Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Khyber Pakhtunkhwa, Pakistan.
Department of Pharmaceutical Chemistry, College of Pharmacy, Najran University, Najran, Saudi Arabia.
Drug Des Devel Ther. 2021 Mar 23;15:1299-1313. doi: 10.2147/DDDT.S292826. eCollection 2021.
Organocatalytic asymmetric Michael addition is a strong approach for C-C bond formation. The objective of the study is to design molecules by exploiting the efficiency of Michael Adducts. We proceeded with the synthesis of Michael adducts by tailoring the substitution pattern on maleimide and trans-β-nitro styrene as Michael acceptors. The synthesized compounds were evaluated for dual cyclooxygenases (COX) and lipoxygenase (LOX) inhibition.
The compounds (4, 9-11) were synthesized through Michael additions. The cyclooxygenases (COX-1 and 2) and lipoxygenase (5-LOX) assays were used for in vitro evaluations of compounds. After the acute toxicity studies, the in vivo analgesic potential was determined with acetic acid induced writhing, tail immersion, and formalin tests. Furthermore, the possible roles of adrenergic and dopaminergic receptors were also studied. Extensive computational studies were performed to get a better understanding regarding the binding of this compound with protein target.
Four Michael adducts (4, 9-11) were synthesized. Compound 4 was obtained in enantio- and diastereopure form. The stereopure compound 4 showed encouraging COX-1 and-2 inhibitions with IC values of 128 and 65 μM with SI of 1.94. Benzyl derivative 11 showed excellent COX-2 inhibition with the IC value of 5.79 μM and SI value 7.96. Compounds 4 and 11 showed good results in in vivo models of analgesia like acetic acid test, tail immersion, and formalin tests. Our compounds were not active in dopaminergic and adrenergic pathways and so were acting centrally. Through extensive computational studies, we computed binding energies, and pharmacokinetic predictions.
Our findings conclude that our synthesized Michael products (pyrrolidinedione 4 and nitroalkane 11) can be potent centrally acting analgesics. Our in silico predictions suggested that the compounds have excellent pharmacokinetic properties. It is concluded here that dual inhibition of COX/LOX pathways provides a convincing step towards the discovery of safe lead analgesic molecules.
有机催化不对称迈克尔加成是形成 C-C 键的有力方法。本研究的目的是通过利用迈克尔加成物的效率来设计分子。我们通过对马来酰亚胺和反式-β-硝基苯乙烯作为迈克尔受体的取代模式进行调整，开始合成迈克尔加成物。合成的化合物被评估为双重环氧化酶（COX）和脂氧合酶（LOX）抑制剂。
通过迈克尔加成合成化合物（4、9-11）。使用环氧化酶（COX-1 和 2）和脂氧合酶（5-LOX）测定法对化合物进行体外评估。在急性毒性研究之后，通过醋酸诱导的扭曲、尾巴浸入和福马林试验来确定体内镇痛潜力。此外，还研究了肾上腺素能和多巴胺能受体的可能作用。进行了广泛的计算研究，以更好地了解该化合物与蛋白质靶标的结合。
合成了四种迈克尔加成物（4、9-11）。化合物 4 以对映体和非对映体纯的形式获得。立体纯化合物 4 对 COX-1 和-2 的抑制作用令人鼓舞，IC 值分别为 128 和 65 μM，SI 为 1.94。苄基衍生物 11 对 COX-2 的抑制作用非常出色，IC 值为 5.79 μM，SI 值为 7.96。化合物 4 和 11 在醋酸试验、尾巴浸入和福马林试验等体内镇痛模型中表现良好。我们的化合物在多巴胺能和肾上腺素能途径中不活跃，因此在中枢神经系统中起作用。通过广泛的计算研究，我们计算了结合能和药代动力学预测。
我们的研究结果表明，我们合成的迈克尔产物（吡咯烷二酮 4 和硝基烷 11）可以作为有效的中枢镇痛药。我们的计算机预测表明，这些化合物具有出色的药代动力学特性。这里的结论是，COX/LOX 途径的双重抑制为发现安全的潜在镇痛分子提供了令人信服的步骤。
