Design and Synthesis of Imidazole and Benzimidazole Derivatives as Antifungal Agents (original) (raw)
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Design, synthesis, and antifungal activity of triazole and benzotriazole derivatives
European Journal of Medicinal Chemistry, 2009
This study describes the design, synthesis and evaluation of a novel series of 1,2,4-triazole and benzotriazole derivatives as inhibitors of cytochrome P450 14a-demethylase (14DM). The chemical structures of the new compounds were confirmed by elemental and spectral ( 1 H NMR, 13 C NMR, Mass) analyses. Compounds were designed by a generating virtual library of compounds and docking them into the enzyme active site. Furthermore, they were found to have in vitro activity against Microsporum canis, Trichophyton mentagrophyte, Trichophyton rubrum, Epidermophyton floccosum, and Candida albicans comparable to fluconazole and clotrimazole.
A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols (1aev, 2aew), which are analogues of fluconazole, have been designed and synthesized as the potential antifungal agents by the click reaction. Click reaction approach toward the synthesis of two sets of novel 1,2,3triazolyl linked triazole antifungal derivatives 1aev, 2aew was achieved by Cu(I)-catalyzed 1,3-dipolar cycloaddition of propargylated intermediate 8 with substituted azidomethyl benzene. The 1,2,3-triazolyl group was inserted into the side chain of the target molecule which can increase the antifungal activity of compounds.
Design and Synthesis of 2-Methyl and 2-Methyl-4-Nitro Imidazole Derivatives as Antifungal Agents
Iranian Journal of …, 2009
Two series (a and b) of N-substituted heteroaromatic compounds related to clotrimazole were synthesized. Imidazole ring of the clotrimazole was replaced by 2-methylimidazole in series a, and by 2-methyl-4-nitroimidazole in series b. Ocholortrityl moiety of clotrimazole was also replaced by trityl, mono or dimethoxy trityl. Chemical structures of all the new compounds were confirmed by spectrophotometric methods. These compounds docked into the active site of MT-CYP51 (PDB code, 1E9X) using Autodock tools software which showed good affinity for the enzyme. Antifungal activities of these compounds were evaluated against Trichophyton mentagrophytes, Microsporum gypseum and Candida albicans using SC, SCC and PDA as media, CHCl 3 and DMSO as solvents and agar dilution assay as method. In this method 1(4-methoxyphenyl-diphenylmethyl)-2-methyl imidazole (2), 1[bis-4-methoxyphenyl-phenylmethyl]-2-methyl imidazole (3) and 1[4-methoxyphenyl-diphenylmethyl]-2-methyl-4-nitroimidazole (5) showed more than 75% activity against fungi. In the second step all of the derivatives also were evaluated against Trichophyton rubrum, Microsporum canis and Epidermaphyton floccosum using PDA medium by agar dilution method. Compound 2 showed more than 75% activity by this method. Then the most active analogue (2) was tested in RPMI 1640 medium which showed desirable biological activity in comparison to clotrimazole.
Synthesis and In Vitro Evaluation of Novel 1, 2, 4-Triazole Derivatives as Antifungal Agents
Letters in Drug Design & Discovery, 2010
Despite the advances in medicine and the emergence of new antifungal agents, fungal infections remain a significant cause of morbidity and mortality. Azoles are widely used as antifungal agents. Azoles interfere with the conversion of lanosterol to ergosterol by inhibiting a fungal cytochrome P450enzyme, lanosterol 14-demethylase. Resistance to azoles, particularly fluconazole, is emerging to Candida albicans, after long-term suppressive therapy. Thus, there is an urgent need for newer potent antifungals to combat resistance developed against widely used azoles. In present work, we report synthesis of novel triazole derivatives of 7-hydroxy-4-methylcoumarin using various substituted aromatic aldehydes and evaluated for their in vitro fungicidal activity against Candida albicans at various concentrations to obtain minimum inhibitory concentration (MIC).
Molecules, 2017
In this study two series of fluconazole derivatives bearing nitrotriazole (series A) or piperazine ethanol (series B) side chain were designed and synthesized and then docked in the active site of lanosterol 14α-demethylase enzyme (1EA1) using the Autodock 4.2 program (The scripps research institute, La Jolla, CA, USA). The structures of synthesized compound were confirmed by various methods including elemental and spectral (NMR, CHN, and Mass) analyses. Then antifungal activities of the synthesized compound were tested against several natural and clinical strains of fungi using a broth microdilution assay against several standard and clinical fungi. Nitrotriazole derivatives showed excellent and desirable antifungal activity against most of the tested fungi. Among the synthesized compounds, 5a-d and 5g, possessing nitrotriazole moiety, showed maximum antifungal activity, in particular against several fluconazole-resistant fungi.
Design, synthesis and evaluation of 1, 2, 4-triazole derivatives as antifungal
Journal of Current Pharma Research
A series of 1, 2, 4-triazoles was designed, synthesized and screened for antifungal activity against strain of Aspergillus niger. The design of the triazole compounds was based on docking studies performed on Lanosterol 14α-demethylase an important enzyme required for the synthesis of ergosterol. The three-dimensional QSAR studies of 1, 2, 4-triazole for analysis of the structural requirements for antifungal activity using Vlife MDS 3.5 has been carried out. The negative logarithm of activity (MICs) of the compounds against resistant Aspergillus niger exhibited a strong correlation with the selected 3D molecular descriptors of the triazole analogues. The present findings suggest that the triazole framework is an attractive template for optimization of targeted antifungal activity to achieve better potency and a wider spectrum of activity.
Exploration of Antifungal Potential of Carbohydrate‐Tethered Triazoles as CYP450 Inhibitors
ChemistrySelect, 2018
In search of potent and novel antifungal agents, herein, the authors report the synthesis, chemical characterization and biological evaluation of triazole tethered glycoconjugates. The structural verification of the molecules was carried out by 13C NMR, 1H NMR and mass spectra analysis. The in vitro antifungal activity was investigated against three filamentous fungi, Trichoderma viride 4329, Aspergillus fumigatus 3007 and Sporothrix schenckii. Among the synthesized compounds, it was observed that compound 10f completely inhibited the fungal growth giving a Minimum Inhibitory Concentration (MIC) value of 800 μg/ml against Aspergillus fumigatus 3007. Moreover through microscopic analysis, using Scanning Electron Microscopy and confocal imaging, it was detected that the compound had induced pronounced irreversible membrane damage and disruption of fungal mycelium.
Bioorganic & Medicinal Chemistry Letters, 2010
In an attempt to find novel azole antifungal agents with improved activity and broader spectrum, computer modeling was used to design a series of new azoles with piperidin-4-one O-substituted oxime side chains. Molecular docking studies revealed that they formed hydrophobic and hydrogen-bonding interactions with lanosterol 14a-demethylase of Candida albicans (CACYP51). In vitro antifungal assay indicates that most of the synthesized compounds showed good activity against tested fungal pathogens. In comparison with fluconazole, itraconazole and voriconazole, several compounds (such as 10c, 10e, and 10i) show more potent antifungal activity and broader spectrum, suggesting that they are promising leads for the development of novel antifungal agents.
Journal of Medicinal Chemistry, 2018
Because of the increase in the number of immunocompromised patients, the incidence of invasive fungal infections is growing, but the treatment efficiency remains unacceptably low. The most potent clinical systemic antifungals (azoles) are the derivatives of two scaffolds: ketoconazole and fluconazole. Being the safest antifungal drugs, they still have shortcomings, mainly because of pharmacokinetics and resistance. Here, we report the successful use of the target fungal enzyme, *
2014
A novel series of biphenyl carbonyl piperazine moiety carrying benzimidazole derivatives, based on an initial design by molecular docking study of this scaffold at the active site of the fungal enzyme of cytochrome P450 family, lanosterol 14 α-demethylase (CYP51) was synthesized by microwave irradiation. The synthesized compounds were characterized by elemental and spectral analysis (IR, 1 H NMR and mass spectrometry).The screening of the synthesized compounds for invitro antifungal activity against Candida albicans revealed activity in many of the compounds as comparable to that of ketoconazole. .