Synthesis and biological activity evaluation of phthalimide-donepezil hybrids / 药学学报

A series of phthalimide-donepezil (PTA-DPZ) hybrids (5a-e, 6a-l) were designed, synthesized and evaluated as selective inhibitors of acetylcholinesterase (AChE). The results showed that some hybrids had strong AChE inhibitory activity with half maximal inhibitory concentration (IC50) at nanomolar range, which was better than the control drugs galanthamine and tacrine, and equivalent to DPZ. Compound 6k exhibited the strongest inhibition to AChE with an IC50 value of 0.13 μmol·L-1. Kinetic and molecular modeling studies showed that 6k targeted both catalytic active site and peripheral anionic site of AChE. Moreover, some compounds could inhibit AChE-induced β-amyloid (Aβ) aggregation. In addition, absorption, distribution, metabolism and excretion prediction results showed 6k conforms to the Lipinski's rule of five and had high partition coefficient P value. These compounds, especially 6k, may be considered as a dual-functional lead compound for in-depth research.

Recent Advances and Future Prospects of Phthalimide Derivatives.

Among bicyclic non-aromatic nitrogen heterocycles, phthalimides are an interesting class of compounds with a large range of applications. Phthalimide contains an imide functional group and may be considered as nitrogen analogues of anhydrides or as diacyl derivatives of ammonia. They are lipophilic and neutral compounds and can therefore easily cross biological membranes in vivo and showing different pharmacological activities. In the present work compounds containing phthalimide subunit have been described as a scaffold to design new prototypes drug candidates with different biological activities and are used in different diseases as, for example AIDS, tumor, diabetes, multiple myeloma, convulsion, inflammation, pain, bacterial infection among others.

Synthesis of Some New Phthalimides as Anti-metabolic Agents with Chemotherapeutic Effects.

A series of new phthalimides 1(a-f) were synthesized via reaction phthalic anhydride with different amino acids under fusion conditions. Esterification of N-phthaloyl acid derivatives 1(a-f) with methanol in the presence of SOCl2 to producing the corresponding esters 2(a-f). Which on reaction with hydrazine hydrate in boiling n-butanol afforded the corresponding N-phthaloyl acid hydrazides 4(a-f) Reaction of compound (4a) with different aldehydes and ketones yielded the corresponding hydrazone derivatives 5(a-d). Some new phthalimides linked to hetero cyclic moieties such as benzimidazoles, benzoxazines and quinazolines were synthesized. The structure of the synthesized compounds was confirmed from their analytical and spectral data such as, IR spectra, 1H-NMR and mass spectra. Antimicrobial against two types of bacteria and anticancer activity for some of the synthesized imides were evaluated. The results showed that most of them have a good antimicrobial and anticancer activities.