Rational Design and Biological Evaluation of Pyrrolidinone-Based ACE2 Inhibitors as Potential Therapeutic Agents Against SARS-CoV-2

SARS-CoV-2, an RNA virus belonging to the Coronavirus (CoV) family [1,2], appears crown-shaped under the electron microscope. This characteristic morphology is due to the presence of spike (S) glycoproteins on its outer envelope, which are responsible for mediating entry into human host cells [3]. Viral entry depends on the interaction between the S1 subunit of the spike protein and a cellular receptor that facilitates the virus’s attachment to the surface of target cells. In particular, it has been demonstrated that SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) as its entry receptor and the transmembrane serine protease 2 (TMPRSS2) for spike protein activation [4]. Our study concerns the rational design and synthesis of novel pyrrolidinone derivatives (Figure 1) targeting the ACE2 receptor, a critical entry point for SARS-CoV-2. Guided by structural insights from known inhibitors such as MLN-4760 [5], several compounds featuring a pyrrolidinone scaffold were synthesized and characterized. Their inhibitory activity toward ACE2 was assessed in vitro and supported by molecular docking simulations [6]. Docking results (Figure 2) highlighted favorable binding interactions within the ACE2 active site, identifying N-(3-(2-oxopyrrolidin-1-yl)propyl)-1H-indole-2-carboxamide as the most promising candidate. These outcomes provide a solid foundation for future in vivo studies aimed at developing new therapeutic strategies for COVID-19 and other ACE2-associated disorders.