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-α). 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-α. Moreover, several of these compounds appeared to be promising in silico when assessed for their binding affinities via docking into the N-terminal 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-2-chloroquinoxalines with t-butyl sulfinamide as the ammonia surrogate under ultrasound irradiation. Most of these compounds showed good to significant inhibition of TNF-α 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.

In silico assessment and sonochemical synthesis of 2-alkynyl 3-chloropyrazines as prospective ligands for SARS-CoV-2.

The recent global pandemic caused by COVID-19 has triggered an intense effort worldwide towards the development of an effective cure for this disease. In our effort we have explored the 2-alkynyl substituted 3-chloropyrazine framework as a potential template for the design of molecules for this purpose. Our strategy was supported by the in silico studies of representative compounds to assess their binding affinities via docking into the N-terminal RNA-binding domain (NTD) of N-protein of SARS-CoV-2. Thus we created a small library of molecules based on the aforementioned template via an environmentally safer method that involved the rapid synthesis of 2-alkynyl 3-chloropyrazine derivatives under Cu-catalysis assisted by ultrasound. The reactions proceeded via the coupling of 2,3-dichloropyrazine with commercially available terminal alkynes in the presence of CuI, PPh3 and K2CO3 in PEG-400. Further molecular modelling studies helped in establishing a virtual SAR (Structure Activity Relationship) within the series and identification of three potential hits. The desirable ADME was also predicted for these three molecules suggesting their prospective medicinal value.

Ultrasound assisted synthesis of 3-alkynyl substituted 2-chloroquinoxaline derivatives: Their in silico assessment as potential ligands for N-protein of SARS-CoV-2.

In view of recent global pandemic the 3-alkynyl substituted 2-chloroquinoxaline framework has been explored as a potential template for the design of molecules targeting COVID-19. Initial in silico studies of representative compounds to assess their binding affinities via docking into the N-terminal RNA-binding domain (NTD) of N-protein of SARS-CoV-2 prompted further study of these molecules. Thus building of a small library of molecules based on the said template became essential for this purpose. Accordingly, a convenient and environmentally safer method has been developed for the rapid synthesis of 3-alkynyl substituted 2-chloroquinoxaline derivatives under Cu-catalysis assisted by ultrasound. This simple and straightforward method involved the coupling of 2,3-dichloroquinoxaline with commercially available terminal alkynes in the presence of CuI, PPh3 and K2CO3 in PEG-400. Further in silico studies revealed some remarkable observations and established a virtual SAR (Structure Activity Relationship) within the series. Three compounds appeared as potential agents for further studies.