Vishwanath Divakar, Shete-Aich Anita, Honnegowda Manjunath B, Anand Mahesh Padukudru, Chidambaram Saravana Babu, Sapkal Gajanan, Basappa Basappa, Yadav Pragya D
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
Indian Council of Medical Research- National Institute of Virology (ICMR-NIV), Pune, Maharashtra411021, India.
ACS Omega. 2023 Jul 14;8(30):27056-27066. doi: 10.1021/acsomega.3c02079. eCollection 2023 Aug 1.
The coronavirus (COVID-19) pandemic, along with its various strains, has emerged as a global health crisis that has severely affected humankind and posed a great challenge to the public health system of affected countries. The replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mainly depends on RNA-dependent RNA polymerase (RdRp), a key enzyme that is involved in RNA synthesis. In this regard, we designed, synthesized, and characterized hybrid thiouracil and coumarin conjugates (HTCAs) by ether linkage, which were found to have anti-SARS-CoV-2 properties. Our real-time quantitative reverse transcription PCR (RT-qPCR) results confirmed that compounds such as , , , and inhibited the replication of SARS-CoV-2 with EC values of 14.3 ± 0.14, 6.59 ± 0.28, 86.3 ± 1.45, and 124 ± 2.38 μM, respectively. Also, compound displayed significant antiviral activity against human coronavirus 229E (HCoV-229E). In addition, some of the HTCAs reduced the replication of SARS-CoV-2 variants such as D614G and B.617.2. In parallel, HTCAs in uninfected Vero CCL-81 cells indicated that no cytotoxicity was noticed. Furthermore, we compared the interaction of lead compounds and toward the cocrystal structure of Suramin and RdRp polymerase with Remdesvir triphosphate, which showed that compounds , , and Remdesvir triphosphate (RTP) share a common catalytical site of RdRp but not Suramin. Additionally, the ADMET properties predicted for the lead HTCAs and RTP showed that the maximum therapeutic doses recommended for compounds and were comparable to those of RTP. Concurrently, the pharmacokinetics of was characterized in male Wistar Albino rats by administering a single oral gavage at a dose of 10 mg/kg, which gave a Cmax value of 0.22 μg/mL and a terminal elimination half-life period of 73.30 h. In conclusion, we established a new chemical entity that acts as a SARS-CoV-2 viral inhibitor with minimal or no toxicity to host cells in the rodent model, encouraging us to proceed with preclinical studies.
冠状病毒（COVID-19）大流行及其各种毒株已成为一场全球健康危机，严重影响了人类，并给受影响国家的公共卫生系统带来了巨大挑战。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的复制主要依赖于RNA依赖性RNA聚合酶（RdRp），这是一种参与RNA合成的关键酶。在这方面，我们通过醚键设计、合成并表征了杂合硫尿嘧啶和香豆素共轭物（HTCAs），发现它们具有抗SARS-CoV-2的特性。我们的实时定量逆转录PCR（RT-qPCR）结果证实，诸如 、 、 和 等化合物抑制了SARS-CoV-2的复制，其半数有效浓度（EC）值分别为14.3±0.14、6.59±0.28、86.3±1.45和124±2.38μM。此外，化合物 对人冠状病毒229E（HCoV-229E）显示出显著的抗病毒活性。此外，一些HTCAs降低了SARS-CoV-2变体如D614G和B.617.2的复制。同时，未感染的非洲绿猴肾细胞（Vero CCL-81）中的HTCAs表明未观察到细胞毒性。此外，我们比较了先导化合物 和 与苏拉明和RdRp聚合酶与瑞德西韦三磷酸酯的共晶体结构的相互作用，结果表明化合物 、 和瑞德西韦三磷酸酯（RTP）共享RdRp的一个共同催化位点，但不与苏拉明共享。此外，对先导HTCAs和RTP预测的药物代谢动力学性质表明，化合物 和 推荐的最大治疗剂量与RTP相当。同时，通过以10mg/kg的剂量单次口服灌胃，对雄性Wistar白化大鼠体内的 进行了药代动力学表征，其最大血药浓度（Cmax）值为0.22μg/mL，终末消除半衰期为73.30小时。总之，我们建立了一种新的化学实体，它在啮齿动物模型中作为SARS-CoV-2病毒抑制剂，对宿主细胞的毒性最小或无毒性，这鼓励我们进行临床前研究。
