Synthesis and evaluation of novel 3-(3,5-dimethylbenzyl)uracil analogs as potential anti-HIV-1 agents

Norikazu Sakakibara; Takayuki Hamasaki; Masanori Baba; Yosuke Demizu; Masaaki Kurihara; Kohji Irie; Masatoshi Iwai; Eriko Asada; Yoshihisa Kato; Tokumi Maruyama

doi:10.1016/j.bmc.2013.06.061

Synthesis and evaluation of novel 3-(3,5-dimethylbenzyl)uracil analogs as potential anti-HIV-1 agents

Bioorg Med Chem. 2013 Sep 15;21(18):5900-6. doi: 10.1016/j.bmc.2013.06.061. Epub 2013 Jul 3.

Authors

Norikazu Sakakibara¹, Takayuki Hamasaki, Masanori Baba, Yosuke Demizu, Masaaki Kurihara, Kohji Irie, Masatoshi Iwai, Eriko Asada, Yoshihisa Kato, Tokumi Maruyama

Affiliation

¹ Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki City, Japan.

PMID: 23916148
DOI: 10.1016/j.bmc.2013.06.061

Abstract

A novel series of uracil derivatives with a 3,5-dimethylbenzyl group at the N(3)-position were synthesized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors. Some of these compounds showed good-to-moderate activity with EC50 values in the submicromolar range. Among them, compound 10c showed significant potency against HIV-1 activity with an EC50 value of 0.03 μM and a high selectivity index of 2863. Preliminary structure-activity relationships and molecular modeling analyses were used to explore the major interactions between HIV-1 reverse transcriptase and the potent inhibitor 10c, which may serve as an important lead for further optimization.

Keywords: Anti-HIV-1 agents; HIV-1 RT; Molecular modeling analysis; NNRTIs; Uracil analogs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Cell Line
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / metabolism
HIV-1 / drug effects
HIV-1 / enzymology
Humans
Molecular Dynamics Simulation
Picolinic Acids / chemical synthesis*
Picolinic Acids / chemistry
Picolinic Acids / pharmacokinetics
Protein Structure, Tertiary
Reverse Transcriptase Inhibitors / chemical synthesis*
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology
Structure-Activity Relationship
Uracil / analogs & derivatives*
Uracil / chemical synthesis
Uracil / chemistry
Uracil / pharmacokinetics
Uracil / pharmacology
Virus Replication / drug effects

Substances

3-(3,5-dimethylbenzyl)uracil
6-amino-3-(3,5-dimethylbenzyl)-1-(4-picolyl)uracil
Picolinic Acids
Reverse Transcriptase Inhibitors
Uracil
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase