Synthesis of distal and proximal fleximer base analogues and evaluation in the nucleocapsid protein of HIV-1

Ku, Therese; Lopresti, Natalie; Shirley, Matthew; Mori, Mattia; Marchant, Jan; Heng, Xiao; Botta, Maurizio; Summers, Michael F.; Seley‐Radtke, Katherine L.

doi:10.1016/j.bmc.2019.05.019

Cited by 10 publications

(7 citation statements)

References 54 publications

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“…In state-of-the-art progress, three classes of NC inhibitors have been explored: (i) covalent modifiers that bind to NC zinc-coordinating residues or directly to the Zn(II) ions that are crucial for NC activity; (ii) small molecules that bind to nucleic acids targets of the NC; (iii) non-covalent NC binders that compete with nucleic acids for the binding site on the NC surface [ 7 ]. While NC inhibitors of classes (i) and (ii) are most suited as topical microbicides because of their weak selectivity and specificity for the NC that might lead to cytotoxic effects, class (iii) inhibitors have a higher potentiality for being developed as novel anti-HIV-1 systemic drugs [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. It is worth noting that natural products have played an important role in the discovery of NC inhibitors [ 16 , 21 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effect of Lithospermic Acid on the HIV-1 Nucleocapsid Protein

2020

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The HIV-1 nucleocapsid protein (NC) is a desirable target in antiretroviral therapy due to its high conservation among HIV-1 strains, and to its multiple and crucial roles in the HIV-1 replication cycle. Natural products represent a valuable source of NC inhibitors, with the catechol group being a privileged scaffold in NC inhibition. By coupling molecular modeling with NMR spectroscopy and fluorescence-based assays, we disclosed lithospermic acid, a catechol derivative extracted from Salvia miltiorrhizza, as a potent and chemically stable non-covalent inhibitor of the NC. Being different from other catechol derivative reported so far, lithospermic acid does not undergo spontaneous oxidation in physiological conditions, thus becoming a profitable starting point for the development of efficient NC inhibitors.

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Section: Introductionmentioning

confidence: 99%

Inhibitory Effect of Lithospermic Acid on the HIV-1 Nucleocapsid Protein

2020

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“…Final attempts at employing the di-boc protecting group tried protecting the stannyl pyrimidine 18 ; however, this method also proved ineffective. As such, attention turned toward using an in situ protection of the amine group followed by Negishi conditions for the 5- i PrAc and 5- t BuAc compounds, as these conditions had previously been successful for other fleximers developed in our lab (Scheme 7) [22].…”

Section: Resultsmentioning

confidence: 99%

Probing the Effects of Pyrimidine Functional Group Switches on Acyclic Fleximer Analogues for Antiviral Activity

et al. 2019

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Due to their ability to inhibit viral DNA or RNA replication, nucleoside analogues have been used for decades as potent antiviral therapeutics. However, one of the major limitations of nucleoside analogues is the development of antiviral resistance. In that regard, flexible nucleoside analogues known as “fleximers” have garnered attention over the years due to their ability to survey different amino acids in enzyme binding sites, thus overcoming the potential development of antiviral resistance. Acyclic fleximers have previously demonstrated antiviral activity against numerous viruses including Middle East Respiratory Syndrome coronavirus (MERS-CoV), Ebola virus (EBOV), and, most recently, flaviviruses such as Dengue (DENV) and Yellow Fever Virus (YFV). Due to these interesting results, a Structure Activity Relationship (SAR) study was pursued in order to analyze the effect of the pyrimidine functional group and acyl protecting group on antiviral activity, cytotoxicity, and conformation. The results of those studies are presented herein.

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“…Structural modification of natural products is one of the most effective methods to develop novel green pesticides. − It is reported that 1,2,3,4-tetrahydroquinoline (THQ), which is widely distributed in natural products (Figure ), − shows good activities such as antitumor activities, antimalarial activities, antivirus activities, and so on. − More interestingly, some compounds possess excellent fungal CHS inhibitory activities together with remarkable antifungal activities. − Additionally, pyrimidine is an active scaffold existing in a variety of commercial fungicides, such as azoxystrobin and pyrimethanil (Figure ). Pyrimidine amine or pyrimidine ether derivatives also have been extensively studied owing to their remarkable activities, such as antifungal activities, antitumor activities, antivirus activities, and so on. − …”

Section: Introductionmentioning

confidence: 99%

Synthesis, Antifungal Activity, and 3D-QASR of Novel 1,2,3,4-Tetrahydroquinoline Derivatives Containing a Pyrimidine Ether Scaffold as Chitin Synthase Inhibitors

Zhang

Yang

et al. 2022

J. Agric. Food Chem.

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The introduction of active groups of natural products into the framework of pesticide molecules is an effective approach for discovering active lead compounds, and thus has been widely used in the development of new agrochemicals. In this work, a novel series of 1,2,3,4-tetrahydroquinoline derivatives containing a pyrimidine ether scaffold were designed and synthesized by the active substructure splicing method. The new compounds showed good antifungal activities against several fungi. Especially, compound 4fh displayed excellent in vitro activity against Valsa mali and Sclerotinia sclerotiorum with EC 50 values of 0.71 and 2.47 μg/mL, respectively. 4fh had slightly stronger inhibitory activity (68.08% at 50 μM) against chitin synthase (CHS) than that of polyoxin D (63.84% at 50 μM) and exhibited obvious curative and protective effects on S. sclerotiorum in vivo. Thus, 4fh can be considered as a new candidate fungicide as a chitin synthase inhibitor. An accurate and reliable three-dimensional quantitative structure−activity relationship (3D-QSAR) model presented a useful direction for the further excogitation of more highly active fungicides. Molecular docking revealed that the conventional hydrogen bond mainly affected the binding affinity of 4fh with chitin synthase. The present results will provide a guidance to discover potential CHS-based fungicides for plant disease control in agriculture.

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Synthesis of distal and proximal fleximer base analogues and evaluation in the nucleocapsid protein of HIV-1

Cited by 10 publications

References 54 publications

Inhibitory Effect of Lithospermic Acid on the HIV-1 Nucleocapsid Protein

Inhibitory Effect of Lithospermic Acid on the HIV-1 Nucleocapsid Protein

Probing the Effects of Pyrimidine Functional Group Switches on Acyclic Fleximer Analogues for Antiviral Activity

Synthesis, Antifungal Activity, and 3D-QASR of Novel 1,2,3,4-Tetrahydroquinoline Derivatives Containing a Pyrimidine Ether Scaffold as Chitin Synthase Inhibitors

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