Synthesis, antibacterial and antifungal activities of hybrid molecules based on Alzheimer disease drugs and bearing an amino acid fragment

ABSTRACT

The objective of the current study was to develop novel compounds – memantine derivatives with antimicrobial activity designed for application in treatment of bacterial and fungal infections in patients suffering Alzheimer disease. To realize this objective a series of six memantine hybrid molecules were synthesized, characterized by data - ¹H NMR, ¹³C NMR, MS, X-ray and tested for their therapeutic properties as anti-Alzheimer agents and their antimicrobial potential.

The structure of the most active hybrid molecule 4-Phe-memantine (3b) was analyzed by single crystal X-ray diffraction and differential thermal analysis (DTA). The DTA measurement shows two endothermic effects the first in the 145 – 165 °C region and the second around 210 – 250 °C the first related to the release of a water molecule the second is the melting of the compound. No polymorphic changes associated to the temperature variations were detected. The single crystal X-ray study showed that compound 3b crystallize in a non-centrosymmetric manner (space group P2₁2₁2₁), with highly preserved geometry of the memantine and amino acid moieties.

The compounds were evaluated for their antimicrobial potential against clinically significant conditionally pathogenic Gram-negative bacteria and Gram-positive bacteria. Compounds 3b, 3c and 3e at 10 mM were the most active against Gram (+), Gram (-) bacteria and the yeast strains. The highest activity was demonstrated by 3b with MIC of 0.156 mM and MBC of 0.3 mM against Salmonella enterica (NBIMCC 8691). This compound as well strongly inhibited (up to 62.9%) the radial growth rate of Fusarium graminearum (NBIMCC 2294).