Synthesis and Anti-HIV-1 and Anti-HCMV Activity of 1-Substituted 3-(3,5-Dimethylbenzyl)uracil Derivatives

Maruyama, Toru; Kozai, Shigetada; Demizu, Yosuke; Witvrouw, Myriam; Pannecouque, Christophe; Balzarini, Jan; Snoeck, Robert; Andrei, Gracíela; Clercq, Erik De

doi:10.1248/cpb.54.325

Cited by 27 publications

(31 citation statements)

References 32 publications

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“…These aryl substituted uracils were shown to block HIV-1 and HCMV replication in vitro in sub-micromolar concentrations. 31,32 Potent activity was also noted for a similar 1,3-dibenzyl inhibitor developed by Nair et al, which exhibited potent activity against the HIV integrase (Fig. 3).…”

Section: Introductionsupporting

confidence: 62%

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1-Benzyl derivatives of 5-(arylamino)uracils as anti-HIV-1 and anti-EBV agents

Новиков

Buckheit

Temburnikar

et al. 2010

Bioorganic & Medicinal Chemistry

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Section: Introductionsupporting

confidence: 62%

“…Additional examples pertinent to our approach can be found in the 1,3-dibenzyl-derivatives of uracil from Maruyama et al 31,32 (Fig. 3).…”

Section: Introductionmentioning

confidence: 99%

1-Benzyl derivatives of 5-(arylamino)uracils as anti-HIV-1 and anti-EBV agents

Новиков

Buckheit

Temburnikar

et al. 2010

Bioorganic & Medicinal Chemistry

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“…This is explainable, since the 6-azido uracil derivative (AzBBU) may be reduced metabolically to its 6-amino congener (AmBBU) in cell cultures (28). These compounds showed higher activity against III B than the 1-substituted 3-(3,5-dimethylbenzyl)uracils previously reported (33). In contrast, AzBBU and AmBBU were not active against III B-R , although the lead compound BBF-29 had weak activity.…”

Section: Discussionmentioning

confidence: 86%

“…Most NNRTIs are engaged in the H-bond with the backbone of the residues Lys101 and/or Lys103 of RT (13,26,41). Previous docking studies suggested an H-bond between the amide of Lys101 and nitrogen of the cyanomethyl and picolyl group of 1-substituted 3-(3,5-dimethylbenzyl)uracils (33). In our previous study, we showed that 6-subtitutions on the uracil ring resulted in elevation of the anti-HIV-1 activity of the uracil derivatives (28).…”

Section: Discussionmentioning

confidence: 99%

Anti-Human Immunodeficiency Virus Type 1 Activity of Novel 6-Substituted 1-Benzyl-3-(3,5-Dimethylbenzyl)Uracil Derivatives

Ordonez

Hamasaki

Isono

et al. 2012

Antimicrob Agents Chemother

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ABSTRACTNonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. In screening of chemical libraries, we found 6-azido-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AzBBU) and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AmBBU) to be highly active and selective inhibitors of HIV-1 replicationin vitro. To determine the resistance profiles of these compounds, we conducted a long-term culture of HIV-1-infected MT-4 cells with escalating concentrations of each compound. After serial passages of the infected cells, escape viruses were obtained, and they were more than 500-fold resistant to the uracil derivatives compared to the wild type. Sequence analysis was conducted for RT of the escape viruses at passages 12 and 24. The amino acid mutation Y181C in the polymerase domain of RT was detected for all escape viruses. Docking studies using the crystal structure of RT showed that AmBBU requires the amino acid residues Leu100, Val106, Tyr181, and Trp229 for exerting its inhibitory effect on HIV-1. Four additional amino acid changes (K451R, R461K, T468P, and D471N) were identified in the RNase H domain of RT; however, their precise role in the acquisition of resistance is still unclear. In conclusion, the initial mutation Y181C seems sufficient for the acquisition of resistance to the uracil derivatives AzBBU and AmBBU. Further studies are required to determine the precise role of each mutation in the acquisition of HIV-1 resistance.

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“…Synthesis of six-membered heterocyclic compounds such as pyrimidine ring is very important because of the synthetic condition and pharmacological properties [6][7][8][9][10]. It is noteworthy that fused heterocyclic structures containing pyrimidine ring exhibited diverse biological activities such as antimicrobial [11,12], DNA cleavage [13], anti-inflammatory [14], antiviral [15], anti-HIV [16] and antitumor [17]. Benzofuran nucleus directly linked at C-2 to various substituted heterocyclic ring systems exhibited promising biological activity [18].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Screening of Benzofuran Fused C-2,4,6-Substituted Pyrimidine Derivatives as a New Antibacterial and Antifungal Agent

Rangaswamy

Naik

2017

Int J Pharm Pharm Sci

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Objective: Benzofuran and their heterocyclic analogs represent an important class of molecules which have a wide range of pharmacological activities. Therefore, in this study synthesis and antimicrobial activity of benzofuran fused C-2,4,6-substituted pyrimidine derivatives was extensively discussed.Methods: Benzofuran fused C-2,4,6-substituted pyrimidine derivatives (4a-k) were built by cyclo condensation, Claisen-Schmidt condensation followed by cyclization via coupling of benzoyl fragments, which include benzofuran, a pyrimidine ring and C-6 substituted phenyl residue with various substituents, connected by linker-S-band. The structures of the synthesized compounds were confirmed by analytical and spectral techniques and evaluated their antimicrobial activity. Results:The results of antibacterial and antifungal activity against various microbes, most of the compounds have shown considerable antimicrobial activity, but compounds 4g and 4e exhibits superior activity compared to standards, this may be due to presence bromo and fluro electron withdrawing substituent on the benzoyl moiety and more lipophilic nature of pyrimidine ring. Conclusion:According to the activity studies, it is observed that the synthesis and antimicrobial activity of benzofuran fused C-2,4,6-substituted pyrimidine derivatives have been shown better antimicrobial activity. The obtained results suggest that these classes of compounds can be considered as new hits for further structural optimization to obtain better antimicrobial drug development program.

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Synthesis and Anti-HIV-1 and Anti-HCMV Activity of 1-Substituted 3-(3,5-Dimethylbenzyl)uracil Derivatives

Cited by 27 publications

References 32 publications

1-Benzyl derivatives of 5-(arylamino)uracils as anti-HIV-1 and anti-EBV agents

1-Benzyl derivatives of 5-(arylamino)uracils as anti-HIV-1 and anti-EBV agents

Anti-Human Immunodeficiency Virus Type 1 Activity of Novel 6-Substituted 1-Benzyl-3-(3,5-Dimethylbenzyl)Uracil Derivatives

Synthesis and Screening of Benzofuran Fused C-2,4,6-Substituted Pyrimidine Derivatives as a New Antibacterial and Antifungal Agent

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