors of RSV replication identified.• Molecular dynamics and molecular docking studies on the RSV M2-1 protein. AbstractRespiratory syncytial virus (RSV) is the main cause of lower respiratory tract diseases in infants and young children, with potentially serious and fatal consequences associated with severe infections. Despite extensive research efforts invested in the identification of therapeutic measures, no vaccine is currently available, while treatment options are limited to ribavirin and palivizumab, which both present significant limitations. While clinical and pre-clinical candidates mainly target the viral fusion protein, the nucleocapsid protein or the viral polymerase, our focus has been the identification of new antiviral compounds targeting the viral M2-1 protein, thanks to the presence of a zinc-ejecting group in their chemical structure.Starting from an anti-RSV hit we had previously identified with an in silico structure-based approach, we have designed, synthesised and evaluated a new series of dithiocarbamate analogues, with which we have explored the antiviral activity of this scaffold. The findings presented in this work may provide the basis for the identification of a new antiviral lead to treat RSV infections.

Recent Progress toward the Discovery of Small Molecules as Novel Anti-Respiratory Syncytial Virus Agents

“…The best compound 54 (Figure ) exhibited an IC 50 of 6 μM in HEp-2 cells infected with a luciferase-expressing RSV. Five years later, the same authors identified compound 55 (Figure ) (EC 50 = 4.4 and 1.3 μM on RSV A and B, respectively), which differed from the hit 54 due to the replacement of the benzyl ring with a phenyl moiety . Docking studies were conducted on the tetrameric crystal structure of M2-1 protein in complex with the interaction domain of P (PDB: 6G0Y, released in 2018) which led to a refinement of the binding mode of this series of dithiocarbamate derivatives.…”

“…Five years later, the same authors identified compound 55 (Figure 17) (EC 50 = 4.4 and 1.3 μM on RSV A and B, respectively), which differed from the hit 54 due to the replacement of the benzyl ring with a phenyl moiety. 141 Docking studies were conducted on the tetrameric crystal structure of M2-1 protein in complex with the interaction domain of P (PDB: 6G0Y, released in 2018) which led to a refinement of the binding mode of this series of dithiocarbamate derivatives. Therefore, the benzothiazole moiety of 55 interacted with Lys18 A through a π-bond with the sulfur atom pointing toward the oxygen of the Gly18 A backbone.…”

Domino assembly of dithiocarbamatesviaCu-catalyzed denitrogenative thiolation of iodotriazole-based diazo precursors

“…Moreover, to the best of our knowledge, the employment of N -sulfonyltriazoles in C–S bond forming cascades may be possible only by the use of very expensive Rh catalysts. 30,31 It is worth mentioning that the structural analogues of the obtained products, containing benzimidazole and benzothiazole units, have been shown to exhibit fungicidal, 32 antiviral, 33 and anticancer 34 activities (Scheme 1D).…”

Simplified Procedure for General Synthesis of Monosubstituted Piperazines—From a Batch Reaction Vessel to a Flow (Microwave) Reactor

“…Nonetheless, over the last few years, some improved procedures based on a simple reaction of a free piperazine with halogenated reagents were published. Although yields were somehow improved, syntheses still feature some particular issues such as the usage of chlorinated solvents [18][19][20], multistep isolation/purification process often including column chromatography [18,19,[21][22][23][24][25] or disadvantageous atom economy when the usual excess of piperazine must be used [3,19,[23][24][25].…”