Iterative Optimization and Structure–Activity Relationship Studies of Oseltamivir Amino Derivatives as Potent and Selective Neuraminidase Inhibitors via Targeting 150-Cavity

With our continuous endeavors in seeking neuraminidase
(NA) inhibitors,
we reported herein three series of novel oseltamivir amino derivatives
with the goal of exploring the druggable chemical space inside the
150-cavity of influenza virus NAs. Among them, around half of the
compounds in series C were demonstrated to be better
inhibitors against both wild-type and oseltamivir-resistant group-1
NAs than oseltamivir carboxylate (OSC). Notably, compounds 12d, 12e, 15e, and 15i showed
more potent or equipotent antiviral activity against H1N1, H5N1, and
H5N8 viruses compared to OSC in cellular assays. Furthermore, compounds 12e and 15e exhibited high metabolic stability
in human liver microsomes (HLMs) and low inhibitory effect on main
cytochrome P450 (CYP) enzymes, as well as low acute/subacute toxicity
and certain antiviral efficacy in vivo. Also, pharmacokinetic
(PK) and molecular docking studies were performed. Overall, 12e and 15e possess great potential to serve
as anti-influenza candidates and are worthy of further investigation.

在持续致力于寻找神经氨酸酶（NA）抑制剂的过程中，本研究报告了三个系列的新型奥司他韦氨基酸衍生物，旨在探索流感病毒NA 150个腔室内的可药物化学空间。其中，系列C中约有一半的化合物被证明在抑制野生型和奥司他韦耐药性1组NA方面优于奥司他韦羧酸盐（OSC）。值得注意的是，化合物12d、12e、15e和15i在细胞实验中表现出比OSC更强的或等效的针对H1N1、H5N1和H5N8病毒的抗病毒活性。此外，化合物12e和15e在人类肝微粒体（HLMs）中表现出高代谢稳定性，对主要细胞色素P450（CYP）酶的抑制效果低，以及在体内具有较低的急性/亚急性毒性和一定的抗病毒疗效。同时，还进行了药代动力学（PK）和分子对接研究。总体而言，12e和15e具有作为抗流感候选药物的巨大潜力，值得进一步研究。