Novel Competitive, Nonpeptidic, SARS-CoV-2 Mpro Inhibitors with Improved Solubility
ACS Medicinal Chemistry Letters, vol.17, no.5, pp.1132-1137, 2026 (SCI-Expanded, Scopus)
- Publication Type: Article / Letter
- Volume: 17 Issue: 5
- Publication Date: 2026
- Doi Number: 10.1021/acsmedchemlett.6c00041
- Journal Name: ACS Medicinal Chemistry Letters
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, EMBASE
- Page Numbers: pp.1132-1137
- Keywords: COVID-19, FEP+, main protease, SARS-CoV-2
- Acibadem Mehmet Ali Aydinlar University Affiliated: Yes
Abstract
In continuation of our previous work wherein we described novel, nonpeptidic competitive inhibitors of the SARS-CoV-2 main protease, we here describe our efforts to improve upon these compounds by improving water solubility and metabolic stability. As predicted by FEP+ solubility studies, disrupting the coplanar arrangement of the aromatic rings led to significantly improved compound aqueous solubility, unfortunately with an unacceptable loss in potency. Attempts to improve compound metabolic stability by avoiding aromatic moieties occupying the S4 pocket, while retaining compound potency by modification of the pyridyl ring occupying the S1 pocket, were also investigated.