Anti-HIV-1 activity of thiadiazole derivatives: structure-activity relationship, reverse transcriptase inhibition, and lipophilicity.
The structure-activity relationship of the non-nucleoside HIV-1-specific reverse transcriptase (RT) inhibitors 4-phenyl-1,2,5-thiadiazol-3-yl N,N-dialkylcarbamate (TDA) derivatives was investigated with respect to their anti-HIV-1 activity, RT inhibition, and lipophilicity. 4-Phenyl-1,2,5-thiadiazol-3-yl N,N-dimethylcarbamate inhibited HIV-1-induced cytopathic effect (CPE) by 50% at a concentration of 28.8 microM in MT-4 cells. The activity increased more than 100-fold when the hydrogens at the 2-position and the 6-position in phenyl moiety were substituted by chlorines. However, the derivative with a chlorine at the 4-position of phenyl moiety did not show any inhibition of HIV-1 replication at its non-toxic concentrations. All of the 4-(2,6-dichlorophenyl)-1,2,5-thiadiazol-3-yl N-methyl-N-alkylcarbamates proved inhibitory to HIV-1 replication in the nanomolar concentration range. The TDA derivatives that showed anti-HIV-1 activity also inhibited RT activity in an enzymatic assay. However, the TDA derivatives did not show any specific inhibition of a non-nucleoside RT inhibitor (NNRTI)-resistant mutant and its RT activity. When the TDA derivatives were examined for their inhibitory effect on HIV-1 replication in the presence of 50% human serum, the activity significantly decreased depending on-their lipophilicity.
Ijichi
K
K
Rational Drug Design Laboratories, Fukushima, Japan.
Fujiwara
M
M
Nagano
H
H
Matsumoto
Y
Y
Hanasaki
Y
Y
Ide
T
T
Katsuura
K
K
Takayama
H
H
Shirakawa
S
S
Aimi
N
N
Shigeta
S
S
Konno
K
K
Matsushima
M
M
Yokota
T
T
Baba
M
M
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*
D019380:Anti-HIV Agents; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D013830:Thiadiazoles; D054303:HIV Reverse Transcriptase