Synthesis, molecular properties, toxicity and biological evaluation of some new substituted imidazolidine derivatives in search of potent anti-inflammatory agents.
Synthesis, molecular properties, toxicity and biological evaluation of some new substituted imidazolidine derivatives in search of potent anti-inflammatory agents.
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DOI：
10.1016/j.jsps.2015.02.008
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Al-Abbasi FA
中科院分区：
文献类型：
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作者：
Husain A;Ahmad A;Khan SA;Asif M;Bhutani R;Al-Abbasi FA
本研究旨在设计合成含咪唑烷杂环的药物制剂，以期研制出有效、安全、口服有效的抗炎药。以乙二胺和芳香族醛为起始原料合成了一些取代咪唑烷衍生物（3a-k）。研究了咪唑烷衍生物（3a-k）对Wistar白化病大鼠和Swiss白化病小鼠的抗炎和镇痛活性。利用Molinspiration和Osiris property explorer在线软件计算咪唑烷衍生物的生物活性评分、分子和药代动力学性质。生物实验结果表明，在合成的化合物中，只有3种咪唑类衍生物4-[1,3-二（2,6-二氯苯基）-2-咪唑基]苯基二乙胺（3g）、4-[1,3-二（3-羟基-4-甲氧基苄基）-2-咪唑基]苯基二乙胺（3i）和4-（1,3-二（4-甲氧基苄基）-4-甲基咪唑基-2-基）-苯基二乙胺（3j）具有良好的抗炎镇痛作用。此外，与阳性对照吲哚美辛相比，这些衍生物显示出更好的GI安全性（低严重指数）。所有合成的化合物均通过Molinspiration软件对药物靶点进行生物活性评分。Osiris在线软件预测，几乎所有化合物的毒性风险都很低。化合物（3i）符合Lipinski的药物相似性五法则，在体内表现出良好的生物活性，并且在计算机辅助筛选中没有毒性风险，因此成为进一步研究的潜在候选者。
The aim of this study was to design and synthesize pharmaceutical agents containing imidazolidine heterocyclic ring in the hope of developing potent, safe and orally active anti-inflammatory agents. A number of substituted-imidazolidine derivatives (3a–k) were synthesized starting from ethylene diamine and aromatic aldehydes. The imidazolidine derivatives (3a–k) were investigated for their anticipated anti-inflammatory, and analgesic activity in Wistar albino rats and Swiss albino mice, respectively. Bioactivity score, molecular and pharmacokinetic properties of the imidazolidine derivatives were calculated by online computer software programs viz. Molinspiration and Osiris property explorer. The results of biological testing indicated that among the synthesized compounds only three imidazolidine derivatives namely 4-[1,3-Bis(2,6-dichlorobenzyl)-2-imidazolidinyl]phenyl-diethylamine (3g), 4-[1,3-Bis(3-hydroxy-4-methoxybenzyl)-2-imidazolidinyl]phenyl-diethylamine (3i) and 4-(1,3-Bis(4-methoxybenzyl)-4-methylimidazolidin-2-yl)-phenyl-diethylamine (3j) possess promising anti-inflammatory and analgesic actions. Additionally these derivatives displayed superior GI safety profile (low severity index) with respect to the positive control, Indomethacin. All synthesized compounds showed promising bioactivity score for drug targets by Molinspiration software. Almost all the compounds were predicted to have very low toxicity risk by Osiris online software. Compound number (3i) emerged as a potential candidate for further research as it obeyed Lipinski’s rule of five for drug likeness, exhibited promising biological activity in-vivo and showed no risk of toxicity in computer aided screening.