Allosteric inhibitors against HIV-1 reverse transcriptase: design and synthesis of MKC-442 analogues having an omega-functionalized acyclic structure.
Based on X-ray crystallographic analysis of MKC-442/human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) complex, analogues in which the N1-substituent is replaced with omega-functionalized alkyl groups were designed to improve the affinity for the enzyme. Synthesis of these compounds was carried out starting from MKC-442 by a sequence of reactions (N3-protection, removal of N1-ethoxymethyl group, alkylation, and N3-deprotection). The compounds were evaluated for anti-HIV activity. Structure-activity relationships are discussed in terms of the possible interaction with the enzyme.
Tanaka
H
H
School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Walker
R T
RT
Hopkins
A L
AL
Ren
J
J
Jones
E Y
EY
Fujimoto
K
K
Hayashi
M
M
Miyasaka
T
T
Baba
M
M
Stammers
D K
DK
Stuart
D I
DI
D000495:Allosteric Site / Q000187:drug effects*; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000737:chemistry; D015497:HIV-1 / Q000201:enzymology*; D006860:Hydrogen Bonding; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; D054303:HIV Reverse Transcriptase; C083858:emivirine