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Considering early-stage drug discovery programs, the Ugi four-component reaction is a valuable, flexible, and pivotal tool, facilitating the creation of two new amide bonds in a one-pot fashion to effectively yield the desired α-aminoacylamides. Here, we highlight the reputation of this reaction approach to access number and scaffold diversity of a library of isatin-based α-acetamide carboxamide oxindole hybrids, promising anticancer agents, in a mild and fast sustainable reaction process. The library was tested against six human solid tumor cell lines, among them, non-small cell lung carcinoma, cervical adenocarcinoma, breast cancer and colon adenocarcinoma. The most potent compounds 8d, 8h and 8k showed GI50 values in the range of 1–10 μM.

The 3-component Passerini reaction (3CPR), discovered little more than 100 years ago, has been demonstrated in the last few decades to be a valuable tool for accessing structural diversity and complexity, essential topics to consider in drug discovery programs. Focusing on accessing a fine-tuned family of α-acyloxyamide–oxindole hybrids, we underline herein our latest insights regarding the use of this mild reaction approach to obtain promising anticancer agents. Cheap and commercially available isatin was used as starting material. The library of α-acyloxyamide–oxindole hybrids was tested against six human solid-tumor cell lines; among them, non-small cell lung carcinoma, cervical and colon adenocarcinoma, and breast and pancreas cancer. The most potent compound displayed GI50 values in the range of 1.3–21 µM.

The oxindole core is an important structural motif in many natural and synthetic substances with various biological activities including anticancer, antineurodegenerative, and antimicrobial properties. This report focuses on the synthesis and biological activity of a series of novel N-substituted 3-aminooxindoles and their assessment in cholinesterase (ChE) and monoamine oxidase (MAO) inhibition. With regard to MAO inhibition, a series of N-propargyl containing derivatives was synthesized and screened. Despite being weak inhibitors of MAO-A and MAO-B, the compounds were selective for butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE). Most of them were strong inhibitors of BuChE with IC50's of less than 1 µM, and one compound showed an IC50 = 27 nM. The mechanism of action of the inhibition was pin-pointed through molecular modeling, and was validated using saturation-transfer-difference (STD) NMR. Some of the compounds were screened for anti-oxidant properties, but showed no activity. The same compounds were screened in the neurodegenerative disease model cell-line SH-SY5Y and although some were found to be non-cytotoxic, others were moderately cytotoxic. Continuous live cell imaging experiments showed that the compounds do not induce relevant cell damage and thus, the compounds might be interesting drug candidates for Alzheimer’s disease. Furthermore, the most active compounds showed excellent drug-likeness and pharmacological properties predicted using Swiss-ADME, and the pharmacokinetic simulations indicated that all these compounds cross the blood-brain-barrier.

In this work, we propose a general methodology to assess the bioactive potential (BP) of extracts in the quest of vegetable-based drugs. To exemplify the method, we studied the anticancer potential (AP) of four endemic species of genus Hypericum (Hypericum canariense L, Hypericum glandulosum Aiton, Hypericum grandifolium Choisy and Hypericum reflexum L.f) from the Canary Islands. Microextracts were obtained from the aerial parts of these species and were tested against six human tumor cell lines, A549 (non-small-cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small-cell lung), T-47D (breast) and WiDr (colon). The methanol–water microextracts were evaluated further for cell migration, autophagy and cell death. The most promising bioactive polar microextracts were analyzed by UHPLC–DAD–MS. The extraction yield, the bioactivity evaluation and the chemical profiling by LC–MS suggested that H. grandifolium was the species with the highest AP. Label-free live-cell imaging studies on HeLa cells exposed to the methanol–water microextract of H. grandifolium enabled observing cell death and several apoptotic hallmarks. Overall, this study allows us to select Hypericum grandifolium Choisy as a source of new chemical entities with a potential interest for cancer treatment.

Natural products represent an excellent source of unprecedented anticancer compounds. However, the identification of the mechanism of action remains a major challenge. Several techniques and methodologies have been considered, but with limited success. In this work, we explored the combination of live cell imaging and machine learning techniques as a promising tool to depict in a fast and affordable test the mode of action of natural compounds with antiproliferative activity. To develop the model, we selected the non-small cell lung cancer cell line SW1573, which was exposed to the known antimitotic drugs paclitaxel, colchicine and vinblastine. The novelty of our methodology focuses on two main features with the highest relevance, (a) meaningful phenotypic metrics, and (b) fast Fourier transform (FFT) of the time series of the phenotypic parameters into their corresponding amplitudes and phases. The resulting algorithm was able to cluster the microtubule disruptors, and meanwhile showed a negative correlation between paclitaxel and the other treatments. The FFT approach was able to group the samples as efficiently as checking by eye. This methodology could easily scale to group a large amount of data without visual supervision.