Comparative Evaluation of the Inhibitory Activities of a Series of Pyrimidinedione Congeners That Inhibit Human Immunodeficiency Virus Types 1 and 2

@article{Buckheit2007ComparativeEO,
  title={Comparative Evaluation of the Inhibitory Activities of a Series of Pyrimidinedione Congeners That Inhibit Human Immunodeficiency Virus Types 1 and 2},
  author={R. Buckheit and T. Hartman and K. Watson and Sun-Gan Chung and E. Cho},
  journal={Antimicrobial Agents and Chemotherapy},
  year={2007},
  volume={52},
  pages={225 - 236}
}
ABSTRACT Seventy-three analogs of SJ-3366 (1-(3-cyclopenten-1-ylmethyl)-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4(1H,3H)-pyrimidinedione) were synthesized and comparatively evaluated for their ability to inhibit the replication of human immunodeficiency virus type 1 (HIV-1) and HIV-2 and for their ability to suppress virus entry and reverse transcription. These studies were performed to identify inhibitors with activity greater than that of the current lead molecule (SJ-3366) and to utilize structure… Expand
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References

SHOWING 1-10 OF 61 REFERENCES
The Structure-Activity Relationships of 2,4(1H,3H)-pyrimidinedione Derivatives as potent HIV type 1 and type 2 inhibitors
TLDR
A series of pyrimidinediones with substantially improved antiviral efficacy and range of action and with significantly reduced cellular cytotoxicity are identified. Expand
Structure-activity and cross-resistance evaluations of a series of human immunodeficiency virus type-1-specific compounds related to oxathiin carboxanilide
TLDR
The results with isolates selected in cell culture indicate that the carboxanilide compounds interact with the RT at two vulnerable sites, selecting UC-resistant virus isolates with the Y-to-C mutation at position 181 (Y181C) or the L100I substitution. Expand
SJ-3366, a Unique and Highly Potent Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1 (HIV-1) That Also Inhibits HIV-2
  • R. Buckheit, K. Watson, +12 authors E.-H. Cho
  • Medicine, Biology
  • Antimicrobial Agents and Chemotherapy
  • 2001
TLDR
A potent new nonnucleoside reverse transcriptase (RT) inhibitor of human immunodeficiency virus type 1 (HIV-1) that also is active against HIV-2 and which interferes with virus replication by two distinct mechanisms is identified. Expand
A new series of pyridinone derivatives as potent non-nucleoside human immunodeficiency virus type 1 specific reverse transcriptase inhibitors.
4-(Arylthio)-pyridin-2(1H)-ones variously substituted in their 3-, 5-, and 6-positions have been synthesized as a new series of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)-pyridinoneExpand
Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative.
TLDR
A novel 6-substituted acyclouridine derivative, HEPT, has proved to be a potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) in vitro. Expand
Resistance to 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives is generated by mutations at multiple sites in the HIV-1 reverse transcriptase.
TLDR
Results suggest that several changes in the conformation of the nonnucleoside inhibitor binding site of the HIV-1 reverse transcriptase can affect the inhibitory activity of the HEPT class of compounds. Expand
Lack of synergy in the inhibition of HIV-1 reverse transcriptase by combinations of the 5'-triphosphates of various anti-HIV nucleoside analogs.
TLDR
Results indicated that synergistic inhibition of the HIV-1 reverse transcriptase is not responsible for the synergistic antiviral activity seen in cell culture with combinations of these nucleoside analogs. Expand
Preclinical evaluation of MKC-442, a highly potent and specific inhibitor of human immunodeficiency virus type 1 in vitro
TLDR
Evaluated MKC-442 for its inhibitory effect on the replication of HIV-1 in various cell cultures, including human peripheral blood lymphocytes and monocyte-macrophages and combinations with either 3'-azido-3'-deoxythymidine, 2,'3'-dideoxycytidine, or 2',3'- dideoxyinosine synergistically inhibited the replicationof HIV- 1. Expand
Comparative anti-HIV evaluation of diverse HIV-1-specific reverse transcriptase inhibitor-resistant virus isolates demonstrates the existence of distinct phenotypic subgroups.
TLDR
Results indicate that the various subgroups of HIV-1-specific inhibitors interact differently with HIV- 1 RT, suggesting important potential implications for drug combination therapeutic strategies. Expand
5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3, 4-dihydropyrimidin-4(3H)-ones: novel potent and selective dihydro-alkoxy-benzyl-oxopyrimidine derivatives.
TLDR
An excellent correlation was found between EC50 and IC50 values which confirmed that these compounds act as inhibitors of the HIV-1 RT. Expand
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4
5
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