Inspired by our previous finding that targeting the 150-cavity with a multisite-binding strategy emerged as an effective approach to obtain more potent and selective neuraminidase (NA) inhibitors against influenza virus, we present here the design, synthesis, and optimization of novel boron-containing N-substituted oseltamivir (OSC) derivatives. Exploratory structure-activity relationship (SAR) studies led to the identification of compounds 27c and 33c as the most potent NA inhibitors, surpassing OSC in potency against both wild-type group-1 NAs and oseltamivir-resistant NAs. These compounds demonstrated significant antiviral activity against several wild-type strains and H1N1pdm09 strains (EC50 = 0.03 ± 0.005 and 0.03 ± 0.0008 μM, respectively). Additionally, these compounds did not exhibit significant toxicity (CC50 > 200 μM in CEF cells; CC50 > 250 μM in MDCK cells). These findings highlight 27c and 33c as promising next-generation anti-influenza agents.

Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH2 position of oseltamivir to occupy 150-cavity contributes to the binding affinity with neuraminidase and anti-influenza activity. To obtain broad-spectrum neuraminidase inhibitors, we designed and synthesised a series of novel oseltamivir derivatives bearing different N-heterocycles substituents that have been proved to induce opening of the 150-loop of group-2 neuraminidases. Among them, compound 6k bearing 4-((r)-2-methylpyrrolidin-1-yl) benzyl group exhibited antiviral activities similar to or weaker than those of oseltamivir carboxylate against H1N1, H3N2, H5N1, H5N6 and H5N1-H274Y mutant neuraminidases. More encouragingly, 6k displayed nearly 3-fold activity enhancement against H3N2 virus over oseltamivir carboxylate and 2-fold activity enhancement over zanamivir. Molecular docking studies provided insights into the explanation of its broad-spectrum potency against wild-type neuraminidases. Overall, as a promising lead compound, 6k deserves further optimisation by fully considering the ligand induced flexibility of the 150-loop.

To yield potent neuraminidase inhibitors with improved drug resistance and favorable drug-like properties, two series of novel oseltamivir derivatives targeting the 150-cavity of neuraminidase were designed, synthesized, and biologically evaluated. Among the synthesized compounds, the most potent compound 43b bearing 3-floro-4-cyclopentenylphenzyl moiety exhibited weaker or slightly improved inhibitory activity against wild-type neur-aminidases (NAs) of H1N1, H5N1, and H5N8 compared to oseltamivir carboxylate (OSC). Encouragingly, 43b displayed 62.70-and 5.03-fold more potent activity than OSC against mutant NAs of H5N1-H274Y and H1N1-H274Y, respectively. In cellular antiviral assays, 43b exerted equivalent or more potent activities against H1N1, H5N1, and H5N8 compared to OSC with no significant cytotoxicity up to 200 mu M. Notably, 43b displayed potent antiviral efficacy in the embryonated egg model, in which achieved a protective effect against H5N1 and H5N8 similar to OSC. Molecular docking studies were implemented to reveal the binding mode of 43b in the binding pocket. Moreover, 43b possessed improved physicochemical properties and ADMET properties compared to OSC by in silico prediction. Taken together, 43b appeared to be a promising lead compound for further investigation.

Hepatitis B virus (HBV) capsid protein (Cp) is necessary for viral replication and the maintenance of viral persistence, having become an attractive target of anti-HBV drugs. To improve the water solubility of HBV capsid protein allosteric modulator (CpAM) NVR 3-778, a series of novel carboxylic acid and phosphate prodrugs were designed and synthesized using a prodrug strategy. In vitro HBV replication assay showed that these prodrugs maintained favorable antiviral potency (EC50 = 0.28–0.42 µM), which was comparable to that of NVR 3-778 (EC50 = 0.38 µM). More importantly, the cytotoxicity of prodrug N8 (CC50 > 256 µM) was significantly reduced compared to NVR 3-778 (CC50 = 13.65 ± 0.21 µM). In addition, the water solubility of prodrug N6 was hundreds of times better than that of NVR 3-778 in three phosphate buffers with various pH levels (2.0, 7.0, 7.4). In addition, N6 demonstrated excellent plasma and blood stability in vitro and good pharmacokinetic properties in rats. Finally, the hemisuccinate prodrug N6 significantly improved the candidate drug NVR 3-778’s water solubility and increased metabolic stability while maintaining its antiviral efficacy.

Currently, HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a major component of the highly active anti-retroviral therapy (HAART) regimen. However, the occurrence of drug-resistant strains and adverse reactions after long-term usage have inevitably compromised the clinical application of NNRTIs. Therefore, the development of novel inhibitors with distinct anti-resistance profiles and better pharmacological properties is still an enormous challenge. Herein, we summarize state-of-the-art medicinal chemistry strategies for the discovery of potent NNRTIs, such as structure-based design strategies, contemporary computer-aided drug design, covalent-binding strategies, and the application of multi-target-directed ligands. The strategies described here will facilitate the identification of promising HIV-1 NNRTIs.

Influenza is an acute respiratory infectious disease caused by the influenza virus, affecting people globally and causing significant social and economic losses. Due to the inevitable limitations of vaccines and approved drugs, there is an urgent need to discover new anti-influenza drugs with different mechanisms. The viral ribonucleoprotein complex (vRNP) plays an essential role in the life cycle of influenza viruses, representing an attractive target for drug design. In recent years, the functional area of constituent proteins in vRNP are widely used as targets for drug discovery, especially the PA endonuclease active site, the RNA-binding site of PB1, the cap-binding site of PB2 and the nuclear export signal of NP protein. Encouragingly, the PA inhibitor baloxavir has been marketed in Japan and the United States, and several drug candidates have also entered clinical trials, such as favipiravir. This article reviews the compositions and functions of the influenza virus vRNP and the research progress on vRNP inhibitors, and discusses the representative drug discovery and optimization strategies pursued.

To address drug resistance to influenza virus neuraminidase inhibitors (NAIs), a series of novel boron-containing N-substituted oseltamivir derivatives were designed and synthesized to target the 150-cavity of neuraminidase (NA). In NA inhibitory assays, it was found that most of the new compounds exhibited moderate inhibitory potency against the wild-type NAs. Among them, compound 2c bearing 4-(3-boronic acid benzyloxy)benzyl group displayed weaker or slightly improved activities against group-1 NAs (H1N1, H5N1, H5N8 and H5N1-H274Y) compared to that of oseltamivir carboxylate (OSC). Encouragingly, 2c showed 4.6 times greater activity than OSC toward H5N1-H274Y NA. Moreover, 2c exerted equivalent or more potent antiviral activities than OSC against H1N1, H5N1 and H5N8. Additionally, 2c demonstrated low cytotoxicity in vitro and no acute toxicity at the dose of 1000 mg/kg in mice. Molecular docking of 2c was employed to provide a possible explanation for the improved anti-H274Y NA activity, which may be due to the formation of key additional hydrogen bonds with surrounding amino acid residues, such as Arg152, Gln136 and Val149. Taken together, 2c appeared to be a promising lead compound for further optimization.

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.

病毒感染严重危害着人类的健康与社会的发展.由于病毒容易突变,已有的抗病毒药物的疗效受到限制,亟需研发结构新颖、机制独特的抗病毒药物.侵入宿主细胞是所有病毒生命周期的第一步,病毒侵入抑制剂通过干预病毒与宿主细胞的吸附和膜融合过程可有效预防和治疗病毒感染,在抗病毒治疗中发挥了巨大的作用.本文作者精选近些年代表性案例,介绍了不同病毒侵入过程,并从药物化学的角度总结了多种病毒的侵入环节抑制剂的研究进展.

Our previous efforts have proved that modifications targeting the 150-cavity of influenza neuraminidase can achieve more potent and more selective inhibitors. In this work, four subseries of C5-NH2 modified oseltamivir derivatives were designed and synthesized to explore every region inside the 150-cavity. Among them, compound 23d was exceptionally potent against the whole panel of Group-1 NAs with IC50 values ranging from 0.26 to 0.73 nM, being 15-53 times better than oseltamivir carboxylate (OSC) and 7-11 times better than zanamivir. In cellular assays, 23d showed more potent or equipotent antiviral activities against corresponding virus strains compared to OSC with no cytotoxicity. Furthermore, 23d exhibited high metabolic stability in human liver microsomes (HLM) and low inhibitory effect on main cytochrome P450 enzymes. Notably, 23d displayed favorable druggability in vivo and potent antiviral efficacy in the embryonated egg model and mice model. Overall, 23d appears to be a promising candidate for the treatment of influenza virus infection.

Encouraged by our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Herein, we report the design, synthesis and biological evaluation of a series of novel oseltamivir derivatives via the structural modifications at C5-NH2 of oseltamivir targeting 150-cavity. Among them, compound 5c bearing 4-(3-methoxybenzyloxy)benzyl group exhibited the most potent activity, which was lower or modestly improved activities than oseltamivir carboxylate (OSC) against N1 (H1N1), N1 (H5N1) and N1 (H5N1-H274Y). Specifically, there was 30-fold loss of activity against the wild-type strain H1N1. However, 5c displayed 4.85-fold more potent activity than OSC against H5N1-H274Y NA. Also, 5c demonstrated low cytotoxicity in vitro and no acute toxicity in mice. Molecular docking studies provided insights into the high potency of 5c against N1 and N1-H274Y mutant NAs. Besides, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability of representative compounds were conducted to evaluate their drug-like properties.

From our research group, it was noticed that oseltamivir derivatives targeting 150-cavity of neuraminidase enzyme (NA) could significantly increase antiviral activity. Thus, we further enriched the C5-NH2 position of oseltamivir structure to obtain more potent oseltamivir derivatives. In this article a series of oseltamivir derivatives were synthesized by modifying C5-NH2 position of oseltamivir. All the compounds were evaluated for in vitro antiviral activity against H5N1 and H5N8. Encouragingly, compounds 9a and 11e were exhibited prominent activity, which is similar to oseltamivir carboxylate (OSC) and in NAs inhibitory assay, 11e showed remarkable potency against N1 (H5N1), N2 (H5N2), N6 (H5N6) and N8 (H5N8). In addition, 11e demonstrated low cytotoxicity and no obvious toxicity at the dose of 1500 mg/kg in mice. Molecular docking studies of 9a and 11e provided a plausible rationale for the high potency against group-1 NAs. This work provided new insights to design further neuraminidase inhibitors, which can help to investigate new potent inhibitors for group-1 and group-2 shortly. (c) 2020 Elsevier Masson SAS. All rights reserved.

流感病毒(influenza virus,IFV)的暴发给人类的健康和生命造成了严重危害,致病性禽流感病毒(avian influenza virus,AIV)感染不断给人类带来致命性威胁,给世界各国带来极大的恐慌.随着流感病毒生物学特征的深入研究以及药物发现筛选技术的迅猛发展,新一代抗流感药物靶点及其抑制剂被陆续发现,为流感病毒的治疗方案提供了更多的选择.本综述精选近几年最具代表性的研究实例,从药物化学的视角总结了抗流感药物新靶标及其小分子抑制剂的研究进展.

寨卡病毒(ZIKV),作为一种由蚊虫传播的黄病毒,感染后期会导致严重的神经系统并发症,如格林-巴利综合征.寨卡病毒感染对孕妇及胎儿的影响尤为显著,会造成新生儿小头畸形.2015年在巴西流行之后,寨卡病毒由于其毒力增加的趋势和传播迅速等特点引起了国际社会的广泛关注.然而目前仍没有可用于治疗寨卡病毒感染的抗病毒药物上市.本综述总结了近几年抗寨卡病毒感染药物研究的新进展,并对该领域的研究趋势进行了展望.

A novel series of 1,2,3-triazole oseltamivir derivatives, which could simultaneously occupy the classical NA catalytic site and the newly reported 430-cavity, were designed, synthesized, and evaluated for their anti-influenza activities. The results demonstrated that four compounds (6g, 6l, 6y and 8c) showed robust anti-influenza potencies against H5N1, H5N2 and H5N6 strains in both enzymatic assay and cellular assay. Especially, 6l was proved to possess the most potent and broad-spectrum anti-influenza activity, with IC50 values of 0.12 μM, 0.049 μM and 0.16 μM and EC50 values of 2.45 μM, 0.43 μM and 2.8 μM against H5N1, H5N2 and H5N6 strains, respectively, which were slightly weaker than oseltamivir carboxylate. In addition, in the embryonated egg model, 6l achieved the similar protective effect against H9N2 strain with oseltamivir carboxylate in the tested concentrations. Preliminary structure-activity relationships (SARs), molecular modeling, and calculated physicochemical properties of selected compounds were also discussed.

Future Medicinal ChemistryVol. 11, No. 5 EditorialDiscovery of novel anti-influenza agents via contemporary medicinal chemistry strategies (2014–2018 update)Ruifang Jia, Jian Zhang, Han Ju, Dongwei Kang, Zengjun Fang, Xinyong Liu & Peng ZhanRuifang Jia Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China, Jian Zhang Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China, Han Ju Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China, Dongwei Kang Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China, Zengjun Fang The Second Hospital of Shandong University, No. 247 Beiyuan Avenue, 250033 Jinan, PR China, Xinyong Liu*Author for correspondence: E-mail Address: xinyongllab@sdu.edu.cn Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China & Peng Zhan**Author for correspondence: E-mail Address: zhanpeng1982@sdu.edu.cn Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR ChinaPublished Online:19 Mar 2019https://doi.org/10.4155/fmc-2018-0397AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: drug designinfluenzamedicinal chemistryReferences1 Yu M, Si L, Wang Y et al. Discovery of pentacyclic triterpenoids as potential entry inhibitors of influenza viruses. J. Med. Chem. 57(23), 10058–10071 (2014).Crossref, Medline, CAS, Google Scholar2 Clark MP, Ledeboer MW, Davies I et al. Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2. J. Med. Chem. 57(15), 6668–6678 (2014).Crossref, Medline, CAS, Google Scholar3 Dilly S, Fotso Fotso A, Lejal N et al. From naproxen repurposing to naproxen analogues and their antiviral activity against influenza A virus. J. Med. Chem. 61(16), 7202–7217 (2018).Crossref, Medline, CAS, Google Scholar4 Wang PC, Fang JM, Tsai KC et al. Peramivir phosphonate derivatives as influenza neuraminidase inhibitors. J. Med. Chem. 59(11), 5297–5310 (2016).Crossref, Medline, CAS, Google Scholar5 Mooney CA, Johnson SA, 't Hart P et al. Oseltamivir analogues bearing N-substituted guanidines as potent neuraminidase inhibitors. J. Med. Chem. 2014, 57(7), 3154–3156 (2014).Crossref, Medline, CAS, Google Scholar6 Schade D, Kotthaus J, Riebling L et al. Development of novel potent orally bioavailable oseltamivir derivatives active against resistant influenza A. J. Med. Chem. 57(3), 759–769 (2014).Crossref, Medline, CAS, Google Scholar7 Wang G, Wan J, Hu Y et al. Synthesis and anti-influenza activity of pyridine, pyridazine, and pyrimidine C-nucleosides as favipiravir (T-705) analogues. J. Med. Chem. 59(10), 4611–4624 (2016).Crossref, Medline, CAS, Google Scholar8 Rey-Carrizo M, Barniol-Xicota M, Ma C et al. Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus. J. Med. Chem. 57(13), 5738–5747 (2014).Crossref, Medline, CAS, Google Scholar9 Kolocouris A, Tzitzoglaki C, Johnson FB et al. Aminoadamantanes with persistent in vitro efficacy against H1N1 (2009) influenza A. J. Med. Chem. 57(11), 4629–4639 (2014).Crossref, Medline, CAS, Google Scholar10 Li F, Ma C, DeGrado WF, Wang J. Discovery of highly potent inhibitors targeting the predominant drug-resistant S31N mutant of the influenza A virus M2 proton channel. J. Med. Chem. 59(3), 1207–1216 (2016).Crossref, Medline, CAS, Google Scholar11 Massari S, Goracci L, Desantis J, Tabarrini O. Polymerase acidic protein-basic protein 1 (PA-PB1) protein–protein interaction as a target for next-generation anti-influenza therapeutics. J. Med. Chem. 59(17), 7699–7718 (2016).Crossref, Medline, CAS, Google Scholar12 Trist IM, Nannetti G, Tintori C et al. 4,6-Diphenylpyridines as promising novel anti-influenza agents targeting the PA-PB1 protein–protein interaction: structure–activity relationships exploration with the aid of molecular modeling. J. Med. Chem. 59(6), 2688–2703 (2016).Crossref, Medline, CAS, Google Scholar13 Massari S, Nannetti G, Desantis J et al. A broad anti-influenza hybrid small molecule that potently disrupts the interaction of polymerase acidic protein-basic protein 1 (PA-PB1) subunits. J. Med. Chem. 58(9), 3830–3842 (2015).Crossref, Medline, CAS, Google Scholar14 Sagong HY, Bauman JD, Patel D, Das K, Arnold E, LaVoie EJ. Phenyl substituted 4-hydroxypyridazin-3(2H)-ones and 5-hydroxypyrimidin-4(3H)-ones: inhibitors of influenza A endonuclease. J. Med. Chem. 57(19), 8086–8098 (2014).Crossref, Medline, CAS, Google Scholar15 Wang W, Yin R, Zhang M et al. Boronic acid modifications enhance the anti-influenza A virus activities of novel quindoline derivatives. J. Med. Chem. 60(7), 2840–2852 (2017).Crossref, Medline, CAS, Google Scholar16 Huchting J, Vanderlinden E, Winkler M, Nasser H, Naesens L, Meier C. Prodrugs of the phosphoribosylated forms of hydroxypyrazinecarboxamide pseudobase T-705 and its de-fluoro analogue T-1105 as potent influenza virus inhibitors. J. Med. Chem. 61(14), 6193–6210 (2018).Crossref, Medline, CAS, Google Scholar17 Zhang J, Poongavanam V, Kang D et al. Optimization of N-substituted oseltamivir derivatives as potent inhibitors of group-1 and -2 influenza A neuraminidases, including a drug-resistant variant. J. Med. Chem. 61(14), 6379–6397 (2018).Crossref, Medline, CAS, Google Scholar18 Zhao X, Li R, Zhou Y et al. Discovery of highly potent pinanamine-based inhibitors against amantadine- and oseltamivir-resistant influenza A viruses. J. Med. Chem. 61(12), 5187–5198 (2018).Crossref, Medline, CAS, Google Scholar19 Leiva R, Barniol-Xicota M, Codony S et al. Aniline-based inhibitors of influenza H1N1 virus acting on hemagglutinin-mediated fusion. J. Med. Chem. 61(1), 98–118 (2018).Crossref, Medline, CAS, Google Scholar20 Fu L, Bi Y, Wu Y et al. Structure-based tetravalent zanamivir with potent inhibitory activity against drug-resistant influenza viruses. J. Med. Chem. 59(13), 6303–6312 (2016).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByNew drug approvals for 2021: Synthesis and clinical applicationsEuropean Journal of Medicinal Chemistry, Vol. 245Discovery of Novel Boron-Containing N-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant29 September 2022 | Molecules, Vol. 27, No. 19Dual-targeting Approach on Histamine H3 and Sigma-1 Receptor Ligands as Promising Pharmacological Tools in the Treatment of CNS-linked DisordersCurrent Medicinal Chemistry, Vol. 28, No. 15New drug approvals for 2020: Synthesis and clinical applicationsEuropean Journal of Medicinal Chemistry, Vol. 215Discovery of highly potent and selective influenza virus neuraminidase inhibitors targeting 150-cavityEuropean Journal of Medicinal Chemistry, Vol. 212New drug approvals for 2019: Synthesis and clinical applicationsEuropean Journal of Medicinal Chemistry, Vol. 205Discovery and optimization of benzenesulfonamides-based hepatitis B virus capsid modulators via contemporary medicinal chemistry strategiesEuropean Journal of Medicinal Chemistry, Vol. 206 Vol. 11, No. 5 Follow us on social media for the latest updates Metrics Downloaded 107 times History Received 6 October 2018 Accepted 10 December 2018 Published online 19 March 2019 Published in print March 2019 Information© 2019 Newlands PressKeywordsdrug designinfluenzamedicinal chemistryFinancial & competing interests disclosureFinancial support from the National Natural Science Foundation of China (NSFC no. 81773574), Shandong Provincial Key Research and Development Program (no. 2015GNC110009), the Science and Technology Development Project of Shandong Province (no. 2014GSF118175), Young Scholars Program of Shandong University (YSPSDU no. 2016WLJH32), Major Project of Science and Technology of Shandong Province (no. 2015ZDJS04001) and Key Research and Development Project of Shandong Province (no. 2017CXGC1401). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download

Encouraged by our earlier discovery of neuraminidase inhibitors targeting 150-cavity or 430-cavity, herein, to yield more potent inhibitors, we designed, synthesized, and biologically evaluated a series of novel oseltamivir derivatives via modification of C-1 and C5-NH2 of oseltamivir by exploiting 150-cavity and/or 430-cavity. Among the synthesized compounds, compound 15e, the most potent N1-selective inhibitor targeting 150-cavity, showed 1.5 and 1.8 times greater activity than oseltamivir carboxylate (OSC) against N1 (H5N1) and N1 (H5N1-H274Y). In cellular assays, 15e also exhibited greater potency than OSC against H5N1 with EC50 of 0.66 mu M. In addition, 15e demonstrated low cytotoxicity in vitro and low acute toxicity in mice. Molecular docking studies provided insights into the high potency of 15e against N1 and N1-H274Y mutant NA. Overall, we envisioned that the significant breakthrough in the discovery of potent group-l-specific neuraminidase inhibitors may lead to further investigation of more potent anti-influenza agents. (C) 2019 Elsevier Masson SAS. All rights reserved.

The HIV-1 capsid (CA) protein plays crucial roles in both early and late stages of the viral life cycle, which has intrigued researchers to target it to develop anti-HIV drugs. Accordingly, in this research, we report the design, synthesis and biological evaluation of a series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors using the Cu(I)-catalyzed azide and alkyne 1,3-dipolar cycloaddition (CuAAC) reaction. Among this series of inhibitors, compound II-10c displayed a remarkable anti-HIV activity (EC50 = 2.13 μM, CC50 > 35.49 μM). Furthermore, surface plasmon resonance (SPR) binding assays showed that compounds II-10c and PF-74 (lead compound) have similar affinities to HIV-1 CA monomer. Further investigation showed that the weak permeability and water solubility of representative compounds were probably the important factors that restricted their cell-based activity. Preliminary structure-activity relationships (SARs) were inferred based on the activities of these compounds, and their known structure. The most promising new compound was studied with molecular dynamics simulation (MD) to determine the preferred interactions with the drug target. Finally, the activities of members of this series of inhibitors were deeply inspected to find the potential reasons for their anti-HIV-1 activity from various perspectives. This highlights the important factors required to design compounds with improved potency.

Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five subseries of oseltamivir derivatives were designed and synthesized to improve their activity toward drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases (NAs). The bioassay results showed that compound 21h exhibited antiviral activities similar to or better than those of oseltamivir carboxylate (OSC) against H5N1, H5N2, H5N6, and H5N8. Besides, 21h was 5- to 86-fold more potent than OSC toward N1, N8, and N1-H274Y mutant NAs in the inhibitory assays. Computational studies provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated acceptable oral bioavailability, low acute toxicity, potent antiviral activity in vivo, and high metabolic stability. Overall, the above excellent profiles make 21h a promising drug candidate for the treatment of influenza virus infection.

On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.