New thiobarbituric acid scaffold-based small molecules: Synthesis, cytotoxicity, 2D-QSAR, pharmacophore modelling and in-silico ADME screening

Abstract A series of twenty five new thiobarbituric acid derivatives, viz. 3a-h , 4–7 , 8a-c , 9 , 10a-c , 11 and 12a-d , were designed and synthesized as potential cytotoxic agents. In-vitro screening of the new compounds against the three human cancer cell lines Caco-2, HepG-2 and MCF-7 was performed to assess their intrinsic activity. Compound 12d exhibited potent sub-micromolar activity against HepG-2 and MCF-7 (IC 50  = 0.07 and 0.08 μM, respectively). In-silico pharmacophore modelling of this chemotype compounds disclosed a five features' pharmacophore model representing essential steric and electronic fingerprints essential for activity. Finally, a 2D-QSAR model was devised to quantitatively correlate the 2D molecular feature descriptors of this series of thiobarbiturates with their cytotoxic activity against MCF-7. Finally, in silico evaluation of the physicochemical and ADME properties of these derivatives was performed.