NEW THIAZOLIDINE-4-ONE DERIVATIVES CAPABLE OF INHIBITING SARS-CoV-2 MPRO

Having caused a great socioeconomical impact worldwide since 2019, SARS-CoV-2, is still a major public health issue. Despite benefits obtained with vaccination campaigns, SARS-CoV-2 has been still mutating for potential immune escape pathways. Among viral targets, the main protease (Mpro) represents a strong candidate due to various reasons: (1) the pivotal role of Mpro in the proteolytic cleveage of viral proteins, (2) the absence of human homolog of this protein,1 (3) high conservation among Coronaviruses, especially in those domains crucial for its enzymatic activity – a potential for broad-spectrum activity.2 One SARS-CoV-2 Mpro inhibitor has been approved so far by the FDA, namely Nirmatrelvir, but this drug has major issues.3 Most recently, Petrou et al. also reported the antiviral activity of thiazolidine-4-one scaffold against SARS-CoV-2 Mpro.4 All these facts rightfully highlight the pivotal importance of seeking out new Mpro inhibitors, more particularly deepening the SAR studies of thiazolidine-4-one class. Herein, we report the synthesis of new thiazolidine-4-one analogues as SARS-CoV-2 Mpro inhibitors. They were designed by derivatizing the thiazolidine-4-one scaffold with a 4-nitrophenyl ring and a variously substituted phenethyl moiety. Followingly, we assayed the enzymatic activity of the newly synthesized derivatives in in vitro assays against SARS-CoV-2 Mpro, showing inhibitory values within the low micromolar range. To deepen our understanding, we have further applied a molecular docking protocol to predict the possible binding mode of the compounds in complex with SARS-CoV-2 Mpro, shedding light on the main structural features involved in the enzymatic inhibition. An in-depth discussion of the data coming from the biological assays will be shown and described.