Structure−Activity Relationship Studies of a Series of Antiviral and Antibacterial Aglycon Derivatives of the Glycopeptide Antibiotics Vancomycin, Eremomycin, and Dechloroeremomycin

• Published in: Journal of medicinal chemistry 2005-06, Vol.48 (11), p.3885-3890
• Main Authors: Printsevskaya, Svetlana S, Solovieva, Svetlana E, Olsufyeva, Eugenia N, Mirchink, Elena P, Isakova, Elena B, De Clercq, Erik, Balzarini, Jan, Preobrazhenskaya, Maria N
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - pharmacology; Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacology; Anti-Retroviral Agents - chemical synthesis; Anti-Retroviral Agents - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Cell Line; Cell Line, Tumor; Drug Resistance, Bacterial; Glycopeptides; HIV-1 - drug effects; HIV-2 - drug effects; Human immunodeficiency virus; Human immunodeficiency virus 1; Human immunodeficiency virus 2; Humans; Mice; Microbial Sensitivity Tests; Moloney murine sarcoma virus - drug effects; Structure-Activity Relationship; Vancomycin - analogs & derivatives; Vancomycin - chemical synthesis; Vancomycin - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0500774

N-(Adamantyl-1)methyl, N-(adamantyl-2), and N-(ω-aminodecyl) amides of vancomycin, eremomycin, and dechloroeremomycin aglycons and their des-(N-Me-d-Leu) derivatives were synthesized and their antibacterial and anti-HIV activities were investigated. Carboxamides with an intact peptide core demonstrated activity against glycopeptide-susceptible and -resistant bacteria (1−32 μM). N-(Adamantyl-1)methylcarboxamide of eremomycin aglycons had good antiretroviral activity (1.6 μM against HIV-1). Compounds with destroyed peptide core [des-(N-Me-d-Leu)-aglycon amides] were inactive against both glycopeptide-sensitive and -resistant bacteria. (Adamantyl-1)methylamide of des-(N-Me-d-Leu)-eremomycin aglycon had good antiretroviral activity (EC50 of 5.5 μM for HIV-1 and 3.5 μM for HIV-2). (Adamantyl-1)methylamides of eremomycin aglycon and its des-(N-Me-d-Leu)-derivative are the most promising and selective antiretroviral agents. Their ability to induce bacterial resistance to glycopeptide antibiotics during prolonged administration may be expected to be very low or absent. This might make the use of these derivatives feasible in the prolonged therapy or prophylaxis of HIV infections.