Synthesis and antiviral activity of distamycin A analogues: substitutions on the different pyrrole nitrogens and in the amidine function.
Several new analogues of the antiviral antibiotic distamycin A were synthesized and assayed for their effects on influenza and herpes simplex virus. The new compounds 5b-j (R1-3 = H, CH3, and C2H5, R4,5 = H and CH3) were obtained via stepwise prepared formylated trimeric benzyl 4-aminopyrrole-2-carboxylates 3a-h, which after catalytic hydrogenolysis were coupled as N-succinimidyl esters directly with the proper beta-aminopropionamidine, unsubstituted or substituted with one or two methyl groups in the amidine function. Most of the new analogues did not exhibit significant effects on the viruses studied, but three compounds (5f-h) displayed activity on herpes virus as demonstrated in plaque formation and virus yield assays. Elevated cytotoxicity was simultaneously observed for 5g and 5h. For compound 5f, a partial separation of antiherpes activity and cytotoxicity was accomplished. The differences in antiherpes activity did not correspond to the differences in the inhibition of herpes virus DNA polymerase.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002522:Chlorocebus aethiops; D004214:Distamycins / Q000031:analogs & derivatives* / Q000494:pharmacology; D007202:Indicators and Reagents; D007668:Kidney; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D019384:Nucleic Acid Synthesis Inhibitors; D011758:Pyrroles; D018139:Simplexvirus / Q000201:enzymology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D004214:Distamycins; D007202:Indicators and Reagents; D019384:Nucleic Acid Synthesis Inhibitors; D011758:Pyrroles; C030000:stallimycin