Synthesis of Pyrimidine Conjugates with 4-(6-Amino-hexanoyl)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and Evaluation of Their Antiviral Activity

Краснов, В. П.; Musiyak, Vera V.; Левит, Г. Л.; Gruzdev, Dmitry А.; Андронова, В. Л.; Галегов, Г. А.; Orshanskaya, Iana R.; Синегубова, Eкатерина O.; Zarubaev, Vladimir V.; Charushin, Valery N.

doi:10.3390/molecules27134236

Cited by 7 publications

(3 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The synthesis of 4‐(6‐aminohexanoyl)‐7,8‐difluoro‐3,4‐dihydro‐3‐methyl‐2H‐[1,4]benzoxazine conjugated compounds of pyrimidine with antiviral activity against the herpes simplex type 1 (HSV‐1) virus was reported by Krasov et al. [53] . Based on the wide biological application of compounds containing the pyrimidine nucleus, these compounds were synthesized and evaluated for their anti‐HSV‐1 activity, with compound 66 being the most active derivative with IC 50 =9.27 μM (Figure 29).…”

Section: Resultsmentioning

confidence: 99%

Pharmacological Potential of Pyrmidine Derivatives: A Review With Emphasis on Antiviral Effects and Virtual Screening Against Sars‐Cov‐2 Molecular Targets

et al. 2023

View full text Add to dashboard Cite

The importance of R&D of new antivirals has been highly evident with the emergence of the pandemic caused by SARS‐CoV‐2. Pyrimidines are heterocyclic compounds with a broad biological spectrum. In this review we emphasize the antiviral application of pyrimidines. Scientific articles, drug and patent registrations were searched using terms involving antiviral pyrimidines. Between 2012 and 2022, more than 100 articles, which show the broad antiviral spectrum of these compounds, were added in this review. The publications of the last five years were prioritized. Anti‐HIV applications were found, their use more evident within the framework of antivirals; among others found were anti‐influenza, anti‐arboviral, and anti‐hepatitis viruses. The results found in the drug and patent databases corroborate the scenario observed in the analysis of scientific articles and demonstrate the importance of researching pyrimidine compounds in periods of great impact on global health. Additionally, through virtual screening of 119 pyrimidines from an in‐house library, we found seventeen pyrimidines with high binding potential with the Mpro and RdRp proteins of SARS‐CoV‐2. Almost all seventeen compounds showed good pharmacokinetic and toxicological profile, mainly compounds 150 and 151 being considered promising for biological evaluation against SARS‐CoV‐2.

show abstract

Section: Resultsmentioning

confidence: 99%

Pharmacological Potential of Pyrmidine Derivatives: A Review With Emphasis on Antiviral Effects and Virtual Screening Against Sars‐Cov‐2 Molecular Targets

et al. 2023

View full text Add to dashboard Cite

show abstract

“…In recent years, we have focused on the preparation of new purine and 2-aminopurine derivatives and the search for highly bioactive compounds in this series [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. In particular, we have synthesized a number of purine conjugates with various N -heterocycles attached via a linker, the omega-amino acid residue, –NH(CH 2 ) n CO–, to position 6 of the purine nucleus [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Cytotoxic Activity of the Derivatives of N-(Purin-6-yl)aminopolymethylene Carboxylic Acids and Related Compounds

et al. 2023

Self Cite

View full text Add to dashboard Cite

Testing a number of N-[omega-(purin-6-yl)aminoalkanoyl] derivatives of 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine in a panel of nine tumor cell lines has shown that the studied compounds exhibit high cytotoxic activity, especially against 4T1 murine mammary carcinoma, COLO201 human colorectal adenocarcinoma, SNU-1 human gastric carcinoma, and HepG2 human hepatocellular carcinoma cells. Synthesis and study of structural analogs of these compounds made it possible to find that the presence of both a difluorobenzoxazine fragment and a purine residue bound via a linker of a certain length is crucial for the manifestation of the cytotoxic activity of this group of compounds. The study of the effect of the most promising compound on the cell cycle of the human tumor cell lines, the most sensitive and least sensitive to cytotoxic action (MDA-MB-231 breast adenocarcinoma and COLO201 colorectal adenocarcinoma, respectively), allows us to conclude that this compound is an inhibitor of DNA biosynthesis. The found group of purine conjugates may be of interest in the design of new antitumor agents.

show abstract

“…For a number of years, we have been conducting research on the synthesis of purine conjugates, which are potential antiviral and antibacterial agents [53][54][55][56][57]. It has been found that (S)-4-[6-(purin-6-yl)aminohexanoyl]-7,8-difluoro-3,4-dihydro-3-methyl-2H- [1,4]benzoxazine] (compound 1, Figure 3) is a selective inhibitor of HSV-1, including an ACV-resistant HSV-1 strain [53], so this conjugate was chosen as the lead compound.…”

Section: Introductionmentioning

confidence: 99%

Large Subunit of the Human Herpes Simplex Virus Terminase as a Promising Target in Design of Anti-Herpesvirus Agents

Krasnov,

Andronova,

Belyavsky

et al. 2023

Molecules

Self Cite

View full text Add to dashboard Cite

Herpes simplex virus type 1 (HSV-1) is an extremely widespread pathogen characterized by recurrent infections. HSV-1 most commonly causes painful blisters or sores around the mouth or on the genitals, but it can also cause keratitis or, rarely, encephalitis. First-line and second-line antiviral drugs used to treat HSV infections, acyclovir and related compounds, as well as foscarnet and cidofovir, selectively inhibit herpesvirus DNA polymerase (DNA-pol). It has been previously found that (S)-4-[6-(purin-6-yl)aminohexanoyl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine (compound 1) exhibits selective anti-herpesvirus activity against HSV-1 in cell culture, including acyclovir-resistant mutants, so we consider it as a lead compound. In this work, the selection of HSV-1 clones resistant to the lead compound was carried out. High-throughput sequencing of resistant clones and reference HSV-1/L2 parent strain was performed to identify the genetic determinants of the virus’s resistance to the lead compound. We identified a candidate mutation presumably associated with resistance to the virus, namely the T321I mutation in the UL15 gene encoding the large terminase subunit. Molecular modeling was used to evaluate the affinity and dynamics of the lead compound binding to the putative terminase binding site. The results obtained suggest that the lead compound, by binding to pUL15, affects the terminase complex. pUL15, which is directly involved in the processing and packaging of viral DNA, is one of the crucial components of the HSV terminase complex. The loss of its functional activity leads to disruption of the formation of mature virions, so it represents a promising drug target. The discovery of anti-herpesvirus agents that affect biotargets other than DNA polymerase will expand our possibilities of targeting HSV infections, including those resistant to baseline drugs.

show abstract

Synthesis of Pyrimidine Conjugates with 4-(6-Amino-hexanoyl)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and Evaluation of Their Antiviral Activity

Cited by 7 publications

References 36 publications

Pharmacological Potential of Pyrmidine Derivatives: A Review With Emphasis on Antiviral Effects and Virtual Screening Against Sars‐Cov‐2 Molecular Targets

Pharmacological Potential of Pyrmidine Derivatives: A Review With Emphasis on Antiviral Effects and Virtual Screening Against Sars‐Cov‐2 Molecular Targets

Synthesis and Cytotoxic Activity of the Derivatives of N-(Purin-6-yl)aminopolymethylene Carboxylic Acids and Related Compounds

Large Subunit of the Human Herpes Simplex Virus Terminase as a Promising Target in Design of Anti-Herpesvirus Agents

Contact Info

Product

Resources

About