Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility.
Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
Mariela
M
Bollini
José A
JA
Cisneros
Krasimir A
KA
Spasov
Karen S
KS
Anderson
William L
WL
Jorgensen
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D012995:Solubility; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D006834:Hydrazines
Anti-HIV agent; Drug solubility; NNRTI