Synthesis, biological investigation, and in silico studies of 2-aminothiazole sulfonamide derivatives as potential antioxidants.

Antioxidant compounds have gained current interest as potential protective agents for several therapeutic applications. Antimicrobial drug resistance and infectious diseases also still be concerning globally health issues. Accordingly, the discovery of new antioxidative and antimicrobial agents is essential for human well-being. Thiazole and sulfonamide are privileged scaffolds in drug discovery due to their various bioactive properties. In this study, a series of 2-aminothiazole sulfonamide derivatives (1 - 12) were synthesized and investigated for their antioxidant (i.e., DPPH and SOD-mimic) and antimicrobial activities. Among tested compounds, compound 8 was the most promising one with potent DPPH and SOD (%DPPH = 90.09 %, %SOD = 99.02 %). However, none of these compounds are active antimicrobial agents. Quantitative structure-activity relationship (QSAR) modeling was performed in which the key findings were further used to guide the rational design of additional derivatives. Two antioxidant QSAR models (i.e., DPPH and SOD) were constructed using multiple linear regression (MLR) with good predictive performance. An additional set of structurally modified compounds were designed based on QSAR findings to finally obtain 112 newly designed compounds in which their activities (DPPH and SOD) were predicted. Most of the modified compounds performed better activities than their prototypes. Mass, polarizability, electronegativity, the presence of C-F bond, van der Waals volume, and structural symmetry were revealed as key properties influencing antioxidant activities. In summary, this study demonstrated the combination used of chemical synthesis, experimental assays, and computer-aided drug design for developing novel antioxidants for potential medicinal applications. See also the graphical abstract(Fig. 1).