Discovery of novel indole and indoline derivatives against Candida albicans as potent antifungal agents

Ma, Jia; Jiang, Yuan; Zhuang, Xingying; Chen, Huiting; Shen, Yunhong; Mao, Zewei; Rao, G. Venkata; Wang, Ruirui

doi:10.1016/j.bmcl.2022.128826

Cited by 10 publications

(8 citation statements)

References 19 publications

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“…The formation of C. albicans biofilm is closely related to drug resistance (Colosi et al, 2009 ). Some studies have found that indole derivatives may inhibit mycelium growth and biofilm formation through the Ras‐cAMP‐PKA pathway (Ma et al, 2022 ). And our previous study also showed (1‐aryloxy‐2‐hydroxypropyl)‐phenylpiperazine compounds disrupt the hypha formation and biofilm formation of C. albicans mostly by interfering with the cAMP‐PKA and MAPK pathways (Zhao et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Anti‐virulence activity of novel (1‐heteroaryloxy‐2‐hydroxypropyl)‐ phenylpiperazine derivatives against both wild‐type and clinical drug‐resistant Candida albicans strains

Huang

Song

Zhao

et al. 2022

Microbial Biotechnology

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Candida albicans is an important human fungal pathogen. Our previous study disclosed that aryloxy‐phenylpiperazine skeleton was a promising molecule to suppress C. albicans virulence by inhibiting hypha formation and biofilm formation. In order to deeply understand the efficacy and mechanism of action of phenylpiperazine compounds, and obtain new derivatives with excellent activity against C. albicans, hence, we synthesized three series of (1‐heteroaryloxy‐2‐hydroxypropyl)‐phenylpiperazines and evaluated their inhibitory activity against C. albicans both in vitro and in vivo in this study. Compared with previously reported aryloxy‐phenylpiperazines, part of these heteroaryloxy derivatives improved their activities by strongly suppressing hypha formation and biofilm formation in C. albicans SC5314. Especially, (9H‐carbazol‐4‐yl)oxy derivatives 25, 26, 27 and 28 exhibited strong activity in reducing C. albicans virulence in both human cell lines in vitro and mouse infection models in vivo. The compound 27 attenuated the virulence of various clinical C. albicans strains, including clinical drug‐resistant C. albicans strains. Moreover, additive effects of the compound 27 with antifungal drugs against drug‐resistant C. albicans strains were also discussed. Furthermore, the compound 27 significantly improved the composition and richness of the faecal microbiota in mice infected by C. albicans. These findings indicate that these piperazine compounds have great potential to be developed as new therapeutic drugs against C. albicans infection.

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Section: Discussionmentioning

confidence: 99%

Anti‐virulence activity of novel (1‐heteroaryloxy‐2‐hydroxypropyl)‐ phenylpiperazine derivatives against both wild‐type and clinical drug‐resistant Candida albicans strains

Huang

Song

Zhao

et al. 2022

Microbial Biotechnology

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“…(Scheme 103). Jia Ma et al [122] developed a protocol for synthesis of indole and indoline derivatives (590-600). N-alkylated indole (587) was reacted with ethylenediamine to yield intermediates (588) and (589) followed by reaction with substituted aldehydes to synthesize final compounds (590-600).…”

Section: (A4)mentioning

confidence: 99%

“…Jia Ma et al [122] . developed a protocol for synthesis of indole and indoline derivatives (590–600) .…”

Section: Chemistry Of Indole Based Heterocycle Scaffoldsmentioning

confidence: 99%

Insight into Indole‐Based Heterocyclic Scaffolds: A Medicinal Chemistry Perspective

Bendi,

Versha,

Rajni

et al. 2023

ChemistrySelect

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The importance of indole‐based heterocycle scaffolds in medicinal chemistry has increased as a result of their significant pharmacological and biological characteristics. These compounds′ importance in the discovery and creation of cutting‐edge medications to treat a variety of diseases is an instance of their worth. The current study highlights the numerous methods available to create different indole‐based heterocycle scaffolds and their favourable medical uses with the literature that has been published up to 2023.

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“…The preparation of new title derivatives 6a−6v was carried out by a general procedure as shown in Scheme 2. All the synthesized compounds were characterized by 1 H NMR, 13 C NMR, and HRMS analysis. Initially, a mixture of N-acetyl-N′-(4-hydroxyphenyl)piperazine and 1,2-dibromoethane was heated in the presence of K 2 CO 3 for 12 h to give compound 1.…”

mentioning

confidence: 99%

“…In recent years, we have focused on finding new antifungal agents alone and combined with FLC against drug-sensitive and drug-resistant C. albicans. − Privileged-structure-based drug design (PSBDD) has been widely used in the design of drug molecules, in which the introduction of dominant structural units or fragments with good drug-like and drug-forming properties into the molecular skeleton of a compound can effectively improve its biological activity and drug-like properties. Based on PSBDD, we have designed and prepared new azole derivatives by recombination of fluconazole and ketoconazole structure units in the present work (Scheme ), and their in vitro antifungal activity against C.…”

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confidence: 99%

Synthesis and Antifungal Evaluation of New Azole Derivatives against Candida albicans

Hu,

Xu,

Huang

et al. 2023

ACS Med. Chem. Lett.

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In this study, we designed and prepared a series of new azole derivatives by recombination of fluconazole (FLC) and ketoconazole units, and in vitro antifungal activities against Candida albicans were evaluated. The results indicated that most azoles showed good antifungal activity against the drug-sensitive C. albicans strain, especially compounds 6a, 6e, 6n, 6p, 6r, 6s, 6t, and 6v, which displayed better antifungal activity (MIC50 < 1.0 μg/mL) than FLC against SC5314. The further mechanism study showed that compound 6r could significantly inhibit the formation of C. albicans biofilm, increase the permeability of the cell membrane, reduce the ergosterol level of the cell membrane, damage the membrane structure, and destroy the integrity of the cell structure to exert excellent antifungal activity. Subsequently, a molecular docking study indicated that azole compounds could inhibit cytochrome P450 14α-demethylase (CYP51). Therefore, these azole derivatives can be considered as potent antifungal drugs to treat fungal infections.

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Discovery of novel indole and indoline derivatives against Candida albicans as potent antifungal agents

Cited by 10 publications

References 19 publications

Anti‐virulence activity of novel (1‐heteroaryloxy‐2‐hydroxypropyl)‐ phenylpiperazine derivatives against both wild‐type and clinical drug‐resistant Candida albicans strains

Anti‐virulence activity of novel (1‐heteroaryloxy‐2‐hydroxypropyl)‐ phenylpiperazine derivatives against both wild‐type and clinical drug‐resistant Candida albicans strains

Insight into Indole‐Based Heterocyclic Scaffolds: A Medicinal Chemistry Perspective

Synthesis and Antifungal Evaluation of New Azole Derivatives against Candida albicans

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