Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions

Held, Felix; Guryev, Anton A.; Fröhlich, Tony; Hampel, Frank; Kahnt, Axel; Hutterer, Corina; Steingruber, Mirjam; Hanife, Bahsi; Bojničić-Kninski, Clemens von; Mattes, Daniela S.; Foertsch, Tobias C.; Nesterov‐Mueller, Alexander; Marschall, Manfred; Tsogoeva, Svetlana B.

doi:10.1038/ncomms15071

Cited by 71 publications

(40 citation statements)

References 42 publications

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“…In the course of our ongoing research work on the design and synthesis of artemisinin‐derived hybrid compounds with antiviral, anticancer, and antimalarial activities, we also synthesized artemisinin‐containing product 9 i in 60 % yield (Figure ), starting from para ‐dihydroartemisinine‐substituted phenyl‐acetaldehyde. Biological investigations of the obtained hybrid 9 i in comparison to its parent compounds dihydroartemisinine and domino product 9 a are under way and will be reported elsewhere.…”

Section: Resultsmentioning

confidence: 99%

Three‐Component Domino Knoevenagel/Vinylogous Michael Reaction: Entry to Challenging o‐Terphenyls

Grau

Hampel

et al. 2018

Chemistry A European J

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An unprecedented organocatalytic three-component domino Knoevenagel/vinylogous Michael reaction starting from simple enolizable aldehydes, malononitrile, and nitroolefins is reported. This facile two-step domino process provides a straightforward stereoselective route to multifunctional vinyl malononitrile products (up to 82 % yield, 85:15 d.r.) containing a nitroalkane moiety, and contributes to the development of sustainability and atom economy. The application of the obtained domino products for synthesis of highly functionalized o-terphenyls (of high interest for materials science and medicinal chemistry) through subsequent new three-step domino reaction involving cyclization-tautomerization-aromatization steps, has been demonstrated.

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Section: Resultsmentioning

confidence: 99%

Three‐Component Domino Knoevenagel/Vinylogous Michael Reaction: Entry to Challenging o‐Terphenyls

Grau

Hampel

et al. 2018

Chemistry A European J

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“…Examples include artemisinin-derived dimer diphenyl phosphate (838), a potent, selective HCMV inhibitor with irreversible activity [332,333] and trimeric artesunate derivative TF27 [326], which exhibits potent in vitro and in vivo activity in the MCMV model [329]. Hybridization of artemisinin-derivatives with bioactive molecules, such as quinazoline, has produced novel compounds with potent anti-HCMV activity significantly better than parental compounds and GCV [334][335][336][337].…”

Section: Artemisinin and Derivativesmentioning

confidence: 99%

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Adamson

Nevels

2020

Viruses

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The human cytomegalovirus (HCMV), one of eight human herpesviruses, establishes lifelong latent infections in most people worldwide. Primary or reactivated HCMV infections cause severe disease in immunosuppressed patients and congenital defects in children. There is no vaccine for HCMV, and the currently approved antivirals come with major limitations. Most approved HCMV antivirals target late molecular processes in the viral replication cycle including DNA replication and packaging. “Bright and early” events in HCMV infection have not been exploited for systemic prevention or treatment of disease. Initiation of HCMV replication depends on transcription from the viral major immediate-early (IE) gene. Alternative transcripts produced from this gene give rise to the IE1 and IE2 families of viral proteins, which localize to the host cell nucleus. The IE1 and IE2 proteins are believed to control all subsequent early and late events in HCMV replication, including reactivation from latency, in part by antagonizing intrinsic and innate immune responses. Here we provide an update on the regulation of major IE gene expression and the functions of IE1 and IE2 proteins. We will relate this insight to experimental approaches that target IE gene expression or protein function via molecular gene silencing and editing or small chemical inhibitors.

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“…LDH: lactate dehydrogenase release assay, 24 h, acute cytotoxicity; “n.d.”—not determined. [b] EC 50 values have been previously reported . [c] EC 50 values have been previously reported .…”

Section: Resultsmentioning

confidence: 99%

(Iso)Quinoline–Artemisinin Hybrids Prepared through Click Chemistry: Highly Potent Agents against Viruses

Çapcı

Lorion

Mai

et al. 2020

Chemistry A European J

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Viral infections cause life‐threatening diseases in millions of people worldwide every year and there is an urgent need for new, effective antiviral drugs. Hybridization of two chemically diverse compounds into a new bioactive effector product is a successful concept to improve the properties of a hybrid drug relative to the parent compounds. In this study, (iso)quinoline–artemisinin hybrids, obtained through copper‐catalyzed azide–alkyne cycloaddition or metal‐free click reactions (in organic solvents or in the presence of water), were analyzed in vitro, for the first time, for their inhibitory activity against human cytomegalovirus (HCMV), relative to their parent compounds and the reference drug ganciclovir. EC50 (HCMV) values were obtained in a range 0.22–1.20 μm, which indicated highly potent antiviral properties in the absence of cytotoxic effects on normal cells (CC50>100 μm). The most active hybrid, 1 (EC50=0.22 μm), is 25 times more potent than its parent compound artesunic acid (EC50=5.41 μm) and 12 times more efficient than the standard drug ganciclovir (EC50=2.6 μm). Interestingly, hybrid 1 also shows inhibitory activity against hepatitis B virus in vitro (EC50 (HBeAg)=2.57 μm).

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Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions

Cited by 71 publications

References 42 publications

Three‐Component Domino Knoevenagel/Vinylogous Michael Reaction: Entry to Challenging o‐Terphenyls

Three‐Component Domino Knoevenagel/Vinylogous Michael Reaction: Entry to Challenging o‐Terphenyls

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

(Iso)Quinoline–Artemisinin Hybrids Prepared through Click Chemistry: Highly Potent Agents against Viruses

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