Discovery of New SARS-CoV-2 Mpro Inhibitors Endowed with Nitrogen-based Scaffold

After the great socioeconomical impact caused by COVID-19 encountered globally, SARS-CoV-2 is still a major public health issue even today. Moreover, the virus has kept mutating for potential immune escape pathways. Therefore, the effectiveness of vaccines remains questionable currently. Among those viral targets of SARS-CoV-2, the main protease (Mpro) stands as an attractive choice. To briefly state why: (I) Mpro has a pivotal role in the proteolytic cleveage of viral proteins [2] (II) it has high degree of conservation, which could contribute to the broad-spectrum efficacy against all variants of SARS-CoV-2, (III) there is no human homolog of this protein[1]. In line with, there are SARS-CoV-2 Mpro inhibitors reported in the literature. The inhibitors can be classified into two classes: (I) covalent inhibitors – lacking suboptimal potency, presents toxicity; (II) non-covalent inhibitors – possessing either peptidomimetic or non-peptidomimetic nature. Among the covalent inhibitors of Mpro, Nirmatrelvir was approved by FDA though this drug has major problems such as restricted efficacy only if administered within the first five days of symptoms, drug interactions, and the need of co-administration with Ritonavir.[3-4] Thus, there is still a need for further developments of new antiviral. Based on our long-standing experience in the design and synthesis of heterocyclic compounds and by considering the aforementioned facts, we designed and synthesized SARS-CoV-2 Mpro small molecule inhibitors endowed with nitrogen-based scaffold. The corresponding data will be shown and discussed.