Potent and specific inhibition of human immunodeficiency virus type 1 replication by 4-(2,6-dichlorophenyl)-1,2,5-thiadiazol-3-Y1 N,N-dialkylcarbamate derivatives.
4-(2,6-Dichlorophenyl)-1,2,5-thiadiazol-3-yl N,N-dialkylcarbamate (TDA) derivatives were found to be highly potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in a variety of cell cultures. The most potent congener of TDA derivatives, RD4-2024, inhibited HIV-1 replication by 50% at concentrations of 12.5 and 4.8 nM in MT-4 cells and peripheral blood mononuclear cells, respectively. These concentrations were more than 2,000- and 30,000-fold lower than its 50% cytotoxic concentrations, respectively. Although the TDA derivatives were active against 3'-azido-3'-deoxythymidine-resistant HIV-1, no antiviral activities were observed against HIV-2 and nonnucleoside reverse transcriptase inhibitor-resistant mutants of HIV-1. The TDA derivatives inhibited recombinant HIV-1 reverse transcriptase activity, depending on the template-primer used for the assay. However, they did not interact with HIV-2 reverse transcriptase. Thus, the TDA derivatives belong to the family of nonnucleoside reverse transcriptase inhibitors. Because of their potent anti-HIV-1 activities in vitro and their low levels of toxicity in mice, the TDA derivatives deserve further evaluation as candidate drugs for the treatment of patients with AIDS.
Ijichi
K
K
Rational Drug Design Laboratories, Kanagawa, Japan.
Fujiwara
M
M
Hanasaki
Y
Y
Watanabe
H
H
Katsuura
K
K
Takayama
H
H
Shirakawa
S
S
Sakai
S
S
Shigeta
S
S
Konno
K
K
D000998:Antiviral Agents / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors