[d4U]-butyne-[HI-236] as a non-cleavable, bifunctional NRTI/NNRTI HIV-1 reverse-transcriptase inhibitor.
The synthesis of bifunctional compound 10 consisting of d4U joined at C-5 to a butynyl spacer attached to HI-236 is reported using a Sonogashira coupling as a key step. As a non-cleavable bifunctional HIV inhibitor incorporating an NRTI with an NNRTI, 10 shows good inhibitory activity (EC(50)=250 nM) against HIV (IIIB) replication in MT-2 cell culture, which is eight times greater than that of d4T and between those of the two component drugs.
Hunter
Roger
R
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa. Roger.Hunter@uct.ac.za
Muhanji
Clare I
CI
Hale
Ian
I
Bailey
Christopher M
CM
Basavapathruni
Aravind
A
Anderson
Karen S
KS
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D019281:Dimerization; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D008956:Models, Chemical; D008968:Molecular Conformation; D009705:Nucleosides / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; C121245:HI 236; D009705:Nucleosides; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D013890:Thiourea