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Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitors.
Beilstein Journal of Organic Chemistry ( IF 2.7 ) Pub Date : 2020-06-08 , DOI: 10.3762/bjoc.16.108
Abimelek Cortes-Pacheco 1, 2 , María Adelina Jiménez-Arellanes 2 , Francisco José Palacios-Can 3 , José Antonio Valcarcel-Gamiño 3 , Rodrigo Said Razo-Hernández 3 , María Del Carmen Juárez-Vázquez 2 , Adolfo López-Torres 1 , Oscar Abelardo Ramírez-Marroquín 1
Affiliation  

Bisphosphonic acids (or bisphosphonates) have been successfully used in the clinic treatment of bone diseases for over decades. Additionally, the antiinflammatory activity of these compounds has been gaining attention. In our previous work, we synthesized and in vivo evaluated the bisphosphonic esters 1 and 2, finding a moderate edema inhibition upon oral and topical administration on BALB/c mice. Thus, in this work, the bioisosteric replacement of an amide functional group for an ester afforded the new bisphosphonates 36, which had a moderate oral edema inhibition (25 mg/kg dose) and a significant topical antiinflammatory activity (2 mg/ear) on BALB/c mice, with 6 being the most active hit (55.9% edema inhibition), comparable to the positive control (55.5% edema inhibition) on a TPA topical model. Next, to assess the acute toxicity of the synthesized derivatives, test animals were administered with 50–100 mg/kg of 36, respectively, by an oral route, and after 14 days, neither lethality nor a significative weight loss were observed. Finally, a structure–activity relationship (SAR) and a molecular docking analysis of 36 helped us to explain the trend observed in biological tests. Considering all these aspects, we propose the inhibition of MMP-8 and MMP-9 as a possible action mechanism of the synthesized derivatives.

中文翻译:

双膦酸酯作为潜在的MMP-8和MMP-9抑制剂的合成,抗炎活性和分子对接研究。

双膦酸(或双膦酸盐)已成功用于骨病的临床治疗数十年。另外,这些化合物的抗炎活性已经引起关注。在我们以前的工作中,我们合成并体内评估了双膦酸酯12,在对BALB / c小鼠口服和局部给药后发现了适度的水肿抑制作用。因此,在该工作中,对于酯的生物电子等排取代的酰胺官能团,得到新的二膦酸盐3 - 6,它具有适中的口服水肿抑制(25 mg / kg剂量)和显著局部抗炎活性(2毫克/耳)在BALB / c小鼠上,有6只是TPA局部模型中最活跃的命中(55.9%的水肿抑制),与阳性对照(55.5%的水肿抑制)相当。接着,以评估合成衍生物的急性毒性,试验动物用50-100毫克/公斤的施用3 - 6分别,通过口服途径,并在14天后,观察到致死性,也不是一个有意义的体重减轻两者都不是。最后,结构活性关系(SAR)和分子对接分析36帮助我们解释了生物学测试中观察到的趋势。考虑到所有这些方面,我们提出抑制MMP-8和MMP-9作为合成衍生物的可能作用机理。
更新日期:2020-06-08
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