Anticancer activity and QSAR study of sulfur-containing thiourea and sulfonamide derivatives

Sulfur-containing compounds are considered as attractive pharmacophores for discovery of new drugs regarding their versatile properties to interact with various biological targets. Quantitative structure-activity relationship (QSAR) modeling is one of well-recognized in silico tools for successful drug discovery. In this work, a set of 38 sulfur-containing derivatives (Types I–VI) were evaluated for their in vitro anticancer activities against 6 cancer cell lines. In vitro findings indicated that compound 13 was the most potent cytotoxic agent toward HuCCA-1 cell line (IC50 = 14.47 μM). Compound 14 exhibited the most potent activities against 3 investigated cell lines (i.e., HepG2, A549, and MDA-MB-231: IC50 range = 1.50–16.67 μM). Compound 10 showed the best activity for MOLT-3 (IC50 = 1.20 μM) whereas compound 22 was noted for T47D (IC50 = 7.10 μM). Subsequently, six QSAR models were built using multiple linear regression (MLR) algorithm. All constructed QSAR models provided reliable predictive performance (training sets: Rtr range = 0.8301–0.9636 and RMSEtr = 0.0666–0.2680; leave-one-out cross validation sets: RCV range = 0.7628–0.9290 and RMSECV = 0.0926–0.3188). From QSAR modeling, chemical properties such as mass, polarizability, electronegativity, van der Waals volume, octanol-water partition coefficient, as well as frequency/presence of C–N, F–F, and N–N bonds in the molecule are essential key predictors for anticancer activities of the compounds. In summary, a series of promising fluoro-thiourea derivatives (10, 13, 14, 22) were suggested as potential molecules for future development as anticancer agents. Key structure-activity knowledge obtained from the QSAR modeling was suggested to be advantageous for suggesting the effective rational design of the related sulfur-containing anticancer compounds with improved bioactivities and properties.