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Design, synthesis and bioactivity evaluation of novel arylalkene-amide derivatives as dual-target antifungal inhibitors.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2020 Nov 01; Vol. 205, pp. 112645. Date of Electronic Publication: 2020 Jul 28. - Publication Year :
- 2020
-
Abstract
- Ergosterol as the core component of fungal cell membrane plays a key role in maintaining cell morphology and permeability. The squalenee epoxidase (SE) and 14-demethylase (CYP51) are the important rate-limiting enzymes for ergosterol synthesis. In the study, these active fragments, which is derived from the structural groups of the common antifungal agents, were docked into the active sites of dual targets (SE, CYP51), respectively. Some of active fragments with the matching MCSS&#95;Score values were selected and connected to construct three different series of novel arylalkene-amide derivatives as dual-target (SE, CYP51) antifungal inhibitors. Subsequently, these compounds were further synthesized, and their bioactivity was evaluated. Most of compounds showed a certain degree of antifungal activity in vitro. It was worth noting that the target compounds 17a and 25a with excellent antifungal activity (0.125-4 μg/mL) can inhibit the fluconazole-resistant Candida Strain 17#, CaR, 632, and 901 in the range of MIC values (4-8 μg/mL). Furthermore, their molecular mechanism, structural stability and low toxicity were further confirmed. The molecular docking and ADMET properties were predicted to guide the subsequent optimization of target compounds.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2020. Published by Elsevier Masson SAS.)
- Subjects :
- 14-alpha Demethylase Inhibitors chemical synthesis
14-alpha Demethylase Inhibitors chemistry
14-alpha Demethylase Inhibitors pharmacology
Amides chemistry
Antifungal Agents chemistry
Candida drug effects
Candida enzymology
Chemistry Techniques, Synthetic
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Targeted Therapy
Protein Conformation
Squalene Monooxygenase antagonists & inhibitors
Squalene Monooxygenase chemistry
Squalene Monooxygenase metabolism
Sterol 14-Demethylase
Alkenes chemistry
Amides chemical synthesis
Amides pharmacology
Antifungal Agents chemical synthesis
Antifungal Agents pharmacology
Drug Design
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 205
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32791399
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112645