Ugi Adducts of Isatin as Promising Antiproliferative Agents with Druglike Properties

Multicomponent reactions (MCRs) are a valuable tool for the sustainable synthesis of new molecules in a fast, effective and eco-friendly manner, leading to the generation of structurally diverse libraries. Their application in synthetic organic chemistry and medicinal chemistry, in combination with privileged scaffolds, is gaining momentum in recent years. The Ugi reaction is one of the most widely used MCRs in medicinal chemistry, and it is even used for the synthesis of several active pharmaceutical ingredients. Isatin, known for its biological activities and synthetic versatility, has been vastly used in several MCRs, however it was rarely used in combination with the Ugi reaction. Herein we report the first library of isatin-based Ugi 4 component reaction (U4CR) derivatives. Reaction optimization and scope were thoroughly explored, as well as mechanistic insights were obtained using DFT calculations. The resulting library was evaluated in what concerns its druglike properties, pharmacokinetic profile assessment in silico and antiproliferative activity in vitro, with several compounds bearing interesting druglike properties. Biological screening against six tumor cell lines, showed that the majority of the compounds display antiproliferative activity in the low and sub-micromolar range, with the achievement of nanomolar activity (0.1 nM, 6.5 nM and 5.4 nM against HBL-100, HeLa and WiDr, respectively) for the more active compound.