Abstract
The design and synthesis of novel sterol hydrazone analogues ( 9, 10, 11 and 12) are described, followed by their evaluation as inhibitors of fungal growth, using Paracoccidioides brasiliensis as the biological tester. Compounds 9, 10, 11 and 12 generated a dose-dependent effect in fungal growth, particularly 9, 11 and 12, which were active at nanomolar concentrations (100 nM). When P. brasiliensis in its pathogenic yeast-like phase was treated individually with each of the aforementioned compounds at concentrations that reduced growth rate around 50%, the analysis of sterol composition in the resulting surviving cells demonstrated a 50% reduction of the final sterols brasicasterol and ergosterol, and concomitant increase in the levels of lanosterol. These results indicate that these compounds inhibit the enzyme Δ 24-sterol methyl transferase (SMT), in a manner dependent on the stereochemical location of the hydrazone group. Compound 12, instead, induced a good antiproliferative activity not associated with blockage of any step in the pathway to sterol biosynthesis, suggesting a different mode of action. The X-ray crystal structure of H1 was determined to obtain information regarding the rings and side chain conformation of the sterol hydrazones. Comparison of the inhibitory effects of sterol hydrazones ( 9– 12) and azasterols (AZA1–AZA3) on SMT with the molecular electrostatic potential, negative isopotential energy surfaces (−10 kcal/mol) and local ionization potential calculated via DFT methods, showed that changes in the electronic moiety introduced by the N and O atoms were not as important as the additional flexibility of the side chain introduced by an extra methylene group.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.