Anti-norovirus activity of C7-modified 4-amino-pyrrolo[2,1-f][1,2,4]triazine C-nucleosides

Abstract

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Noroviruses—The State of the Art, Nearly Fifty Years after Their Initial Discovery

“…Recent in vivo and in vitro findings have added to the understanding of host immunity in response to norovirus infection [ 272 , 273 , 274 ]. While neither approved vaccines nor small molecule treatments are yet available, vaccine development has progressed to preclinical and even clinical trial testing of candidates [ 281 , 306 , 307 , 308 ] and ongoing development of therapeutic agents includes promising direct-acting small molecules and host-factor drugs [ 145 , 292 , 296 , 302 ]. Many of these discoveries have been facilitated by novel in vitro and in vivo culture systems that have inspired fascinating new avenues of norovirus research.…”

“…Nucleoside analogues under investigation include the cytidine analogue 2′-C-methylcytidine [ 292 ] and its derivatives, and purine analogues favipiravir [ 293 ] and ribavirin, the latter of which is licensed to treat chronic hepatitis C infections [ 145 , 294 , 295 ]. Modified C-nucleosides have been recently identified as viable starting scaffolds for further optimisation of nucleoside-based inhibitors of norovirus replication [ 296 ]. Their inhibitory effects are attributed to multiple modes of action including chain termination, provocation of an error catastrophe scenario for the viral quasispecies via ambiguous base pairing (lethal mutagenesis), direct RdRp inhibition, and unbalancing of intracellular NTP pools [ 297 , 298 ].…”

Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2

“…Compound 1a and 1b were synthesized starting from GS-441254 with reference to reported method. [26] 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.26 (br, 1H), 7.96 (s, 1H), 7.10 (br, 1H), 6.99 (s, 1H), 6.25 (d, J = 6.1 Hz, 1H), 5.19 (d, J = 5.7 Hz, 1H), 4.93 (t, J = 5.7 Hz, 1H), 4.53 (t, J = 5.5 Hz, 1H), 4.06–4.00 (m, 1H), 3.96–3.88 (m, 1H), 3.69–3.61 (m, 1H), 3.54–3.45 (m, 1H). 13 C NMR (126 MHz, DMSO- d 6 ) δ 154.91, 148.42, 124.07, 116.77, 112.09, 110.30, 102.84, 84.87, 78.01, 74.68, 69.60, 60.25.MS m/z = 326.0 [M+1] + .…”

A Potential Practical Process for Remdesivir

“…In order to mitigate this issue, the standard approach of catalytic hydrogenation using Pd/C was evaluated using HTS. 17 Unfortunately after extensive screening, we were unable to completely remove all three benzyl groups and observed two impurities from incomplete deprotection, 17 and 18 as major side products. For catalytic hydrogenation details see SI.…”