Antiviral (RNA) activity of selected Amaryllidaceae isoquinoline constituents and synthesis of related substances.
A series of 23 Amaryllidaceae isoquinoline alkaloids and related synthetic analogues were isolated or synthesized and subsequently evaluated in cell culture against the RNA-containing flaviviruses (Japanese encephalitis, yellow fever, and dengue viruses), bunyaviruses (Punta Toro, sandfly fever, and Rift Valley fever viruses), alphavirus (Venezuelan equine encephalomyelitis virus), lentivirus (human immunodeficiency virus-type 1) and the DNA-containing vaccinia virus. Narciclasine [1], lycoricidine [2], pancratistatin [4], 7-deoxypancratistatin [5], and acetates 6-8, isonarciclasine [13a], cis-dihydronarciclasine [14a], trans-dihydronarciclasine [15a], their 7-deoxy analogues 13b-15b, lycorines 16 and 17, and pretazettine [18] exhibited consistent in vitro activity against all three flaviviruses and against the bunyaviruses, Punta Toro and Rift Valley fever virus. Activity against sandfly fever virus was only observed with 7-deoxy analogues. In most cases, however, selectivity of the active compounds was low, with toxicity in uninfected cells (TC50) occurring at concentrations within 10-fold that of the viral inhibitory concentrations (IC50). No activity was observed against human immunodeficiency virus-type 1, Venezuelan equine encephalomyelitis virus, or vaccinia viruses. Pancratistatin [4] and its 7-deoxy analogue 5 were evaluated in two murine Japanese encephalitis mouse models (differing in viral dose challenge, among other factors). In two experiments (low LD50 viral challenge, variant I), prophylactic administration of 4 at 4 and 6 mg/kg/day (2% EtOH/saline, sc, once daily for 7 days, day -1 to +5) increased survival of Japanese-encephalitis-virus-infected mice to 100% and 90%, respectively. In the same model, prophylactic administration of 5 at 40 mg/kg/day in hydroxypropylcellulose (sc, once daily for 7 days, day -1 to +5) increased survival of Japanese-encephalitis-virus-infected mice to 80%. In a second variant (high LD50 viral challenge), administration of 4 at 6 mg/kg/day (ip, twice daily for 9 days, day -1 to +7) resulted in a 50% survival rate. In all cases, there was no survival in the diluent-treated control mice. Thus, 4 and 5 demonstrated activity in mice infected with Japanese encephalitis virus but only at near toxic concentrations. To our knowledge, however, this represents a rare demonstration of chemotherapeutic efficacy (by a substance other than an interferon inducer) in a Japanese-encephalitis-virus-infected mouse model.
Gabrielsen
B
B
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland 21702.
Monath
T P
TP
Huggins
J W
JW
Kefauver
D F
DF
Pettit
G R
GR
Groszek
G
G
Hollingshead
M
M
Kirsi
J J
JJ
Shannon
W M
WM
Schubert
E M
EM
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D004672:Encephalitis, Japanese / Q000188:drug therapy / Q000382:microbiology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000302:isolation & purification* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010946:Plants, Medicinal / Q000737:chemistry*; D012328:RNA Viruses / Q000187:drug effects; D010948:Viral Plaque Assay; D014780:Viruses / Q000187:drug effects
D000998:Antiviral Agents; D007546:Isoquinolines