Structure-based rational design, synthesis and antifungal activity of oxime-containing azole derivatives

Xu, Yulan; Sheng, Chunquan; Wang, Wenya; Che, Xiaoying; Cao, Yongbing; Dong, Guoqiang; Wang, Shengzheng; Ji, Haitao; Miao, Zhenyuan; Yao, Jing; Zhang, Wannian

doi:10.1016/j.bmcl.2010.03.014

Cited by 31 publications

(20 citation statements)

References 29 publications

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“…Various functional fragments have been designed and combined to fit the model (Fig. ), and most of the resulting compounds showed good antifungal activity against clinically important pathogenic fungi . Several new triazole derivatives showed better activity than itraconazole and fluconazole with minimum inhibitory concentration (MIC) values ranging from 0.25 μg/mL to 0.001 μg/mL.…”

Section: From Fragments To Leads: De Novo Drug Designmentioning

confidence: 99%

Fragment Informatics and Computational Fragment‐Based Drug Design: An Overview and Update

Sheng

Zhang

2012

Medicinal Research Reviews

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Fragment-based drug design (FBDD) is a promising approach for the discovery and optimization of lead compounds. Despite its successes, FBDD also faces some internal limitations and challenges. FBDD requires a high quality of target protein and good solubility of fragments. Biophysical techniques for fragment screening necessitate expensive detection equipment and the strategies for evolving fragment hits to leads remain to be improved. Regardless, FBDD is necessary for investigating larger chemical space and can be applied to challenging biological targets. In this scenario, cheminformatics and computational chemistry can be used as alternative approaches that can significantly improve the efficiency and success rate of lead discovery and optimization. Cheminformatics and computational tools assist FBDD in a very flexible manner. Computational FBDD can be used independently or in parallel with experimental FBDD for efficiently generating and optimizing leads. Computational FBDD can also be integrated into each step of experimental FBDD and help to play a synergistic role by maximizing its performance. This review will provide critical analysis of the complementarity between computational and experimental FBDD and highlight recent advances in new algorithms and successful examples of their applications. In particular, fragment-based cheminformatics tools, high-throughput fragment docking, and fragment-based de novo drug design will provide the focus of this review. We will also discuss the advantages and limitations of different methods and the trends in new developments that should inspire future research.

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Section: From Fragments To Leads: De Novo Drug Designmentioning

confidence: 99%

Fragment Informatics and Computational Fragment‐Based Drug Design: An Overview and Update

Sheng

Zhang

2012

Medicinal Research Reviews

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“…2). The search for new antifungals structurally related to fluconazole still continues [10,[22][23][24][25]. Moreover, some oxiconazole analogs are potent antifungal agents having oxime ether group in their structures [26][27][28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

“…Azole derivatives are the most extensively studied class of antifungal agents due to their high therapeutic index, good bioavailability, and favorable safety profile [10,11]. In addi- tion, antifungal azoles are known as significant lead compounds and useful templates in drug discovery since they offer a clear identity of the target enzyme and adequate specificity for fungal organisms [1,12].…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological activities of novel azole-bonded $$\upbeta $$ β -hydroxypropyl oxime O-ethers

et al. 2014

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The synthesis and biological effects of 15 novel azole-bonded β-hydroxypropyl oxime O-ethers have been described. In this synthesis, the oximation of aromatic ketones followed by an O-alkylation reaction with epichlorohydrin and/or epibromohydrin led to the corresponding O-oxime ether adducts. Subsequently, the attained O-oxime ether adducts were used to synthesize the target molecules after treating them with the appropriate azole derivatives. The in vitro antifungal and antibacterial activities of title compounds were obtained against several pathogenic fungi, Gram-positive and/or Gram-negative bacteria. Benzophenone O-2-hydroxy-3-(2-phenyl-1 H-imidazol-1-yl) propyl oxime and 9H-fluoren-9-one O-2-hydroxy-3-(2-phenyl-1 H-imidazol-1-yl)propyl oxime proved to have considerable antifungal activity against Candida albicans, Candida krusei, Aspergillus niger, and Trichophyton rubrum. These two compounds demonstrated comparable antifungal activity to clotrimazole and fluconazole (standard drugs). All compounds were also tested against Escherichia coli and Staphylococcus aureus as Gram-negative and Gram-positive bacteria, respectively, and their activities were compared to gentamycin and ampicillin (reference drugs). In general, marginal antibacterial activity against tested bacteria was observed for the title compounds. A molecular docking study is also discussed for the two most potent compounds against fungi. The docking study reveals a considerable interaction between the two most potent compounds and the active site of Mycobacterium P450DM. Moreover, these two compounds are much strongly bound to the active site of Mycobacterium P450DM compared to fluconazole.

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“…The azole derivatives are known for exhibiting good bioavailability, high therapeutic index, favourable safety profile and low toxicity [9,10]. It is well established that azole cores in most azole antifungal drugs are the main pharmacophoric sites for establishing antifungal activity.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of novel 1,2,3-triazolyl $$\upbeta $$ β -hydroxy alkyl/carbazole hybrid molecules

Rad

Behrouz

et al. 2016

Mol Divers

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The design, synthesis and biological study of several novel 1,2,3-triazolyl [Formula: see text]-hydroxy alkyl/carbazole hybrid molecules as a new type of antifungal agent has been described. In this synthesis, the N-alkylation reaction of carbazol-9-ide potassium salt with 3-bromoprop-1-yne afforded 9-(prop-2-ynyl)-9H-carbazole. The 'Click' Huisgen cycloaddition reaction of 9-(prop-2-ynyl)-9H-carbazole with diverse [Formula: see text]-azido alcohols in the presence of copper-doped silica cuprous sulphate led to target molecules in excellent yields. The in vitro antifungal and antibacterial activities of title compounds were screened against various pathogenic fungal strains, Gram-positive and/or Gram-negative bacteria. In particular, 1-(4-((9H-carbazol-9-yl) methyl)-1H-1,2,3-triazol-1-yl)-3-butoxypropan-2-ol (10e) proved to have potent antifungal activity against all fungal tests compared with fluconazole and clotrimazole as studied reference drugs. Our molecular docking analysis revealed an appropriate fitting and a potential powerful interaction between compound 10e and an active site of the Mycobacterium P450DM enzyme. The strong hydrogen bondings between [Formula: see text]-hydroxyl and ether groups in 10e were found to be the main factors that drive the molecule to fit in the active site of enzyme. The in silico pharmacokinetic studies were used for a better description of 10a-10n as potential lead antifungal agents for future investigations.

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Structure-based rational design, synthesis and antifungal activity of oxime-containing azole derivatives

Cited by 31 publications

References 29 publications

Fragment Informatics and Computational Fragment‐Based Drug Design: An Overview and Update

Fragment Informatics and Computational Fragment‐Based Drug Design: An Overview and Update

Design, synthesis, and biological activities of novel azole-bonded $$\upbeta $$ β -hydroxypropyl oxime O-ethers

Design, synthesis and biological evaluation of novel 1,2,3-triazolyl $$\upbeta $$ β -hydroxy alkyl/carbazole hybrid molecules

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