Ugi Adducts of Isatin as Promising Antiproliferative Agents with Druglike Properties

Abstract

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.

Easy access to Ugi-derived isatin-peptoids and their potential as small-molecule anticancer agents

“…Considering the potential anti-tumour activity of these compounds and previous experience demonstrating the antiproliferative activity of analogous compounds, 13 we screened our 25 compounds and N -benzyl-2-( N -(1-benzyl-2,3-dioxoindolin-5-yl) acetamido) butanamide (9aaaa) , against a battery of human solid tumour cell-lines. Five human solid tumour cell lines were tested, A549 (lung), HBL-100, T-47D (breast), HeLa (cervix) and WiDr (colon) (Fig.…”

“…The advantages of using InCl 3 as a catalyst in Ugi MRs were underlined recently. 13,16 We decided to test this cheap, safe, and easy to handle Lewis acid catalyst in this Ugi4CR using the same solvents (Table 1, entries 4-6). No significant advantages were observed (as the yields were low) with prolonged reaction times, and the same was observed for triflic acid (TfOH) 17 (Table 1, entries 7-9).…”

“…Gratifyingly, in all the experiments, only the Ugi adduct was obtained validating the importance of using carboxylic acids with pKa values around 4 or below for the Ugi reaction to occur. 13,18 Considering the carbonyl component, a plethora of aldehydes were examined in this MCR. Overall, no difference in the yields of the desired products (5) was observed using aliphatic ((3a-c), (3e), (3i)) or aromatic ((3d), (3g-h)) aldehydes (Fig.…”

“…Ketones can also be used as the carbonyl unit donor in the Ugi MCR. 13,18,19 Aliphatic ketones usually work better than aromatic ones, so we decided to test several aliphatic ketones as the carbonyl contribution in this Ugi4CR. The results are shown in Scheme 4.…”

“…The synthetic value of multicomponent reactions (MCRs) in drug discovery is well recognized, 10 particularly the Ugi 4 component reaction (Ugi4CR), allowing the introduction of two new amide bonds, using a carbonyl compound (an aldehyde or ketone), a carboxylic acid, an amine and an isocyanide. 11 Considering the value of amide groups in medicinal chemistry 12 and the feasibility of conducting the isatin-based Ugi reaction 13 (Scheme 1A), we decided to explore the use of amino-isatin derivatives as the amine component in Ugi4CR, which is so far unknown, in the literature (Scheme 1B).…”