The ongoing COVID-19 has not only caused millions of deaths worldwide, but it has also led to economic recession and the collapse of public health systems. The vaccines and antivirals developed in response to the pandemic have improved the situation markedly; however, the pandemic is still not under control with recurring surges. Thus, it is still necessary to develop therapeutic agents. In our previous studies, we designed and synthesized a series of novel 2-anilinoquinazolin-4(3H)-one derivatives, and demonstrated inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and MERS-CoV in vitro. We then conducted in vivo studies using modified compounds that are suitable for oral administration. These compounds demonstrated no toxicity in rats and inhibited viral entry. Here, we investigated the in vivo efficacy of these drug candidates against SARS-CoV-2. Three candidate drugs, 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (1), N-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N-(3,5-dichlorophenyl)acetamide (2), and N-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N-(3,5-difluorophenyl)acetamide (3) were administered orally to hACE2 transgenic mice at a dose of 100 mg/kg. All three drugs improved survival rate and reduced the viral load in the lungs. These results show that the derivatives possess in vivo antiviral efficacy similar to that of molnupiravir, which is currently being used to treat COVID-19. Overall, our data suggest that 2-anilinoquinazolin-4(3H)-one derivatives are promising as potential oral antiviral drug candidates against SARS-CoV-2 infection.

中文翻译：

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新型 SARS-CoV-2 进入抑制剂 2-anilininoquinazolin-4(3H)-one 衍生物在人类 ACE2 转基因小鼠模型中显示出作为 SARS-CoV-2 抗病毒药物的效力

持续蔓延的 COVID-19 不仅导致全球数百万人死亡，还导致经济衰退和公共卫生系统崩溃。针对这一流行病开发的疫苗和抗病毒药物使情况明显改善；但疫情仍未得到控制，疫情反复激增。因此，仍然有必要开发治疗剂。在前期的研究中，我们设计并合成了一系列新型2-苯胺基喹唑啉-4(3 H)-一种衍生物，并在体外表现出对严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 和 MERS-CoV 的抑制活性。然后，我们使用适合口服给药的修饰化合物进行了体内研究。这些化合物对大鼠没有毒性并抑制病毒进入。在这里，我们研究了这些候选药物针对 SARS-CoV-2 的体内功效。三种候选药物，7-氯-2-((3,5-二氯苯基)氨基)喹唑啉-4(3 H )-一( 1 )、N- (7-氯-4-氧代-3,4-二氢喹唑啉- 2-基)-N- ( 3,5-二氯苯基)乙酰胺( 2 )和N- (7-氯-4-氧代-3,4-二氢喹唑啉-2-基) -N将-(3,5-二氟苯基)乙酰胺( 3 )以100mg/kg的剂量口服给予hACE2转基因小鼠。所有三种药物都提高了存活率并减少了肺部的病毒载量。这些结果表明，这些衍生物具有与目前用于治疗 COVID-19 的莫努匹拉韦相似的体内抗病毒功效。总体而言，我们的数据表明 2-anilininoquinazolin-4(3 H )-one 衍生物有望作为潜在的口服抗病毒候选药物来对抗 SARS-CoV-2 感染。