Nouvelles synthèses d’hétérocycles Azotés et Oxygénés, évaluation biologique et étude théorique

Abstract

The objective of the work presented in this thesis is to develop new approaches to access a variety of nitrogen- and oxygen-containing polyheterocyclic compounds, as well as to evaluate their biological activity and conduct theoretical studies using DFT and molecular docking. The first chapter of the thesis is structured into three parts. In the first part of the first chapter, we investigated the effect of two new catalysts, Pyridinium-p-toluenesulfonate and triethylamine, for synthesizing derivatives of 2-amino-4-(aryl)-7-methyl-5-oxo-4H,5Hpyrano[4,3-b]pyran-3-carbonitrile, achieving high yields in reduced time. The structures of the compounds were confirmed by RMN and HRMS. The antibacterial tests on the synthesized compounds showed promising results. However, the tests for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition, as well as the evaluation of antioxidant activity, yielded limited performances. A DFT study was conducted on three representative molecules, and molecular docking assessed the antibacterial activity of the most promising compound. In the second part of the first chapter, we investigated a selective multi-component transformation of salicylaldehydes, 4-hydroxy-6-methyl-2H-pyran-2-one, and malononitrile in the presence of 10 mol% of PPTS. This reaction led to the formation of 2,4-diamino-5-[4- hydroxy-6-methyl-2-oxo-2H-pyran-3-yl]-5H-chromeno[2,3-b]pyridine-3-carbonitrile with excellent yields. The synthesized molecules showed promising potential in terms of biological activity. In the third part of the first chapter, we investigated the synthesis of several derivatives of tacrine successfully, with satisfactory yields. Spectroscopic analyses by RMN 1H and 13C confirmed the structures of the synthesized compounds, revealing characteristics consistent with expectations. In the second chapter, we developed a novel, simple, and effective method using DMAP as a catalyst without solvent to synthesize derivatives of 5-arylidene-thiazolidine-2,4-dione, obtained with excellent yields via Knoevenagel reaction. The compounds were characterized by RMN spectroscopy, and their physical properties were determined. Evaluation of antioxidant activity revealed the impact of substituents on their biological activity, with some compounds showing promising antioxidant activity. Computational simulations corroborated these observations. Additionally, we explored the potential of molecular docking for studying inhibition of PIM-1 kinase. In the third chapter, we investigated the synthesis of 4-arylmethylene-3-methylisoxazole- 5(4H)-ones using Na₂SO₃ as a catalyst. This choice of catalyst proved advantageous due to its non-hazardous and non-toxic nature, being a safe and easily handled food additive. The use of water as a solvent, environmentally friendly, allowed the reaction to proceed under mild conditions. The obtained products were pure with excellent yields. Additionally, all parts are accompanied by a recent, rich, and varied bibliography.