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

• Published in: Antiviral chemistry & chemotherapy Vol. 9; no. 3; pp. 205 - 223
• Main Authors: Renoud-Grappin, M, Fossey, C, Fontaine, G, Ladurée, D, Aubertin, AM, Kirn, A
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.05.1998; International Medical Press; Sage Publications Ltd
• Subjects: AIDS/HIV; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral drugs; Antiviral activity; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line; Cytotoxicity; Drug Resistance; Enzyme Inhibitors; HIV; HIV-1 - drug effects; HIV-2 - drug effects; Human immunodeficiency virus; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Medical sciences; Molecular Structure; Nevirapine; Nevirapine - pharmacology; Nucleoside analogs; Nucleosides - chemical synthesis; Nucleosides - pharmacology; Pharmacology. Drug treatments; Protein Conformation; Pyridazines - chemical synthesis; Pyridazines - pharmacology; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - pharmacology; RNA-directed DNA polymerase; Stavudine; Stavudine - analogs & derivatives; Stavudine - pharmacology; Virus Replication - drug effects; HIV-1; imidazo [1,5–b]pyridazine; heterodimers; reverse transcriptase; d4T analogues; RNA-directed DNA polymerase; HIV-1 virus; Angular nitrogen heterocycle; Stavudine; Heterodimer; Structure activity relation; Antiviral; Pyrimidine nucleoside; Immunopathology; Enzyme; Transferases; Chain length; Retroviridae; Enzyme inhibitor; AIDS; Immune deficiency; Lentivirus; Infection; Virus; Diamine; Nucleotidyltransferases; Viral disease; Dideoxynucleoside; Human immunodeficiency virus; Conjugated compound; Ethylenic compound
• ISSN: 2040-2066; 0956-3202; 2040-2066
• DOI: 10.1177/095632029800900302

In an attempt to combine the human immunodeficiency virus type 1 (HIV-D-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-HlV-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.