Design, synthesis and evaluation of heteroaryldihydropyrimidine analogues bearing spiro ring as hepatitis B virus capsid protein inhibitors

Ma, Yue; Zhao, Shujie; Ren, Yujie; Cherukupalli, Srinivasulu; Li, Qilan; Woodson, Molly; Bradley, Daniel P.; Tavis, John E.; Liu, Xinyong; Zhan, Peng

doi:10.1016/j.ejmech.2021.113780

Cited by 13 publications

(10 citation statements)

References 34 publications

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“…This reaction was well supported with 15 mol% chiral catalyst based on secondary amine (Cat.12) and 15 mol% of benzoic acid as an additive in toluene at room temperature. Under optimal reaction conditions target spirocyclopentaneoxindole derivatives (20) were obtained in excellent reaction yields (up to 86 %) and stereoselectivities (dr > 90 : 1, and ee > 99 %) (Scheme 16). [108] First, functionalized oxindole performs a Si-face nucleophilic attack on iminium-activated α,β-unsaturated alde-Scheme 24.…”

Section: Double Michael Cascade Reactionsmentioning

confidence: 99%

“…[11] Enantioenriched spiro derivatives [12] are characterized by the interesting fusion of two molecular rings linked by a common tetrasubstituted stereogenic center. They are an important component of several natural products, [13][14][15] bioactive compounds, [16][17][18][19][20] and find applications in asymmetric catalysis, [21][22][23][24] thermally stable OLED, [25][26][27][28][29][30][31] sensing, [32][33][34][35][36] and HMT (hole-transporting material). [37][38][39][40][41][42][43][44][45][46] Compared with singly condensed heterocycles spiro-hetero/carbocycles have the obvious advantage of structural compactness, which reduces lipophilicity.…”

Section: Introductionmentioning

confidence: 99%

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Catalytic Stereoselective Multicomponent Reactions for the Synthesis of Spiro Derivatives: Recent Progress

Patel

2022

Eur J Org Chem

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Spiro derivatives are important scaffolding substances found in many natural products and pharmaceuticals. In the last decade, numerous new approaches based on multicomponent reactions have been explored for the selective and efficient development of new spiro derivatives using various organocatalytic and transition metal‐based catalytic systems. This Review discusses pioneering advances in the field of catalytic stereoselective multicomponent reactions for the preparation of various spiro derivatives. These include stereoselective Michael cascade cyclization reactions, cycloadditions, diastereoselective reactions, and miscellaneous reactions for the synthesis of spiro‐hetero/carbocycles. Advances in the last decade have made it possible to synthesize various spiro compounds with good to excellent stereoselectivity under appropriate reaction conditions. However, achieving high regioselectivity in several described multicomponent reactions remains a challenge. Organocatalysts and transition‐metal‐based catalysts play a crucial role in achieving this milestone. Proposed catalytic mechanisms and supporting evidence are highlighted in this Review. The progress described in catalytic stereoselective approaches for spiro derivatives is immense. However, it is expected that new stereoselective synthetic methods will soon be developed that can be widely used for the preparation of spiro‐heterocycles/carbocycles.

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Section: Double Michael Cascade Reactionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Catalytic Stereoselective Multicomponent Reactions for the Synthesis of Spiro Derivatives: Recent Progress

Patel

2022

Eur J Org Chem

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“…Many compounds have been designed to target viral proteins: 3-(4-Pyridyl)-2-imidazolidinone derivatives (GPP3, EC 50 10 nM), licochalcone A (EC 50 9.30 μM), and aminothiazole derivatives (e.g., 12s , EC 50 0.27 μM) have been designed and synthesized using the enterovirus A71 CP as the target. − Pyrazolopyridine analogues (e.g., 7a , EC 50 16.7 μM) are antiviral compounds targeting the enterovirus D68 CP . Heteroaryldihydropyrimidines (e.g., GLS4, EC 50 0.012 mM) are antiviral drugs that target the HBV CP and induce aberrant self-assembly, and GS-6207 (EC 50 105 pM) is an HIV replication inhibitor that targets the HIV-1 CP …”

Section: Introductionmentioning

confidence: 99%

Plant Viral Coat Proteins as Biochemical Targets for Antiviral Compounds

Zhu

et al. 2022

J. Agric. Food Chem.

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Coat proteins (CPs) of RNA plant viruses play a pivotal role in virus particle assembly, vector transmission, host identification, RNA replication, and intracellular and intercellular movement. Numerous compounds targeting CPs have been designed, synthesized, and screened for their antiviral activities. This review is intended to fill a knowledge gap where a comprehensive summary is needed for antiviral agent discovery based on plant viral CPs. In this review, major achievements are summarized with emphasis on plant viral CPs as biochemical targets and action mechanisms of antiviral agents. This review hopefully provides new insights and references for the further development of new safe and effective antiviral pesticides.

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“…Therefore, it is important to find nucleocapsid efficient and less toxic. Currently, several new HAP compoun RG7907(R07049389), are promising candidates for clinical trials [22,23 The molecular mechanism of action of CAMs is still unclear. To avoid the confusion in the literature about class I versus class II CAMs, depending on the mechanism of action [24,25], we will further use the nomenclature proposed by Wang S et al [26].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, it is important to find nucleocapsid modulators that are efficient and less toxic. Currently, several new HAP compounds, e.g., R10 and RG7907(R07049389), are promising candidates for clinical trials [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Hepatitis B Virus (HBV) Capsid Assembly Modulators and Evaluation of Their Activity in Mammalian Cell Model

et al. 2022

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Background: Capsid assembly modulators (CAMs) have emerged as a promising class of antiviral agents. We studied the effects of twenty-one newly designed and synthesized CAMs including heteroaryldihydropyrimidine compounds (HAPs), their analogs and standard compounds on hepatitis B virus (HBV) capsid assembly. Methods: Cytoplasmic expression of the HBV core (HBc) gene driven by the exogenously delivered recombinant alphavirus RNA replicon was used for high level production of the full-length HBc protein in mammalian cells. HBV capsid assembly was assessed by native agarose gel immunoblot analysis, electron microscopy and inhibition of virion secretion in HepG2.2.15 HBV producing cell line. Induced fit docking simulation was applied for modelling the structural relationships of the synthesized compounds and HBc. Results: The most efficient were the HAP class compounds—dihydropyrimidine 5-carboxylic acid n-alkoxyalkyl esters, which induced the formation of incorrectly assembled capsid products and their accumulation within the cells. HBc product accumulation in the cells was not detected with the reference HAP compound Bay 41-4109, suggesting different modes of action. A significant antiviral effect and substantially reduced toxicity were revealed for two of the synthesized compounds. Conclusions: Two new HAP compounds revealed a significant antiviral effect and a favorable toxicity profile that allows these compounds to be considered promising leads and drug candidates for the treatment of HBV infection. The established alphavirus based HBc expression approach allows for the specific selection of capsid assembly modulators directly in the natural cell environment.

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Design, synthesis and evaluation of heteroaryldihydropyrimidine analogues bearing spiro ring as hepatitis B virus capsid protein inhibitors

Cited by 13 publications

References 34 publications

Catalytic Stereoselective Multicomponent Reactions for the Synthesis of Spiro Derivatives: Recent Progress

Catalytic Stereoselective Multicomponent Reactions for the Synthesis of Spiro Derivatives: Recent Progress

Plant Viral Coat Proteins as Biochemical Targets for Antiviral Compounds

Design and Synthesis of Hepatitis B Virus (HBV) Capsid Assembly Modulators and Evaluation of Their Activity in Mammalian Cell Model

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