Design, synthesis &amp; evaluation of condensed 2H-4-arylaminopyrimidines as novel antifungal agents

Jain, Kishor S.; Khedkar, Vijay M.; Arya, Nikhilesh; Rane, Prasad V.; Chaskar, Pratip K.; Coutinho, Evans C.

doi:10.1016/j.ejmech.2014.02.066

Cited by 20 publications

(7 citation statements)

References 18 publications

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“…Several studies have been performed, and many of them have supported the finding that benzimidazole and triazole rings were significant structural moieties for antifungal activity [18][19][20][21][22][23][24][25][26][27][28]. In the present study, prompted from anticandidal potential of azole compounds, new benzimidazoletriazole hybrid compounds were synthesized and evaluated for antifungal activity.…”

Section: Introductionmentioning

confidence: 97%

Synthesis, Molecular Docking Studies, and Antifungal Activity Evaluation of New Benzimidazole-Triazoles as Potential Lanosterol 14α-Demethylase Inhibitors

Can

Çevik

Sağlık

et al. 2017

Journal of Chemistry

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Due to anticandidal importance of azole compounds, a new series of benzimidazole-triazole derivatives ( a-s) were designed and synthesized as ergosterol inhibitors. The chemical structures of the target compounds were characterized by spectroscopic methods. The final compounds were screened for antifungal activity against Candida glabrata (ATCC 90030), Candida krusei (ATCC 6258), Candida parapsilosis (ATCC 22019), and Candida albicans (ATCC 24433). Compounds i and s exhibited significant inhibitory activity against Candida strains with MIC 50 values ranging from 0.78 to 1.56 g/mL. Cytotoxicity results revealed that IC 50 values of compounds i and s against NIH/3T3 are significantly higher than their MIC 50 values. Effect of the compounds i and s against ergosterol biosynthesis was determined by LC-MS-MS analysis. Both compounds caused a significant decrease in the ergosterol level. The molecular docking studies were performed to investigate the interaction modes between the compounds and active site of lanosterol 14--demethylase (CYP51), which is as a target enzyme for anticandidal azoles. Theoretical ADME predictions were also calculated for final compounds.

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Section: Introductionmentioning

confidence: 97%

Synthesis, Molecular Docking Studies, and Antifungal Activity Evaluation of New Benzimidazole-Triazoles as Potential Lanosterol 14α-Demethylase Inhibitors

Can

Çevik

Sağlık

et al. 2017

Journal of Chemistry

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“…In detail, it is reported that there are three distinct parts in the CYP51 active site (Figure 2A): (a) an azole ring (coordinated to the heme iron of CYP51); (b) hydrophobic channel I; (c) another narrow hydrophobic channel II (substrate entry channel). 16 Another reason why coumarin is selected as a merging fragment is that it can bind to the hydrophobic channel II of CYP51 as a hydrophobic fragment. Considering the structural features of CYP51 inhibitors and coumarin, a series of novel coumarin-containing azole derivatives were designed and synthesized for activity validation.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Developing Novel Coumarin-Containing Azoles Antifungal Agents by the Scaffold Merging Strategy for Treating Azole-Resistant Candidiasis

Yan,

Huang,

Zhao

et al. 2023

J. Med. Chem.

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The extensive use of antifungal drugs has resulted in severe drug resistance, making clinical treatment of fungal infections more difficult. Biofilm inhibitors can overcome drug resistance by inhibiting fungal biofilm formation. In this study, some coumarins with antibiofilm activity were merged into CYP51 inhibitors to produce novel molecules possessing potent antiresistance activity. As expected, most compounds exhibited excellent in vitro antifungal activity against pathogenic fungi, especially fluconazole-resistant candidiasis. Then, their mechanism was confirmed by sterol composition analysis and morphological observation. Biofilm inhibition and down-regulation of resistancerelated genes were employed to confirm the compounds' antiresistance mechanisms. Significantly, compound A32 demonstrated fungicidal activity against fluconazole-resistant strain 904. Most importantly, compound A32 showed potent in vivo antifungal activity against pathogenic fungi and fluconazole-resistant strains. Preliminary pharmacokinetic and toxicity tests demonstrated that the compounds possessed favorable druggability. Taken together, compound A32 represents a promising lead to develop novel antifungal agents for treating azole-resistant candidiasis.

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“…In addition to the categories previously mentioned, numerous reports have been published describing the creation of novel structures for antifungal activities. Jain et al (2014) reported and synthesized a series of 2 H ‐4‐arylaminopyridimines derivatives and evaluated them for antifungal activity. The results of the test showed that most of the prepared compounds were found to display remarkable potential against the various strains.…”

Section: Synthetic Antifungal Agentsmentioning

confidence: 99%

Recent advances in antifungal drug development targeting lanosterol 14α‐demethylase (CYP51): A comprehensive review with structural and molecular insights

Singh

Sharma

et al. 2023

Chem Biol Drug Des

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Fungal infections are posing serious threat to healthcare system due to emerging resistance among available antifungal agents. Among available antifungal agents in clinical practice, azoles (diazole, 1,2,4‐triazole and tetrazole) remained most effective and widely prescribed antifungal agents. Now their associated side effects and emerging resistance pattern raised a need of new and potent antifungal agents. Lanosterol 14α‐demethylase (CYP51) is responsible for the oxidative removal of 14α‐methyl group of sterol precursors lanosterol and 24(28)‐methylene‐24,25‐dihydrolanosterol in ergosterol biosynthesis hence an essential component of fungal life cycle and prominent target for antifungal drug development. This review will shed light on various azole‐ as well as non‐azoles‐based derivatives as potential antifungal agents that target fungal CYP51. Review will provide deep insight about structure activity relationship, pharmacological outcomes, and interactions of derivatives with CYP51 at molecular level. It will help medicinal chemists working on antifungal development in designing more rational, potent, and safer antifungal agents by targeting fungal CYP51 for tackling emerging antifungal drug resistance.

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Design, synthesis & evaluation of condensed 2H-4-arylaminopyrimidines as novel antifungal agents

Cited by 20 publications

References 18 publications

Synthesis, Molecular Docking Studies, and Antifungal Activity Evaluation of New Benzimidazole-Triazoles as Potential Lanosterol 14α-Demethylase Inhibitors

Synthesis, Molecular Docking Studies, and Antifungal Activity Evaluation of New Benzimidazole-Triazoles as Potential Lanosterol 14α-Demethylase Inhibitors

Developing Novel Coumarin-Containing Azoles Antifungal Agents by the Scaffold Merging Strategy for Treating Azole-Resistant Candidiasis

Recent advances in antifungal drug development targeting lanosterol 14α‐demethylase (CYP51): A comprehensive review with structural and molecular insights

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