Pyrrolo[2,3-b]quinoxalines in attenuating cytokine storm in COVID-19: their sonochemical synthesis and in silico / in vitro assessment

In view of the recent global pandemic caused by COVID-19 intense efforts have been devoted worldwide towards the development of an effective treatment for this disease. Recently, PDE4 inhibitors have been suggested to attenuate the cytokine storm in COVID-19 especially tumour necrosis factor alpha (TNF-alpha). In our effort we have explored the 2-substituted pyrrolo[2,3-b]quinoxalines for this purpose because of their potential inhibitory properties of PDE-4 / TNF-alpha. Moreover, several of these compounds appeared to be promising in silico when assessed for their binding affinities via docking into the Nterminal RNA-binding domain (NTD) of N-protein of SARS-CoV-2. A rapid and one-pot synthesis of this class of molecules was achieved via the Cu-catalyzed coupling-cyclization-desulfinylation of 3-alkynyl-2chloroquinoxalines with t-butyl sulfinamide as the ammonia surrogate under ultrasound irradiation. Most of these compounds showed good to significant inhibition of TNF-alpha in vitro establishing a SAR (Structure Activity Relationship) within the series. One compound e.g. 3i was identified as a promising hit for which the desirable ADME and acceptable toxicity profile was predicted in silico. (C) 2020 Elsevier B.V. All rights reserved.

Automated summary

Efforts are being made worldwide to develop an effective treatment for COVID-19, with PDE4 inhibitors suggested to attenuate the cytokine storm. Some 2-substituted pyrrolo[2,3-b]quinoxalines have shown potential inhibitory properties towards TNF-alpha, with promising results in silico docking studies against the N-protein of SARS-CoV-2.