Synthesis, Antitumor Evaluation, Molecular Modeling and Quantitative Structure–Activity Relationship (QSAR) of Novel 2-[(4-Amino-6-<i>N</i>-substituted-1,3,5-triazin-2-yl)methylthio]-4-chloro-5-methyl-<i>N</i>-(1<i>H</i>-benzo[<i>d</i>]imidazol-2(3<i>H</i>)-ylidene)Benzenesulfonamides

• Main Authors: Łukasz Tomorowicz, Jarosław Sławiński, Beata Żołnowska, Krzysztof Szafrański, Anna Kawiak
• Format: Article
• Language: English
• Published: MDPI AG 2020-04-01
• Series: International Journal of Molecular Sciences
• Subjects: benzenesulfonamide; synthesis; 1,3,5-triazines; cytotoxicity; QSAR; molecular docking
• Online Access: https://www.mdpi.com/1422-0067/21/8/2924

A series of novel 2-[(4-amino-6-R²-1,3,5-triazin-2-yl)methylthio]-4-chloro-5-methyl-<i>N</i>-(5-R¹-<i>1H</i>-benzo[<i>d</i>]imidazol-2(<i>3H</i>)-ylidene)benzenesulfonamides <b>6</b>–<b>49</b> was synthesized by the reaction of 5-substituted ethyl 2-{5-R¹-2-[<i>N</i>-(5-chloro-<i>1H</i>-benzo[<i>d</i>]imidazol-2(<i>3H</i>)-ylidene)sulfamoyl]-4-methylphenylthio}acetate with appropriate biguanide hydrochlorides. The most active compounds, <b>22</b> and <b>46</b>, showed significant cytotoxic activity and selectivity against colon (HCT-116), breast (MCF-7) and cervical cancer (HeLa) cell lines (IC₅₀: 7–11 µM; 15–24 µM and 11–18 µM), respectively. Further QSAR (Quantitative Structure–Activity Relationships) studies on the cytotoxic activity of investigated compounds toward HCT-116, MCF-7 and HeLa were performed by using different topological (2D) and conformational (3D) molecular descriptors based on the stepwise multiple linear regression technique (MLR). The QSAR studies allowed us to make three statistically significant and predictive models for them. Moreover, the molecular docking studies were carried out to evaluate the possible binding mode of the most active compounds, <b>22</b> and <b>46</b>, within the active site of the MDM2 protein.