Computational and In vitro Elucidation of Indolenine-barbituric Acid Zwitterions as Potential Chemotherapeutical Agents

Introduction: The continuous pursuit of novel chemotherapeutical agents with improved efficacy and reduced adverse effects remains a critical area of research despite advancements in chemotherapy. We have previously synthesized indolenine and barbituric acid zwitterion scaffolds 1–10 sustainably; however, their precise chemotherapeutical properties are still lacking. Methods: In this present work, we conducted in silico ADMET analyses, molecular docking calculations, DNA binding studies, and cytotoxicity assays on these zwitterions. Results and Discussion: Among the 10 zwitterions, zwitterion 3 bearing a methoxy group demonstrated the highest drug-likeness score, low toxicity, as well as no violation of Lipinski’s rule of five and Veber’s rule. Both molecular docking calculations and DNA binding studies suggested that the minor groove of DNA is the most probable molecular target of 3 among the others (i.e., topoisomerase and tubulin). In addition, zwitterion 3 exhibited selective cytotoxicity against a wide array of human cancer cell lines without noticeable effect against the normal human colon fibroblast CCD- 18Co. Conclusion: Overall, these preliminary findings from our combined computational and experimental strategy suggested that 3 remains promising for further elaboration as a chemotherapeutic agent.