Quinoxaline derivatives as potent compounds against both 3CLpro and PLpro enzymes of SARS-CoV-2 virus: an insight from experimental and theoretical approaches

Abstract

A few computational studies indicated that some inhibitors of viral RNA–polymerase such as favipiravir could also inhibit cysteine proteases. The potential dual action of favipiravir as an inhibitor for both RNA–polymerase and proteases promises enhanced therapeutic efficacy of the drug against coronaviruses. To shed more light on this phenomenon, in view of the chemical structure of favipiravir and the recent advances in this field, six novel derivatives of 3-methyl quinoxaline were synthesized. In silico methods confirmed the abilities of these compounds to occupy the active-site clefts of both 3CL^pro and PL^pro with favorable interactions, while the ADMET evaluations predicted low toxicity and high bioavailability for them. Then, due to the high similarities between PL^pro and papain, the inhibitory impacts of favipiravir and the synthesized quinoxalines on the kinetics of papain were thoroughly investigated. The outcome revealed that the potential dual-action of favipiravir-like compounds is a possibility that should be taken into account in designing more effective and safe drugs against coronavirus.