title: Structure-activity relationship studies of a series of antiviral and antibacterial aglycon derivatives of the glycopeptide antibiotics vancomycin, eremomycin, and dechloroeremomycin.
abstract: N-(adamantyl-1)methyl, N-(adamantyl-2), and N-(omega-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 microM). N-(adamantyl-1)methylcarboxamide of eremomycin aglycons had good antiretroviral activity (1.6 microM 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 microM for HIV-1 and 3.5 microM 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.
authors.affiliation: Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, B. Pirogovskaya 11, Moscow 119021, Russia.
authors.forename: Svetlana S
authors.initials: SS
authors.lastname: Printsevskaya
authors.forename: Svetlana E
authors.initials: SE
authors.lastname: Solovieva
authors.forename: Eugenia N
authors.initials: EN
authors.lastname: Olsufyeva
authors.forename: Elena P
authors.initials: EP
authors.lastname: Mirchink
authors.forename: Elena B
authors.initials: EB
authors.lastname: Isakova
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Maria N
authors.initials: MN
authors.lastname: Preobrazhenskaya
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology; D044966:Anti-Retroviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D024881:Drug Resistance, Bacterial; D006020:Glycopeptides; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008980:Moloney murine sarcoma virus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D000970:Antineoplastic Agents; D006020:Glycopeptides; C053759:eremomycin; C501702:dechloroeremomycin; D014640:Vancomycin