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Novel naphthylamide derivatives as dual-target antifungal inhibitors: Design, synthesis and biological evaluation.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2021 Jan 15; Vol. 210, pp. 112991. Date of Electronic Publication: 2020 Nov 05. - Publication Year :
- 2021
-
Abstract
- Fungal infections have become a serious medical problem due to the high infection rate and the frequent emergence of drug resistance. Squalene epoxidase (SE) and 14α-demethylase (CYP51) are considered as the important antifungal targets, they can show the synergistic effect on antifungal therapy. In the study, a series of active fragments were screened through the method of De Novo Link, and these active fragments with the higher Ludi&#95;Scores were selected, which can show the obvious binding ability with the dual targets (SE, CYP51). Subsequently, three series of target compounds with naphthyl amide scaffolds were constructed by connecting these core fragments, and their structures were synthesized. Most of compounds showed the antifungal activity in the treatment of pathogenic fungi. It was worth noting that compounds 10b-5 and 17a-2 with the excellent broad-spectrum antifungal properties also exhibited the obvious antifungal effects against drug-resistant fungi. Preliminary mechanism study has proved these target compounds can block the biosynthesis of ergosterol by inhibiting the activity of dual targets (SE, CYP51). Furthermore, target compounds 10-5 and 17a-2 with low toxicity side effects also demonstrated the excellent pharmacological effects in vivo. The molecular docking and ADMET prediction were performed, which can guide the optimization of subsequent lead 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 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Amides chemical synthesis
Amides chemistry
Antifungal Agents chemical synthesis
Antifungal Agents chemistry
Dose-Response Relationship, Drug
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Amides pharmacology
Antifungal Agents pharmacology
Aspergillus drug effects
Candida drug effects
Drug Design
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 210
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33183866
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112991