Ugi Reaction Synthesis of Oxindole–Lactam Hybrids as Selective Butyrylcholinesterase Inhibitors

Abstract

Molecular hybridization is a valuable approach in drug discovery. Combining it with multicomponent reactions is highly desirable, since structurally diverse libraries can be attained efficiently in an eco-friendly manner. In this work, isatin is used as the key building block for the Ugi 4-center 3-component reaction synthesis of oxindole–lactam hybrids, under catalyst-free conditions. The resulting oxindole−β-lactam and oxindole−γ-lactam hybrids were evaluated for their potential to inhibit relevant central nervous system targets, namely cholinesterases and monoamine oxidases. Druglikeness evaluation was also performed, and compounds 4eca and 5dab exhibited great potential as selective butyrylcholinesterase inhibitors, at the low micromolar range, with an interesting predictive pharmacokinetic profile. Our findings herein reported suggest oxindole–lactam hybrids as new potential agents for the treatment of Alzheimer’s disease.

Ugi Four-Component Reactions Using Alternative Reactants

“…In order to investigate the inhabitation product’s potential, the final products were evaluated to inhibit relevant central nervous system targets, such as monoamine oxidases and cholinesterases. In addition, a drug-likeness evaluation was conducted, and a number of compounds demonstrate significant potential as selective butyrylcholinesterase inhibitors at low micromolar concentrations, with an intriguing predictive pharmacokinetic profile [ 79 ].…”

Recent developments on microwave-assisted organic synthesis of nitrogen- and oxygen-containing preferred heterocyclic scaffolds

“…Isatin is a heterocyclic compound used extensively as a foundational component in the synthesis and advancement of novel drug candidates. [148][149][150] The remarkable versatility of isatins, which can serve as electrophiles and nucleophiles, coupled with their ready availability, positions them as highly prized building blocks in organic synthesis. [151][152][153] They participate in a range of transformations, including electrophilic aromatic substitution at the C-5 and C-6 positions of the phenyl ring, 154 N-substitutions, 154 nucleophilic additions to the C-3 carbonyl group, 154 selective oxidations, reductions, ring expansions, spiroannulations, and more reactions.…”

review on green multicomponent synthesis of heterocyclic compounds

“…A molecule of pyridine contains a ring of six atoms-five carbon atoms and one nitrogen atom. Pyrrole, furan, and thiophene molecules each contain five-membered rings, composed of four atoms of carbon and one atom of nitrogen, oxygen, or sulfur, respectively [14][15][16][17][18]. Pyridine and pyrrole are both nitrogen heterocyclestheir molecules contain nitrogen atoms along with carbon atoms in the rings [19][20][21][22].…”