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作为抗莱什曼病剂的皮拉衍生物:生物评估,分子对接研究,DFT分析和ADME预测

Razieh Sabet¹, Gholamreza Hatam², Leila Emami³

¹Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

|December 11, 2024

概括

新的pyrazole和pyrano[2,3-c]pyrazole衍生物显示出对Leishmania major的强烈抗莱什曼病毒活性. 这些化合物为开发针对莱什曼病的新型治疗提供了有希望的途径,解决了对当前药物替代品的需求.

科学领域:

药用化学医学化学
寄生虫学的寄生虫学
药物发现药物发现药物发现

背景情况:

莱什曼病是一种被忽视的热带疾病,在热带和亚热带地区普遍存在.
现有的莱什曼病治疗方法存在局限性,包括严重的副作用和新兴的耐药性.
迫切需要新型抗莱什曼病毒药物和有效疫苗.

研究的目的:

评估14种合成的pyrazole和pyrano[2,3-c]pyrazole衍生物对Leishmania major的抗莱什曼病毒疗效.
为了识别比目前的标准药物,Glucantime.Glucantime.Glucantime.Glucantime.Glucantime.Glucantime.Glucantime.Glucantime.Glucantime.Glucantime.Glucantime.
研究最活跃化合物的分子相互作用和理论性质.

主要方法:

在体外抗莱什曼病活性测定对大莱什曼病.
对合成衍生物的IC50值的确定和与Glucantime的比较.
针对14-α脱甲基酶的分子对接研究.
密度函数理论 (DFT) 对稳定性和电子性质的计算.
理论吸收,分布,新陈代谢和分泌 (ADME) 属性的评估.

主要成果:

七种pyrazole和pyrano[2,3-c]pyrazole衍生物显示出显著的antileishmanial活性,IC50值在34.79-43.55μg/mL之间,优于Glucantime (IC50 = 97.31μg/mL).
化合物P1和P2表现出最高的强度,IC50值分别为34.79和38.51μg/mL.
分子对接揭示了P1和P2与14-α脱甲基酶的关键残留物之间的有利相互作用.
DFT分析表明,最活跃的化合物 (P1) 在热力学上更稳定,更硬,并且具有比最不活跃的化合物 (P14) 更大的能量差距.
研究的化合物显示了令人满意的理论ADME配置文件.

结论:

合成的pyrazole和pyrano[2,3-c]pyrazole衍生物代表了一类有希望的化合物,用于开发新的antileishmaniasis疗法.
化合物P1和P2被确定为进一步临床前开发的主要候选物,因为它们具有强大的活性和有利的理论特性.
这些发现支持在设计新型抗莱什曼病剂时准14-α脱甲基酶的潜力.

关键词:

在 ADME 预测预测.抗莱什曼尼亚尔 (Antileishmanial) 是一种反莱什曼尼亚尔的药物.对DFT的分析分子对接是分子对接.皮拉 (Pyrazole) 是一种可怕的药物.

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