Novel aryloxy-hydrazone-thiazoles: Design, synthesis, ADMET prediction and antifungal activity against Sporothrix spp.

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Vanessa Gouveia de Melo Silva , Bruna Rodrigues de Sousa , Débora Lopes de Santana , Robert da Silva Tibúrcio , Lucas Manoel da Silva Sousa , Graziella Leite Brondani , Vanessa Soares Sales , Policarpo Ademar Sales Junior , Valéria Rêgo Alves Pereira , Danielle Patrícia Cerqueira Macêdo , Reginaldo Gonçalves de Lima-Neto , Ana Cristina Lima Leite
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引用次数: 0

Abstract

Sporotrichosis is an emerging fungal infection caused by species of the genus Sporothrix. Itraconazole is the first-line treatment for cutaneous sporotrichosis; however, there is a growing number of strains resistant to this drug. Recently, acylhydrazone derivatives have demonstrated activity against itraconazole-resistant sporotrichosis cases, and thiazole derivatives have emerged as promising antifungal agents. These findings led us to investigate twenty aryloxy-hydrazone-thiazoles against Sporothrix spp. In vitro antifungal testing showed that among the aryloxy-hydrazone-thiazoles (1–20), compounds 1, 2, 5, 6, and 8 exhibited significant activity, with minimum inhibitory concentration values below 2 μg/mL against strains S. brasiliensis, S. mexicana and S. chilensis. Compounds 1, 2, and 5, in particular, demonstrated MICs ≤2 μg/mL across all tested species and inhibited biofilm formation in both yeast-like and filamentous forms of S. brasiliensis more effectively than itraconazole and amphotericin B. These compounds were also capable of eradicating mature biofilms, especially in the filamentous phase. Itraconazole could not achieve. Molecular docking studies were performed to analyze intermolecular interactions and evaluate the phenoxy-1,3-thiazole derivatives as potential inhibitors of CYP51. It was observed that compounds 1, 2 and 5 which exhibited MICs ≤2 μg/mL for all tested Sporothrix species, shared common intermolecular interactions with itraconazole, the co-crystallized ligand. In silico ADME analysis showed that compounds 120 meet at least two of Lipinski's and Veber's criteria for drug-likeness, and cytotoxicity tests indicated low toxicity to L929 cells. These data suggest that aryloxy-hydrazone-thiazoles possess promising properties that position them as candidates for new antifungal agents.

Abstract Image

新型芳氧腙噻唑:设计、合成、ADMET预测及抗孢子菌活性研究。
孢子菌病是一种由孢子菌属引起的新型真菌感染。伊曲康唑是皮肤孢子菌病的一线治疗药物;然而,越来越多的菌株对这种药物有抗药性。最近,酰基腙衍生物已被证明对伊曲康唑耐药的孢子菌病有活性,噻唑衍生物已成为有前途的抗真菌药物。体外抑菌实验表明,20种芳氧腙噻唑类化合物(1 ~ 20)中,化合物1、2、5、6、8对巴西丝孢菌、墨西哥丝孢菌和智利丝孢菌的抑菌浓度均在2 μg/mL以下,抑菌活性显著。特别是化合物1、2和5,在所有被试物种中mic≤2 μg/mL,并且比伊曲康唑和两性霉素b更有效地抑制了酵母样和丝状巴西葡萄球菌的生物膜形成。这些化合物还能够根除成熟的生物膜,特别是在丝状阶段。伊曲康唑不能达到。分子对接研究分析了分子间相互作用,并评价了苯氧基1,3-噻唑衍生物作为CYP51的潜在抑制剂。结果表明,化合物1、2和5与共结晶配体伊曲康唑具有共同的分子间相互作用,其mic≤2 μg/mL。计算机ADME分析表明化合物1-20至少符合Lipinski和Veber的药物相似标准中的两个,细胞毒性测试表明对L929细胞的毒性较低。这些数据表明,芳氧腙噻唑具有很好的特性,使它们成为新的抗真菌药物的候选物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.70
自引率
3.90%
发文量
410
审稿时长
36 days
期刊介绍: Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.
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