Scaffold hopping: Exploration of acetanilide-containing uracil analogues as potential NNRTIs

Babkov, Denis A.; Valuev-Elliston, Vladimir T.; Paramonova, Maria P.; Озеров, А. А.; Ivanov, Alexander V.; Chizhov, Alexander O.; Khandazhinskaya, Anastasia L.; Kochetkov, S. N.; Balzarini, Jan; Daelemans, Dirk; Pannecouque, Christophe; Seley‐Radtke, Katherine L.; Новиков, Михаил С.

doi:10.1016/j.bmc.2015.01.002

Cited by 13 publications

(8 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[75] For further investigation for the structure of this class of NNRTIs, two new series of 3benzyloxy-linked acetamide-containingu racil derivatives-A and Bs eries-were prepared by the same group by using the molecular hybridization of the benzophenone derivative 123 and previous uracil-based NNRTIs 124 and 125 ( Figure 56). [76] Althought he As eries of the synthesized compounds showed no activity against wild-type HIV-1 RT,t he Bs eries demonstrated remarkable anti-HIV-1 potencyi nM T-4c ells. The molecular docking studies of the As eries predicted ah ydrogen bond between the C 4 -carbonyl group of uracil and the NH group of www.chemmedchem.org the W229 side chain.T his hydrogen bond forced the lone pairs of oxygen to interact unfavorably with the p-systemo fW 229, which could more likely be the reason for their antiviral inactivity.H owever, 126 was the most potent compound of the B series with an EC 50 value of 1.71 mm (Figure 57).…”

Section: Uracil-based Nnrtismentioning

confidence: 96%

“…Several series of potent uracil‐based NNRTIs have been reported by Seley‐Radtke and co‐workers . For further investigation for the structure of this class of NNRTIs, two new series of 3‐benzyloxy‐linked acetamide‐containing uracil derivatives—A and B series—were prepared by the same group by using the molecular hybridization of the benzophenone derivative 123 and previous uracil‐based NNRTIs 124 and 125 (Figure ) . Although the A series of the synthesized compounds showed no activity against wild‐type HIV‐1 RT, the B series demonstrated remarkable anti‐HIV‐1 potency in MT‐4 cells.…”

Section: Modification Of Existing Nnrti Scaffoldsmentioning

confidence: 99%

See 1 more Smart Citation

Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

2018

View full text Add to dashboard Cite

Non‐nucleoside reverse transcriptase inhibitors (NNRTIs) have always been an important part of the anti‐HIV‐1 combination therapy known as combination antiretroviral therapy (cART) since 1996. The use of NNRTIs for about 22 years has led to some mutations in the residues that compose the reverse transcriptase active site, resulting in the emergence of drug‐resistant viruses. Thus, the search for new potent NNRTIs with an improved safety profile and activity against drug‐resistant HIV strains is indispensable, and many hit and lead NNRTIs have been discovered in the last decade. This review provides an overview of the development in this field from 2013 to August 2018.

show abstract

Section: Uracil-based Nnrtismentioning

confidence: 96%

Section: Modification Of Existing Nnrti Scaffoldsmentioning

confidence: 99%

Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

2018

View full text Add to dashboard Cite

show abstract

“…Chloromethyl ether 18 was obtained via the classical Henry method. 23 As outlined in Scheme 7 2,4-bis(trimethylsilyloxy)pyrimidine and 4-(4-bromophenoxy)benzyl bromide (21) were reacted in DCE at reflux for 20 h to give 23. Being more reactive than bromides 3a-i and 11, the reaction proceeds under rather mild conditions in DCE at ambient temperature.…”

Section: Chemistrymentioning

confidence: 99%

Toward the discovery of dual HCMV–VZV inhibitors: Synthesis, structure activity relationship analysis, and cytotoxicity studies of long chained 2-uracil-3-yl-N-(4-phenoxyphenyl)acetamides

Babkov

Khandazhinskaya

Chizhov

et al. 2015

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

The need for novel therapeutic options to fight herpesvirus infections still persists. Herein we report the design, synthesis and antiviral evaluation of a new family of non-nucleoside antivirals, derived from 1-[ω-(4-bromophenoxy)alkyl]uracil derivatives--previously reported inhibitors of human cytomegalovirus (HCMV). Introduction of the N-(4-phenoxyphenyl)acetamide side chain at N(3) increased their potency and widened activity spectrum. The most active compounds in the series exhibit submicromolar activity against different viral strains of HCMV and varicella zoster virus (VZV) replication in HEL cell cultures. Inactivity against other DNA and RNA viruses, including herpes simplex virus 1/2, points to a novel mechanism of antiviral action.

show abstract

“…The anti-human immunodeficiency virus type 1 (HIV-1) agent W-1 ( Figure S1) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) (Wang et al 2012;Wright et al 2012;Li et al 2013;Melikian et al 2014;Babkov et al 2015). Unlike the marketed NNRTIs (Ren and Stammers 2008;Agneskog et al 2013;Sluis-Cremer 2014;Gallien et al 2015;Zhang et al 2015), W-1 exhibited more potent antiviral activity against NNRTIs-resistant HIV-1 strains (Lu et al 2007;Qin et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats

Wang

et al. 2016

Arch. Pharm. Res.

View full text Add to dashboard Cite

The purpose of this study was to characterize the disposition, distribution, excretion and plasma protein binding of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) in rats. Concentrations of W-1 within biological samples were determined using a validated high performance liquid chromatography method. The plasma protein binding of W-1 was examined by equilibrium dialysis method. After oral administration of W-1 (50, 100 and 200 mg/kg, respectively) in self-microemulsifying drug delivery system formulation, the pharmacokinetic parameters of W-1 were as follows: the peak plasma concentrations (C max) were 0.42, 1.50 and 2.55 μg/mL, the area under the curve (AUC0-t) were 0.89, 2.27 and 3.96 µg/h mL and the plasma half-life (t 1/2) were 5.15, 3.77 and 3.77 h, respectively. Moreover, the prototype of W-1 was rapidly and extensively distributed into fifteen tissues, especially higher concentrations were detected in intestine, stomach and liver, respectively. The plasma protein binding of W-1 in rat, beagle dog and human were in the range of 97.96-99.13 %. This study suggested that W-1 has an appropriate pharmacokinetics in rats, such as rapid absorption, moderate clearance, and rapid distribution to multiple tissues. Those properties provide important information for further development W-1 as an anti-HIV-1 drug candidate.

show abstract

Scaffold hopping: Exploration of acetanilide-containing uracil analogues as potential NNRTIs

Cited by 13 publications

References 40 publications

Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

Toward the discovery of dual HCMV–VZV inhibitors: Synthesis, structure activity relationship analysis, and cytotoxicity studies of long chained 2-uracil-3-yl-N-(4-phenoxyphenyl)acetamides

Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats

Contact Info

Product

Resources

About