Imidazo[1,5-b]Pyridazine-D4T Conjugates: Synthesis and Anti-Human Immunodeficiency Virus Evaluation

Abstract

In an attempt to combine the human immunodeficiency virus type 1 (HIV-1)-inhibitory capacity of 2',3'-dideoxy-2',3'-didehydronucleoside analogues [nucleoside reverse transcriptase (RT) inhibitors; NRTI] and non-nucleoside RT inhibitors (NNRTI), we have designed, synthesized and evaluated for their anti-HIV activity several heterodimers of the general formula [d4T]-NH-(CH2)n-NH-[imidazo[1,5-b]pyridazine]. The synthesis of these heterodimers was conducted in three parts. The first part focused on the synthesis of the NRTI. The second part was devoted to the NNRTI and the NNRTI linked to appropriate spacers: [NNRTI]-NH-(CH2)n-NH2. In the third part, the condensation between the NRTI and the [NNRTI]-NH-(CH2)n-NH2 was performed. The in vitro inhibitory activities against HIV-1 of the [d4T]-NH-(CH2)n-NH-[imidazo[1,5-b]pyridazine] heterodimers were found to be comparable to that of d4T (stavudine) in HIV-infected cells. Moreover, the heterodimers were endowed with anti-HIV-2 activity and with anti-nevirapine-resistant HIV-1 activity. None of the heterodimers proved markedly cytotoxic to CEM-SS or MT-4 cells. There was not a clear trend toward antiviral potency on lengthening the methylene spacer in the [d4T]-NH-(CH2)n-NH-[imidazo[1,5-b]pyridazine] heterodimers.

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

“…Previous studies on C-5-substituted d4T derivatives yielded mixed results but mostly resulted in inactive analogues. 24,25,40–43 Moreover, earlier attempts to show efficient HIV replication inhibition of bifunctional compounds all failed. 44,45 We hypothesized that one of the possible reasons for these unsuccessful attempts could be impaired phosphorylation of the nucleoside end of bifunctional analogues catalyzed by cellular kinases.…”

Current Developments in the Synthesis and Biological Activity of HIV-1 Double-Drug Inhibitors

“…It is also effective against HIV replication and inhibits HIV-1 RT by blocking the pyrophosphate binding site [30]. The design, synthesis and anti-HIV-1 evaluation of several noncleavable bifunctional heterodimers of the general formula [d4T]-NH(CH 2 ) n -NH-[imidazo[1,5-b]pyridazine] (n = 6-12) involving a C-5 linkage to d4T and a C-2 linkage to the heteroaromatic was reported by Ladurée et al [31] in 1998. The imidazo[1, 5-b] pyridazine template was chosen as the NNRTI due to its exceptional potency.…”

A Review of Recent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Research Activity

“…One example of such a hybride is compound 13. Another publication has appeared discussing the synthesis and biological activity of "mixed site inhibitors" [91]. The functionalities of nucleoside and of non-nucleoside reverse transcriptase inhibitors were combined to yield unique [d4T]-NH -(CH 2 ) n -NH -[imidazo [1,5-b]bipyrazine heterodimers.…”