Natural macrocycloxime-like compounds with anti-influenza virus H1N1 activity

Recently, researcher Weibo Yang, researcher Wei Huang, associate researcher Li Yang of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and Professor Kendall N. Houk of the University of California, Los Angeles, USA, used a bionic modular strategy to discover natural macrocycloxime-like compounds with anti-influenza virus H1N1 activity.

On November 10, 2022, the related research results were published in the journal Chem under the title “Multicomponent coupling and macrocyclization enabled by Rh(III)-catalyzed dual C–H activation: Macrocyclic oxime inhibitor of influenza H1N1”.

The co-corresponding authors are Weibo Yang, Wei Huang, Li Yang and Kendall N. Houk. Researcher Zheng Mingyue and researcher Zuo Jianping of Shanghai Institute of Materia Medica, gave technical support. Hao Wang, Zhongyu Li, Tongyu Bi, Xiangyang Chen and Jonathan J. Wong, graduate students of Shanghai Institute of Materia Medica, are co-first authors.

The influenza virus seriously affects human life and health, with millions of severe cases and about 250,000 to 500,000 deaths every year during influenza season. They pose a great threat to the world’s public health system. Influenza viruses have a complete replication cycle of adsorption release. Throughout the viral replication process, antiviral drugs with different targets have been discovered for the virus itself and the host. However, with the mutation of influenza virus, existing anti-influenza drugs are facing a severe drug resistance situation, and people urgently need to develop new skeleton molecules and promote the research and development of anti-influenza virus drugs.

Natural products are a treasure trove of drug discovery, and they play a very important role in target identification and lead discovery. Nevertheless, natural products present challenges such as low separations, complex total synthesis, and difficulty in molecular editing. On the contrary, natural products have the characteristics of high availability, diverse structure and rich functions, which have attracted widespread attention from medicinal chemists. In particular, natural macrocyclic compounds, which are cyclic compounds consisting of twelve or more atoms, possess a special 3D conformation, appropriate rigidity and flexibility, not only enhance selectivity and affinity with target proteins, but also intervene in difficult-to-drug targets such as protein-protein interactions (PPIs) (Figure 1).

Figure 1: Natural macrocycles with multiple biological activities

In this work, Weibo Yang’s group adopted the strategy of biomimetic modularity (Nat. Commun. 2020, 11, 2151.; J. Am. Chem. Soc. 2020, 142, 9982 − 9992.; Nat. Commun. 2021, 12, 1304.)。 The core idea of the bionic modular strategy is to retain the active natural fragments, or develop new methodologies to mimic natural fragments and replace the complex natural chiral backbone with simple and readily available chiral amino acids. This strategy can simplify synthesis and accelerate lead discovery. The molecular design is shown in Figure 2.

Figure 2: Biomimetic modular strategy building class natural macrocycloxime

In order to efficiently synthesize the above molecules, the research group developed Rh(III)-catalyzed bimolecular double-carbon-hydrogen bond-activated macrocyclization reaction. It is worth noting that this reaction mode uses the method of in-situ generation of guide groups, and highly chemically selectively achieves tandem amidation-alkylation, tandem amidation-alkenylation and tandem amidation-allyl macrocyclization, respectively. In this way, they provide an effective tool for quickly and efficiently constructing structurally diverse natural oxime-like macrocyclic libraries (Figure 3).

Figure 3: Rh(III)-catalyzed bimolecular bicarbon-hydrogen bond-activated macrocyclization

Subsequently, the research team performed PMI analysis on the conformation of the molecule (Figure 4) and found that the resulting natural oxime macrocyclic library has a rare spherical conformation in addition to linear and planar conformations. Finally, the research team performed phenotypic screening on the natural oxime-like macrocyclic library, and the results showed that such compounds had activity against influenza virus H1N1 (where the active latest compounds IC50 = 0.57 μM, CC50> 100 μM, SI >176), and further, through structure-activity relations, it was found that the oxime groups and α in the target molecule β indispensable for the maintenance of activity (Figure 5). At non-cytotoxic concentrations, the lead compound has a good protective effect against cytopathies caused by viruses. At the same time, immunofluorescence experiments demonstrated that the target compound can significantly reduce the fluorescence intensity of infected viral nucleoproteins (Figure 4).

Figure 4: Natural macrocycloxime-like PMI analysis and anti-influenza virus H1N1 study

Figure 5: Structure-activity relationship between natural macrocycloxime-like phenotypic screening and anti-influenza virus H1N1

The research project was supported by the National Natural Science Foundation of China NSFC (22171275), the Ministry of Science and Technology, the Chinese Academy of Sciences, the Shanghai Municipal Science and Technology Commission, and the US NSF. (Source: Science Network)

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