Shin Young Sup, Lee Jun Young, Jeon Sangeun, Cho Jung-Eun, Myung Subeen, Jang Min Seong, Kim Seungtaek, Song Jong Hwan, Kim Hyoung Rae, Park Hyeung-Geun, Jeong Lak Shin, Park Chul Min
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
Center for Convergent Research of Emerging Virus Infection (CEVI), Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea.
Pharmaceuticals (Basel). 2022 Jul 4;15(7):831. doi: 10.3390/ph15070831.
We previously reported the potent antiviral effect of the 2-aminoquinazolin-4-(3)-one , which shows significant activity (IC = 0.23 μM) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with no cytotoxicity. However, it is necessary to improve the in vivo pharmacokinetics of compound because its area under the curve (AUC) and maximum plasma concentration are low. Here, we designed and synthesized -substituted quinazolinone derivatives that had good pharmacokinetics and that retained their inhibitory activity against SARS-CoV-2. These compounds were conveniently prepared on a large scale through a one-pot reaction using Dimroth rearrangement as a key step. The synthesized compounds showed potent inhibitory activity, low binding to hERG channels, and good microsomal stability. In vivo pharmacokinetic studies showed that compound had the highest exposure (AUC = 41.57 μg∙h/mL) of the synthesized compounds. An in vivo single-dose toxicity evaluation of compound at 250 and 500 mg/kg in rats resulted in no deaths and an approximate lethal dose greater than 500 mg/kg. This study shows that -acetyl 2-aminoquinazolin-4-(3)-one is a promising lead compound for developing anti-SARS-CoV-2 agents.
我们之前报道了2-氨基喹唑啉-4-(3)-酮的强效抗病毒作用，其对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）显示出显著活性（IC = 0.23 μM）且无细胞毒性。然而，由于化合物的曲线下面积（AUC）和最大血浆浓度较低，有必要改善其体内药代动力学。在此，我们设计并合成了具有良好药代动力学且保留对SARS-CoV-2抑制活性的N-取代喹唑啉酮衍生物。这些化合物通过以Dimroth重排为关键步骤的一锅法反应方便地大规模制备。合成的化合物显示出强效抑制活性、与hERG通道低结合以及良好的微粒体稳定性。体内药代动力学研究表明，化合物在合成的化合物中具有最高的暴露量（AUC = 41.57 μg∙h/mL）。在大鼠中对化合物以250和500 mg/kg进行单剂量毒性评估未导致死亡，且近似致死剂量大于500 mg/kg。本研究表明N-乙酰基2-氨基喹唑啉-4-(3)-酮是开发抗SARS-CoV-2药物的有前景的先导化合物。
