Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia.
Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City 11884, Cairo, Egypt.
Bioorg Chem. 2023 Jan;130:106255. doi: 10.1016/j.bioorg.2022.106255. Epub 2022 Nov 17.
COVID-19 and associated substantial inflammations continue to threaten humankind triggering death worldwide. So, the development of new effective antiviral and anti-inflammatory medications is a major scientific goal. Pyranopyrazoles have occupied a crucial position in medicinal chemistry because of their biological importance. Here, we report the design and synthesis of a series of sixteen pyranopyrazole derivatives substituted with two aryl groups at N-1 and C-4. The designed compounds are suggested to show dual activity to combat the emerging Coronaviruses and associated substantial inflammations. All compounds were evaluated for their in vitro antiviral activity and cytotoxicity against SARS-CoV infected Vero cells. As well, the in vitro assay of all derivatives against the SARS-CoV M target was performed. Results revealed the potential of three pyranopyrazoles (22, 27, and 31) to potently inhibit the viral main protease with IC values of 2.01, 1.83, and 4.60 μM respectively compared with 12.85 and 82.17 μM for GC-376 and lopinavir. Additionally, in vivo anti-inflammatory testing for the most active compound 27 proved its ability to reduce levels of two cytokines (TNF-α and IL-6). Molecular docking and dynamics simulation revealed consistent results with the in vitro enzymatic assay and indicated the stability of the putative complex of 27 with SARS-CoV-2 M. The assessment of metabolic stability and physicochemical properties of 27 have also been conducted. This investigation identified a set of metabolically stable pyranopyrazoles as effective anti-SARS-CoV-2 M and suppressors of host cell cytokine release. We believe that the new compounds deserve further chemical optimization and evaluation for COVID-19 treatment.
新型冠状病毒肺炎（COVID-19）及其引发的严重炎症继续威胁着人类健康，导致全球死亡。因此，开发新的有效抗病毒和抗炎药物是一个主要的科学目标。吡喃并吡唑类化合物由于其重要的生物学意义，在药物化学中占有重要地位。在这里，我们报告了一系列十六个吡喃并吡唑衍生物的设计和合成，这些衍生物在 N-1 和 C-4 位取代有两个芳基。设计的化合物被认为具有双重活性，可以对抗新兴的冠状病毒和相关的严重炎症。所有化合物都进行了体外抗病毒活性和对 SARS-CoV 感染的 Vero 细胞的细胞毒性评估。此外，还对所有衍生物进行了体外 SARS-CoV M 靶标试验。结果表明，有三个吡喃并吡唑（22、27 和 31）具有抑制病毒主要蛋白酶的潜力，IC 值分别为 2.01、1.83 和 4.60μM，而 GC-376 和洛匹那韦的 IC 值分别为 12.85 和 82.17μM。此外，对最活跃的化合物 27 的体内抗炎测试证明了它降低两种细胞因子（TNF-α和 IL-6）水平的能力。分子对接和动力学模拟与体外酶促试验结果一致，表明 27 与 SARS-CoV-2 M 的假定复合物稳定。还对 27 的代谢稳定性和物理化学性质进行了评估。这项研究确定了一组代谢稳定的吡喃并吡唑类化合物，它们是有效的抗 SARS-CoV-2 M 和宿主细胞细胞因子释放抑制剂。我们相信，这些新化合物值得进一步的化学优化和评估，以用于 COVID-19 的治疗。
