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.

High-throughput screening for inhibitors of Mycobacterium tuberculosis H37Rv

“…Adamantyl analogs have been shown to bind in substrate binding sites in ATPases and kinases such as sphingosine kinase 115-116. Furthermore, adamantyl-substituted aglycones of vancomycin and quinoline carboxamides show antibacterial and antimycobacterial activity 117-118. It is not clear at this time, however, just how the adamantyl-containing actives reported herein are acting.…”

Structures of Staphylococcus aureus Cell-Wall Complexes with Vancomycin, Eremomycin, and Chloroeremomycin Derivatives by 13C{19F} and 15N{19F} Rotational-Echo Double Resonance

“…The calculated value is in good agreement with the 2×7.3% = 15% value from the dephasing fit. The observed increase in dephasing for evolution times longer than 30 msec in Figure 8 suggests that the 19 F of the eremomycin derivatives is within range of a second bridge.…”

“…These arrangements provided the best match between calculated and observed dephasing and placed the 19 F of both glycopeptides approximately 6 Å from the nearest glycyl carbonyl carbon, and 11 Å from the farthest, at either end of the helical bridge. The dotted lines show the calculated dephasing if the 19 F is moved away from the ends and placed near the middle of the bridge.…”

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

“…This goal has been followed with the lipophilically modified glycopeptide derivatives described here by using the aglycons, which led to a significant decrease or loss of antibacterial activity. 25 For that reason, we present 152 here as it was devoid of any antibacterial activity and, at the same time, about as potent against HIV as related glycopeptide aglycons (Table 3). However, SAR with a number of glycopeptide aglycons derived from Vancomycin, Eremomycin, and Dechloroeremomycin did not yield compounds with enhanced anti-HIV potency, as exemplified by the des-( N -Methyl-D-Leu) aglycon of Eremomycin 152 (Scheme 20, Table 3).…”