Synthesis, Biological Studies, and In Silico-Driven Design of 8-Aminoquinoline-Based Sulfonamide Derivatives as...

Eleven 8-aminoquinoline-based sulfonamide derivatives (3-13) were synthesized and experimentally investigated for their antioxidant effects (using superoxide dismutase [SOD] and 2,2-diphenyl-1-picrylhydrazyl [DPPH] assays) and antimicrobial activities (using agar dilution method). Most of the tested compounds were active antioxidants as indicated by SOD assay, affording SOD half-maximal inhibitory concentration in the range of 83.34 to 600.81 μM. However, their DPPH activities were considerably weak (%DPPH = 7.74% to 36.49%). Additionally, 7 compounds (3, 4, 5, 6, 8, 10, and 12) displayed growth-inhibiting effects against various gram-positive and gram-negative microbes (minimum inhibitory concentration values = ≤4 to 256 μg/ml). Quantitative structure-activity/property relationship (QSAR/QSPR) modeling was performed to obtain predictive models, including antioxidant QSAR (SOD and DPPH) and antimicrobial QSPR models. The constructed models displayed acceptable predictive performance and robustness (QSAR models: R² _Tr = 0.9980 to 0.9996, Q² _LOO-CV = 0.9930 to 0.9978, RMSE_Tr = 0.0121 to 0.1677, RMSE _LOO-CV = 0.0233 to 0.3830 and QSPR model: accuracy = 90.91% for training and 63.64% for leave-one-out cross-validation [LOO-CV] sets). The constructed models were subsequently utilized to guide rational design and predict activities of an additional set of 84 structurally modified compounds. Finally, newly designed compounds with promising predicted antioxidant activity (SOD: 13c, 13f, 8c, 12e, and 11c; DPPH: 9b, 6f, 9c, 11h, and 3d) as well as a set of 34 compounds predicted as active antimicrobial agents are summarized for potential investigations. Furthermore, key essential properties influencing bioactivities (electronegativity, polarizability, I-state, van der Waals volume, connectivity, and ionization potential) were also revealed for future beneficial design of the related compounds for medical applications.