Parallel one-pot synthesis and structure–activity relationship study of symmetric formimidoester disulfides as a novel class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 12; pp. 6353 - 6363
• Main Authors: Cesarini, Sara, Spallarossa, Andrea, Ranise, Angelo, Schenone, Silvia, Bruno, Olga, La Colla, Paolo, Casula, Laura, Collu, Gabriella, Sanna, Giuseppina, Loddo, Roberta
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.06.2008; Elsevier Science
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cell Line; Disulfides - chemical synthesis; Disulfides - chemistry; Disulfides - pharmacology; Drug Resistance, Viral - genetics; HIV-1; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Humans; Medical sciences; Non-nucleoside reverse transcriptase inhibitors; Nucleosides - chemistry; Parallel one-pot synthesis; Pharmacology. Drug treatments; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship; Symmetric formimidoester disulfides; HIV-1; Non-nucleoside reverse transcriptase inhibitors; Symmetric formimidoester disulfides; Parallel one-pot synthesis; Cyclopropane derivatives; RNA-directed DNA polymerase; HIV-1 virus; Non nucleoside compound; Imide; Organic disulfide; Structure activity relation; Reverse transcriptase inhibitor; Antiviral; Chemical synthesis; Enzyme; Transferases; Benzene derivatives; Retroviridae; Enzyme inhibitor; Lentivirus; Naphthalene derivatives; In vitro; Virus; Nucleotidyltransferases; Human immunodeficiency virus
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.05.010

The molecular duplication of non-nucleoside reverse transcriptase inhibitor (NNRTI) O-(2-phthalimidoethyl)– N-arylthiocarbamates (C-TCs) led to the identification of symmetric formimidoester disulfides (DSs) as a novel class of potent NNRTIs. The lead compound 1 [dimer of the isothiocarbamic form of TC O-(2-phthalimidoethyl)– N-phenylthiocarbamate] turned out to prevent the wild-type HIV-1 multiplication in MT-4 cell culture with an EC 50 value of 0.35 μM. In order to perform a structure–activity relationship (SAR) study, we prepared 40 analogues of 1 by an unprecedented one-pot method of solution-phase parallel synthesis. The SAR strategy was focused on the variation of the N-aryl portion (mono-, di- and trisubstitution of the phenyl ring and its replacement with a 1-naphthyl, cyclopropyl or benzyl group) and of the 2-phthalimidoethyl moiety (introduction of a methyl on the phthalimide substructure, replacement of the phthalimide moiety with a phenyl ring and elongation of the ethyl linker). Most DSs proved to inhibit the wild-type HIV-1 replication in cell-based assays and 15 of them were active at nanomolar concentrations. The most potent congeners ( 11, 15, 16, 17, 18, 19, 20 and 32, EC 50: 10–70 nM) shared the N- para-substituted phenyl moiety. Compound 17 tested in enzyme assay against recombinant wild-type reverse transcriptase displayed an IC 50 value of 0.74 μM. Compounds 19 and 33 were active at micromolar concentrations against the clinically relevant Y181C and/or K103R resistant mutants.