Structure-activity relationship studies of a series of antiviral and antibacterial aglycon derivatives of the glycopeptide antibiotics vancomycin, eremomycin, and dechloroeremomycin.
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.
Printsevskaya
Svetlana S
SS
Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, B. Pirogovskaya 11, Moscow 119021, Russia.
Solovieva
Svetlana E
SE
Olsufyeva
Eugenia N
EN
Mirchink
Elena P
EP
Isakova
Elena B
EB
De Clercq
Erik
E
Balzarini
Jan
J
Preobrazhenskaya
Maria N
MN
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
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