Synthesis and antiviral activity of aryl phosphoramidate derivatives of beta-D- and beta-L-C-5-substituted 2',3'-didehydro-2',3'-dideoxy-uridine bearing linker arms.

We have previously reported the synthesis and evaluation of potent anti-human immunodeficiency virus compounds based on beta-D-d4T analogues bearing a tether attached at the C-5 position and their beta-L-counterparts. Initial study revealed a requirement for an alkyl side-chain with an optimal length of 12 carbons for a weak antiviral activity. As a continuation of that work, we have now prepared the corresponding phosphoramidate derivatives as possible membrane-permeable prodrugs.

Synthesis of 5-alkynylated d4T analogues as potential HIV-1 reverse transcriptase inhibitors.

A series of 2',3'-didehydro-2',3'-dideoxynucleosides substituted with an alkynylhydroxy- (6, 7, 12 and 13) and alkynylamino- (20) groups at the C-5 position were synthesized. All these five target modified nucleosides were tested for anti-human immunodeficiency virus type 1 activity in CEM-SS and MT-4 cells and unfortunately displayed no improvement in antiviral activity.

Synthesis and anti-HIV activity of some [Nucleoside Reverse Transcriptase Inhibitor]-C5'-linker-[Integrase Inhibitor] heterodimers as inhibitors of HIV replication.

Selected for their expected ability to inhibit HIV replication, a series of eight heterodimers containing a Nucleoside Reverse Transcriptase Inhibitor (NRTI) and an Integrase Inhibitor (INI), bound by a linker, were designed and synthesized. For the NRTIs, d4U, d2U and d4T were chosen. For the INIs, 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid (6) and 4-(3,5-dibenzyloxyphenyl)-2,4-dioxobutyric acid (9) (belonging to the beta-diketo acids class) were chosen.

Synthesis of certain heterodimers expected as HIV-1 reverse transcriptase inhibitors.

Expected for the ability to inhibit HIV replication, we report the synthesis of two heterodimers of the general formula: [2NRTI]-C5-GLY-SUCCINYL-Npiperazinyl-[NNRTI] (18, 19) containing both a Nucleoside Reverse Transcriptase Inhibitor (10, 11) and a Non-Nucleoside Reverse Transcriptase Inhibitor (8) [Trovirdine Analogue belonging of the phenethyl thiazolyl thiourea class] connected through the "succinyl-glycine" spontaneously cleavable linker.

Synthesis and anti-HIV activity of some heterodimers [NRTI]-glycyl-succinyl-[trovirdine analogue] of known HIV-1 reverse transcriptase inhibitors.

Expected for their ability to inhibit HIV replication, four heterodimers with a Nucleoside Reverse Transcriptase Inhibitor (NRTI) and a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) bound by a linker arm were designed and synthesized. For the NRTIs, d4U, d2U, d4T and 5'-O-acetyl-5-(3-hydroxypropynyl)d2U were chosen. For the NNRTI, a Trovirdine Analogue (belonging to the phenethylthiazolylthiourea class) was chosen.