126916-76-5Relevant academic research and scientific papers
Fluconazole analogues with metal-binding motifs impact metal-dependent processes and demonstrate antifungal activity in Candida albicans
Franz, Katherine J.,Hunsaker, Elizabeth W.,McAuliffe, Katherine J.
, (2020)
Abstract: Azole antifungals are an important class of antifungal drugs due to their low cost, ability to be administered orally, and broad-spectrum activity. However, their widespread and long-term use have given rise to adaptation mechanisms that render these compounds less effective against common fungal pathogens, including Candida albicans. New antifungals are desperately needed as drug-resistant strains become more prevalent. We recently showed that copper supplementation potentiates the activity of the azole antifungal fluconazole against the opportunistic fungal pathogen C. albicans. Here, we report eight new azole analogues derived from fluconazole in which one triazole group has been replaced with a metal-binding group, a strategy designed to enhance potentiation of azole antifungal activity by copper. The bioactivity of all eight compounds was tested and compared to that of fluconazole. Three of the analogues showed activity against C. albicans and two had lower levels of trailing growth. One compound, Flu-TSCZ, was found to impact the levels, speciation, and bioavailability of cellular metals. Graphic abstract: [Figure not available: see fulltext.]
Synthesis and antifungal activity of new hybrids thiazolo[4,5-d]pyrimidines with (1H-1,2,4)triazole
Blokhina, Svetlana V.,Doroshenko, Irina A.,Levshin, Igor B.,Ol'khovich, Marina V.,Perlovich, German L.,Sharapova, Angelica V.
supporting information, (2021/03/26)
Synthesis and antifungal activity of hybrids of thiazolo[4,5-d]pyrimidines with (1H-1,2,4)triazoles are presented. The solubility and lipophilicity of compounds was assessed and it was discovered that compounds with piperazine linker exhibited significant
Antifungal activity, mode of action variability, and subcellular distribution of coumarin-based antifungal azoles
Elias, Rebecca,Benhamou, Raphael I.,Jaber, Qais Z.,Dorot, Orly,Zada, Sivan Louzoun,Oved,Pichinuk, Edward,Fridman
, p. 779 - 790 (2019/07/10)
Azole antifungals inhibit the biosynthesis of ergosterol, the fungal equivalent of cholesterol in mammalian cells. Here we report an investigation of the activity of coumarin-substituted azole antifungals. Screening against a panel of Candida pathogens, including a mutant lacking CYP51, the target of antifungal azoles, revealed that this enzyme is inhibited by triazole-based antifungals, whereas imidazole-based derivatives have more than one mode of action. The imidazole-bearing antifungals more effectively reduced trailing growth associated with persistence and/or recurrence of fungal infections than triazole-based derivatives. The imidazole derivatives were more toxic to mammalian cells and more potently inhibited the activity of CYP3A4, which is one of the main causes of azole toxicity. Using live cell imaging, we showed that regardless of the type of azole ring fluorescent 7-diethylaminocoumarin-based azoles localized to the endoplasmic reticulum, the organelle that harbors CYP51. This study suggests that the coumarin is a promising scaffold for development of novel azole-based antifungals that effectively localize to the fungal cell endoplasmic reticulum.
Design and synthesis of new fluconazole analogues
Pore, Vandana S.,Agalave, Sandip G.,Singh, Pratiksha,Shukla, Praveen K.,Kumar, Vikash,Siddiqi, Mohammad I.
, p. 6551 - 6561 (2015/06/16)
We have synthesized new fluconazole analogues containing two different 1,2,3-triazole units in the side chain. The synthesis of new amide analogues using a variety of acids is also described. All the compounds showed very good antifungal activity. A hemol
Novel conformationally restricted triazole derivatives with potent antifungal activity
Wang, Wenya,Wang, Shengzheng,Liu, Yang,Dong, Guoqiang,Cao, Yongbing,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian,Sheng, Chunquan
scheme or table, p. 6020 - 6026 (2011/01/13)
In continuation of our work on azole antifungal agents, a series of new conformationally restricted triazole derivatives possessing benzylpiperidin-4-yl methyl amino side chains were designed and synthesized. All the new azoles showed moderate to excellent in vitro antifungal activity against most of the tested pathogenic fungi. Several compounds (such as 12e, 12f, 12h and 12n) showed higher antifungal activity against Candida albicans than fluconazole. Moreover, compounds 12g-i also showed good activity against Aspergillus fumigatus with their MIC80 on the level of 1 μg/mL. Flexible molecular docking was used to analyze the binding mode of the designed compounds. They interact with CACYP51 through hydrophobic and van der Waals interactions.
A short synthesis of 3,6-disubstituted N-2-thienyl/aryl-indoles
Borate, Hanumant B.,Sawargave, Sangmeshwer P.,Maujan, Suleman R.
, p. 6562 - 6566 (2011/03/17)
A short synthetic strategy for 3,6-disubstituted-N-2-thienyl/aryl-indoles, involving reaction of substituted 2,4-difluoro/dichloro-styrene epoxide with substituted 2-formylaminothiophenes or substituted N-formylanilines in the presence of a base followed by treatment with an acid, has been developed. The method was applied for the synthesis of a number of indoles with a variety of substituents at 1, 3, and 6 positions of the indole moiety.
Design, synthesis, and antifungal activity of novel conformationally restricted triazole derivatives
Wang, Wenya,Sheng, Chunquan,Che, Xiaoying,Ji, Haitao,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
experimental part, p. 732 - 739 (2010/06/11)
A series of new triazole derivatives were designed and synthesized on the basis of the active site of lanosterol 14α-demethylase from Candida albicans (CACYP51). 2-(2,4-Difluorophenyl)-3-(methyl-(3-phenoxyalkyl)amino)-1- (1H-1,2,4-triazol-1-yl)propan-2-ols show excellent in-vitro activity against most of the tested pathogenic fungi. The MIC80 value of compound 8a against Candida albicans is 0.01 μM, which provides a good starting template for further structural optimization. The binding modes of the designed compounds were investigated by flexible molecular docking. The compounds interacted with CACYP51 through hydrophobic, van-der-Waals, and hydrogenbonding interactions.
