Synthesis of alkenyldiarylmethanes (ADAMs) containing benzo[ d]isoxazole and oxazolidin-2-one rings, a new series of potent non-nucleoside HIV-1 reverse transcriptase inhibitors

• Published in: European journal of medicinal chemistry 2009-03, Vol.44 (3), p.1210-1214
• Main Authors: Deng, Bo-Liang, Zhao, Yujie, Hartman, Tracy L., Watson, Karen, Buckheit, Robert W., Pannecouque, Christophe, De Clercq, Erik, Cushman, Mark
• Format: Article
• Language: English
• Subjects: Alkenyldiarylmethanes (ADAMs); Anti-HIV; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cell Line; HIV-1 - drug effects; Humans; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Non-nucleoside reverse transcriptase inhibitors (NNRTIs); Oxazolidinones - chemical synthesis; Oxazolidinones - chemistry; Oxazolidinones - pharmacology; Pharmacology. Drug treatments; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Fourier Transform Infrared
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2008.09.013

As a continuation of efforts to replace the metabolically labile methyl esters of lead alkenyldiarylmethanes (ADAMs) with stable bioisosteres, compounds bearing benzo[ d]isoxazole and oxazolidine-2-one rings were designed and evaluated as a new series of potent HIV-1 non-nucleoside reverse transcriptase inhibitors with anti-HIV activity. All of the resulting ADAMs were found to inhibit HIV-1 RT with poly(rC)·oligo(dG) as the template primer. The most promising compound in this series was ADAM 3, with EC 50 values of 40 nM (vs HIV-1 RF) and 20 nM (vs HIV-1 IIIB). Compound 3 also inhibited HIV-1 reverse transcriptase with an IC 50 of 0.91 μM. ADAM 4 has an antiviral EC 50 of 0.6 μM in CEM-SS cells and a plasma half-life of 51.4 min. ADAMs incorporating a benzo[ d]isoxazole ring were synthesized and evaluated as NNRTIs. Compound 3 [IC 50 0.91 μM; EC 50 40 nM (HIV-1 RF) and 20 nM (HIV-1 IIIB)] displayed the most potent activity. [Display omitted]