Synthesis and biological evaluation of novel tricyclic matrinic derivatives as potential anti-filovirus agents

Abstract

Twenty-six novel tricyclic sophoridinic and matrinic derivatives containing a common chlorinated benzene fragment were designed, synthesized and evaluated for their anti-ebolavirus (EBOV) activities. Structure—activity relationship analysis indicated: (i) 12N-dichlorobenzyl motif was beneficial for the activity; (ii) the chiral configuration at C5 atom might not affect the activity much. Among the target compounds, compound 7d exhibited the most potent potency against EBOV with an IC50 value of 5.29 μmol/L and an SI value of over 37.8. Further in vivo anti-EBOV assay of 7d identified its high effectiveness, and in vivo anti-MARV assay of 7d suggested its inspiring broad-spectrum anti-filovirus activity. The results provided powerful information on further strategic optimization and development of this kind of compounds against filoviruses.

Research Progress of Natural Matrine Compounds and Synthetic Matrine Derivatives

“…Professor Song Danqing research team constructed a compound library of tricyclic Sophorae japonicum derivatives in the early years. Using sertraline as a positive control, 12-N-p-chlorobenzyl dihydrochloride (compound 73) shows good anti-EBOV activity in the pseudotype EBOV virus model (pHIV-EBOVGP-Fluc) [74]. Compound 73 is found to have a chlorobenzene fragment at C-12, similar to that of sertraline, suggesting that the chlorobenzene fragment may contribute to the inhibitory effect on EBOV.…”

“…Scheme 15. The synthetic route of compounds 74a-74c and 75a-75c [74]. The synthetic route of compounds 74a-74c and 75a-75c [74].…”

“…Molecules 2023, 28, x FOR PEER REVIEW 22 of 28 Scheme 16. The synthetic route of compounds 76a-76d and 77a-77c [74].…”