1,3,5-Triazine Nitrogen Mustards with Different Peptide Group as Innovative Candidates for AChE and BACE1 Inhibitors.

Beata Kolesińska,Danuta Drozdowska,Agnieszka Wróbel,Dawid Maliszewski,Justyna Frączyk

doi:10.3390/molecules26133942

Abstract

A series of new analogs of nitrogen mustards (4a–4h) containing the 1,3,5-triazine ring substituted with dipeptide residue were synthesized and evaluated for the inhibition of both acetylcholinesterase (AChE) and β-secretase (BACE1) enzymes. The AChE inhibitory activity studies were carried out using Ellman’s colorimetric method, and the BACE1 inhibitory activity studies were carried out using fluorescence resonance energy transfer (FRET). All compounds displayed considerable AChE and BACE1 inhibition. The most active against both AChE and BACE1 enzymes were compounds A and 4a, with an inhibitory concentration of AChE IC50 = 0.051 µM; 0.055 µM and BACE1 IC50 = 9.00 µM; 11.09 µM, respectively.

Highlights

Medicinal chemistry plays a crucial role in the design, synthesis, and development of novel bioactive molecules, and this allows for the potential use of different drug discovery strategies
We presented a synthesis of triazine derivatives bearing one, two, or three 2-chloroethylamine residues [16], which can be classified as derivatives of nitrogen mustards (NMs) used as antiproliferative agents in the treatment of ovarian carcinoma, leukemia, lymphoma, and multiple myelomas [17,18]
Dine)The intosynthesis the peptide fragment because it was expected that these amino acids would of new analogs of nitrogen mustards 4a–4h containing the 1,3,5-triazine form substituted ionic bondswith withdipeptide carboxylate anionsisina the active center of enzymes and The facilitate ring residue multi-step process (Scheme 1)

Summary

Introduction

Medicinal chemistry plays a crucial role in the design, synthesis, and development of novel bioactive molecules, and this allows for the potential use of different drug discovery strategies. Owing to the immense and varied bioactivities of triazine derivatives, e.g., as an anticancer [5] antimicrobial [6], antiviral [7], antimalarial [8], antitubulin [9], and anti-inflammatory [7], several attempts have been made to modify the structure of triazine derivatives to improve their activities and to search for new attractive targets [10]. It has been reported that modifications at the 2-, 4-, and 6- positions of the triazine ring have allowed a wide group of derivatives associated with anti-cancer, anti-inflammatory, antibacterial properties, among others, to be obtained [12,13,14]. We presented a synthesis of triazine derivatives bearing one, two, or three 2-chloroethylamine residues [16], which can be classified as derivatives of nitrogen mustards (NMs) used as antiproliferative agents in the treatment of ovarian carcinoma, leukemia, lymphoma, and multiple myelomas [17,18]

Methods

Results

Conclusion