Synthesis and biological evaluation of novel 3-substituted amino-4-hydroxylcoumarin derivatives as chitin synthase inhibitors and antifungal agents

Abstract

A series of novel 3-substituted amino-4-hydroxycoumarin derivatives have been designed and synthesized as chitin synthase (CHS) inhibitors. All the synthesized compounds have been screened for their CHS inhibition activity and antimicrobial activity in vitro. The enzymatic assay indicated that most of the compounds have good inhibitory activity against CHS, in which compound 6o with IC 50 of 0.10 mmol/L had stronger activity than that of polyoxins B, which acts as control drug with IC 50 of 0.18 mmol/L. As far as the antifungal activity is concerned, most of the compounds possessed moderate to excellent activity against some representative pathogenic fungi. Especially, compound 6b was found to be the most potent agent against Cryptococcus neoformans with minimal inhibitory concentration (MIC) of 4 lg/mL. Moreover, the results of antibacterial screening showed that these compounds have negligible actions to some tested bacteria. Therefore, these compounds would be promising to develop selective antifungal agents.

Preliminary Study on Antifungal Mechanism of Aqueous Extract of Cnidium monnieri Against Trichophyton rubrum

“…In addition, when combined with common antifungals, natural compounds can minimize the side effects of the dose-related toxicity of these drugs ( Zhang et al, 2014 ) and contribute to the treatment of drug-resistant strains ( Ghelardi et al, 2014 ; Ghannoum, 2016 ; Danielli et al, 2018 ; Singh et al, 2018 ). Coumarin in C. monnieri (L.) has recently attracted much attention because it can be used as a common fragment to design new compounds with pharmacological activities ( Mladenović et al, 2009 ; Kurdelas et al, 2010 ; Ge et al, 2016 ). For example, researchers have designed novel antifungal CHS inhibitors based on coumarins from C. monnieri (L.) that share a side chain with neomycin and polymyxin ( Ge et al, 2016 ).…”

“…Coumarin in C. monnieri (L.) has recently attracted much attention because it can be used as a common fragment to design new compounds with pharmacological activities ( Mladenović et al, 2009 ; Kurdelas et al, 2010 ; Ge et al, 2016 ). For example, researchers have designed novel antifungal CHS inhibitors based on coumarins from C. monnieri (L.) that share a side chain with neomycin and polymyxin ( Ge et al, 2016 ). We can also try to modify and transform the chemical structure of the Cnidium Cnidii monomer to improve the antimicrobial efficacy of traditional Chinese medicine monomer.…”

Fungal cell wall: An underexploited target for antifungal therapies

“…For example, a Chs1-specific inhibitor, RO-09-3143, blocked septum formation by Chs1 and arrested cell growth, but inhibition of Chs1 was only lethal in chs2Δ deletion mutant suggesting functional redundancy [3]. Other chitin synthase inhibitors such as the 3-substituted amino-4-hydroxycoumarin derivatives have also been found to have antifungal activity [4], but none has made it to the clinic.…”

Synthesis, Characterization, and Molecular Docking Study of Some Novel Imidazole Derivatives as Potential Antifungal Agents

“…Clinically, representative antifungal drugs have certain limitation such as narrow spectrum of activity, non‐optimal pharmacokinetics, and the emergence of drug resistance (generally azoles). Therefore, there is an urgent need for development of antifungal agents of new molecular scaffolds with high efficiency, broad spectrum, and optimal pharmacokinetics that are highly desirable .…”