Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
Daru. 2012 Oct 4;20(1):46. doi: 10.1186/2008-2231-20-46.
The currently available antifungal drugs suffer from toxicity, greatest potential drug interactions with other drugs, insufficient pharmacokinetics properties, and development of resistance. Thus, development of new antifungal agents with optimum pharmacokinetics and less toxicity is urgent task. In the search for new azole antifungals, we have been previously described azolylchromanone oxime ethers as rigid analogs of oxiconazole. In continuation of our work, we incorporated phenylhydrazone moiety instead of oxime ether fragment in azolylchromanone derivatives.
The 3-azolyl-4-chromanone phenylhydrazones were synthesized via ring closure of 2-azolyl-2'-hydroxyacetophenones and subsequent reaction with phenylhydrazine. The biological activity of title compounds was evaluated against different pathogenic fungi including Candida albicans, Saccharomyces cerevisiae, Aspergillus niger, and Microsporum gypseum. Docking study, in silico toxicity risks and drug-likeness predictions were used to better define of title compounds as antifungal agents.
The in vitro antifungal activity of compounds based on MIC values revealed that all compounds showed good antifungal activity against C. albicans, S. cerevisiae and M. gypseum at concentrations less than 16 μg/mL. Among the test compounds, 2-methyl-3-imidazolyl derivative 3b showed the highest values of drug-likeness and drug-score.
The 3-azolyl-4-chromanone phenylhydrazones considered as analogs of 3-azolyl-4-chromanone oxime ethers basically designed as antifungal agents. The antifungal activity of title compounds was comparable to that of standard drug fluconazole. The drug-likeness data of synthesized compounds make them promising leads for future development of antifungal agents.
现有的抗真菌药物存在毒性、与其他药物相互作用的最大潜力、药代动力学特性不足以及耐药性等问题。因此，迫切需要开发具有最佳药代动力学和较低毒性的新型抗真菌药物。在寻找新型唑类抗真菌药物的过程中，我们之前曾描述过唑基色满酮肟醚作为奥昔康唑的刚性类似物。在我们的工作基础上，我们用苯腙取代唑基色满酮衍生物中的肟醚片段。
3-唑基-4-色满酮苯腙通过 2-唑基-2'-羟基苯乙酮的环闭合和随后与苯肼反应合成。标题化合物的生物活性通过测定其对不同致病性真菌的抑制作用来评价，包括白色念珠菌、酿酒酵母、黑曲霉和石膏样毛癣菌。基于对接研究、计算毒性风险和药物相似性预测，进一步明确了这些化合物作为抗真菌药物的作用。
基于 MIC 值的体外抗真菌活性研究表明，所有化合物在浓度低于 16μg/mL 时均对白色念珠菌、酿酒酵母和石膏样毛癣菌表现出良好的抗真菌活性。在所测试的化合物中，2-甲基-3-咪唑基衍生物 3b 表现出最高的药物相似性和药物评分。
作为 3-唑基-4-色满酮肟醚类似物的 3-唑基-4-色满酮苯腙类化合物被认为是基本设计为抗真菌药物的化合物。标题化合物的抗真菌活性与标准药物氟康唑相当。合成化合物的药物相似性数据使它们成为未来抗真菌药物开发的有前途的先导化合物。
