Abdallah Abdallah E, Al Kamaly Omkulthom, El-Fakharany Esmail M, El-Maradny Yousra A, Shahat Abdelaaty A, Alesawy Mohamed S, Hammad Ali, El-Zahabi Mohamed Ayman, El-Sebaey Samiha A, El-Zoghbi Mona S
Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt.
Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, 11671, Riyadh, Saudi Arabia.
Mol Divers. 2025 Jun 13. doi: 10.1007/s11030-025-11237-z.
In an attempt to develop broad-spectrum antiviral agents, we designed non-nucleoside small molecules as deubiquitinating enzyme inhibitors. The newly developed candidates are based on the quinazolinone nucleus and have been biologically evaluated as antiviral agents against four viruses: adenovirus, HSV-1, coxsackievirus, and SARS-CoV-2. Additionally, activity against papain-like protease (PL), a DUB enzyme of SARS-CoV-2, was evaluated. Structure-activity association was established dependent on the obtained data. Regarding adenovirus, HSV-1, and coxsackievirus, most of the new candidates showed promising antiviral activity. Among them, compounds 8d and 8c have the highest potential, with IC values reaching from 12.77 to 15.96 μg/mL and 16.71 to 19.58 μg/mL, respectively, compared to acyclovir's IC of 3.45-15.97 μg/mL. However, 8c outperformed acyclovir in terms of selectivity index, with selectivity indices ranging from 19.04 to 22.31, whereas acyclovir's selectivity indices ranged from 4.77 to 22.10. While 8d had selectivity indices comparable to those of acyclovir. Interestingly, compound 8d revealed very potent activity against SARS-CoV-2, showing an IC value of 0.948 μg/mL in comparison to IC of 1.141 μg/mL for remdesivir. Additionally, 8d displayed a far better selectivity index than remdesivir. Furthermore, 8d showed promising inhibition of papain-like protease with an IC of 5.056 μg/mL. In addition, the proposed binding modes and affinities of the new derivatives to papain-like protease were significant. Overall, the majority of such synthesized compounds, especially compound 8d, have shown strong antiviral activity and good safety profiles, making them promising candidates for future development in antiviral therapies.
为了开发广谱抗病毒药物，我们设计了非核苷小分子作为去泛素化酶抑制剂。新开发的候选药物以喹唑啉酮为核心，并已作为抗四种病毒的抗病毒药物进行了生物学评估：腺病毒、单纯疱疹病毒1型、柯萨奇病毒和严重急性呼吸综合征冠状病毒2（SARS-CoV-2）。此外，还评估了其对SARS-CoV-2的一种去泛素化酶——木瓜蛋白酶样蛋白酶（PL）的活性。根据获得的数据建立了构效关系。对于腺病毒、单纯疱疹病毒1型和柯萨奇病毒，大多数新候选药物显示出有前景的抗病毒活性。其中，化合物8d和8c潜力最高，其半数抑制浓度（IC）值分别为12.77至15.96μg/mL和16.71至19.58μg/mL，而阿昔洛韦的IC值为3.45 - 15.97μg/mL。然而，8c在选择性指数方面优于阿昔洛韦，其选择性指数范围为19.04至22.31，而阿昔洛韦的选择性指数范围为4.77至22.10。而8d的选择性指数与阿昔洛韦相当。有趣的是，化合物8d对SARS-CoV-2显示出非常强的活性，其IC值为0.948μg/mL，而瑞德西韦的IC值为1.141μg/mL。此外，8d的选择性指数比瑞德西韦好得多。此外，8d对木瓜蛋白酶样蛋白酶显示出有前景的抑制作用，IC值为5.056μg/mL。此外，新衍生物与木瓜蛋白酶样蛋白酶的拟议结合模式和亲和力也很显著。总体而言，大多数此类合成化合物，尤其是化合物8d，已显示出强大的抗病毒活性和良好的安全性，使其成为未来抗病毒治疗开发的有前景的候选药物。
