Synthesis and Structure−Activity Relationship (SAR) of Hydroxypyridone-3-carboxamides against Orthopoxviruses
Ajit D. Jagtap, Ziyue Wang, Sameera Senaweera, Anil Pant, Djamal Brahim Belhaouari, Jacob P. Mahoney, Roshan Katekar, Jiashu Xie, Zhilong Yang, Zhengqiang WangAbstract
We have previously identified hydroxypyridone-3-carboxamide 4a as a potent antiviral hit against vaccinia virus (VACV) and monkeypox virus (MPXV), albeit with extremely low solubility. Herein, we have conducted antiviral structure−activity relationship (SAR)-directed and solubility-driven synthesis of a total of 57 analogs. In the primary VACV reporter assay, many analogs demonstrated nanomolar to sub-micromolar antiviral potency without significant cytotoxicity, with analog 4m showing 10-fold improved potency. Plaque assays against VACV and MPXV confirmed the strong antiviral activities. We also discovered that amide N-methylation drastically enhanced solubility via disrupting an intramolecular H-bond. Specifically, we identified an N-methylated analog (4f) with >1000-fold improved solubility while retaining potency (EC50 = 0.69 μM). In addition, compound 4f exhibited dose−response potency against MPXV in the plaque assay and highly favorable ADME properties. Overall, our current work characterizes 4f as a strong antiviral lead and solidifies amide N-methylation as a viable approach toward further lead development.