Fanny Roussi

Resistance to carbapenems in Gram-negative bacteria is a major public health concern. This resistance is primarily mediated by carbapenemase enzymes, which hydrolyze and inactivate carbapenem antibiotics. These enzymes fall into two main categories: serine carbapenemases (e.g., OXA-48 and KPC-2) and zinc-dependent metallo-β-lactamases (e.g., NDM-1). Over recent years, their dissemination has dramatically increased worldwide, accompanied by the continuous emergence of novel variants. Notably, KPC-2 and OXA-48 are among the most prevalent carbapenemases. The current combinations of antibiotics and inhibitors available are insufficient to counteract the rapid spread of these enzyme variants. In this context, the bark extract of the Malasyan Fissistigma litseifolium (King) Merr, was selected following the screening of a large collection of plant extracts. This study describes and compares the metabolomic profile of this extract, for which no previous studies have been reported, with those of 13 other Fissistigma species. Phytochemical investigation resulted in the isolation of nine compounds, including three unreported natural products. Of these, fissisteifolin, a quinone, features a unique tetracyclic structure deriving from a chalcone and an uncommon monoterpene. Finally, fissistidin, an original chalcone-sesquiterpene dimer, exhibited 83% reduction in KPC-2 enzyme activity, establishing its potential as a candidate for developing novel carbapenemase inhibitors.

Herein, we report the first biomimetic asymmetric total synthesis of sarglamides A, B, and C, recently isolated from a shrub of the genus Sarcandra. Our synthesis features an efficient one-step intermolecular [4 + 2] Diels-Alder cycloaddition between (S)-α-phellandrene and both enantiomers of toussaintine C, which proceeds with endo-selectivity to give these 6/6/6/5 tetracyclic structures comprising seven stereogenic centers. By this approach, we also elaborated a sarglamide that had not been isolated, which we named sarglamide G. It resulted from the Diels-Alder reaction of (S)-α-phellandrene with (R,R)-toussaintine C via an endo-ortho transition state. Importantly, our study provides the shortest route to this family of unique indolidinoid-monoterpenoid hybrids as well as strong evidence to support their putative biosynthesis.

An antiviral screening of plant extracts from Rutaceae and Annonaceae families led to the isolation of a series of new cycloheptapeptides, comptonellins A-H (1-8), along with the known ternatin (9). These compounds were isolated from the ethyl acetate bark extract of Comptonella drupacea (Labill.) Guillaumin, an endemic Rutaceae species of New Caledonia. Following targeted isolation guided by multi-informative molecular networks, the structures of compounds 1-9 were elucidated through a comprehensive analysis of spectroscopic data. This revealed novel molecules featuring previously unreported and noncanonical amino acids. The absolute configuration of stereocenters was partially determined by advanced Marfey's method. Biological evaluation against Zika virus demonstrated the potent antiviral properties of comptonellin A and comptonellins C-G, with IC₅₀ values ranging from 7 to 240 nM. Further investigations revealed that comptonellin A displayed broad-spectrum antiviral activity, inhibiting Dengue virus, Ross River virus, and SARS-CoV-2. These findings highlight comptonellins as promising antiviral scaffolds, supporting further investigation into their therapeutic potential against emerging viral infections.

Herein, we report the first biomimetic asymmetric total synthesis of sarglamides A, B and C, recently isolated from a shrub of the genus Sarcandra. Our synthesis features an efficient one-step intermolecular [4+2] Diels-Alder cycloaddition between (S)-⍺-phellandrene and both enantiomers of toussaintine C, which proceeds with an endo-selectivity to give these 6/6/6/5 tetracyclic structures comprising seven stereogenic centers. By this approach, we also elaborated a sarglamide that had not been isolated, which we named sarglamide G. It resulted from the Diels-Alder reaction of (S)-⍺-phellandrene with (R,R)-toussaintine C via an endo ortho transition state. Importantly, our study provides the shortest route to this family of unique indolidinoid-monoterpenoid hybrids, as well as strong evidence to support their putative biosynthesis.

The development of innovative antiviral strategies is critical to address the global health threats posed by RNA viruses, including the Zika virus (ZIKV), which can cause severe neurological complications. The lipid transporter Oxysterol Binding Protein (OSBP), essential for cholesterol and phosphatidylinositol 4‐phosphate trafficking, is exploited by many positive‐strand RNA viruses, making it an attractive novel antiviral target. This study investigates simplified analogues of macarangin B, a natural compound with potent OSBP‐targeted antiviral activity against ZIKV, but limited stability due to its flavonol moiety. A series of analogues was synthesized, replacing the flavonol with a flavone core while retaining the essential hexahydroxanthene (HHX) motif. These compounds demonstrated improved stability (t_1/2=16 hours), high OSBP binding affinity (4 – 69 nM), and low cytotoxicity (>20 μM). The most active compounds exhibited antiviral activity comparable to established OSBP inhibitors and were stable in physiologic media, highlighting their potential as leads for therapeutic development. This work advances the structure‐activity relationship (SAR) understanding of macarangin B analogues and provides a foundation for designing effective antivirals targeting in ZIKV infections.

The first synthesis of hybrid molecules that combine the pharmacophores of two natural compounds: schweinfurthin E (SW-E) and the glycosidic moiety of OSW-1 has been developped.

The development of innovative antiviral strategies is critical to address the global health threats posed by RNA viruses, including the Zika virus (ZIKV), which can cause severe neurological complications. The lipid transporter OxySterol Binding Protein (OSBP), essential for cholesterol and phosphatidylinositol 4-phosphate trafficking, is exploited by many positive-strand RNA viruses, making it an attractive novel antiviral target. This study investigates simplified analogues of macarangin B, a natural compound with potent OSBP-targeted antiviral activity against ZIKV, but limited stability due to its flavonol moiety. A series of analogues was synthesized, replacing the flavonol with a flavone core while retaining the essential hexahydroxanthene (HHX) motif. These compounds demonstrated improved stability, high OSBP binding affinity, and low cytotoxicity. The most active compounds exhibited antiviral activity comparable to established OSBP inhibitors and were stable in physiologic media, highlighting their potential as leads for therapeutic development. This work advances the structure-activity relationship (SAR) understanding of macarangin B analogues and provides a foundation for designing effective antivirals targeting in ZIKV infections.

OSBP ligands from the ORPphilin family are chemically complex natural products with promising anticancer properties. Here, we describe macarangin B, a natural racemic flavonoid selective for OSBP, which stands out from other ORPphilins due to its structural simplicity and distinct biological activity. Using a bioinspired strategy, we synthesized both (R,R,R) and (S,S,S)-macarangin B enantiomers, enabling us to study their interaction with OSBP based on their unique optical properties. Experimental and computational analyzes revealed that (R,R,R)-macarangin B has the highest affinity for OSBP. Importantly, both enantiomers showed significantly decreased cytotoxicity compared to other ORPphilins, suggesting OSBP is not the primary target in ORPphilin-induced cell death. Yet, OSBP is an attractive antiviral target, as it is hijacked by many positive-strand RNA viruses. Remarkably, (R,R,R)-macarangin B significantly inhibited Zika virus replication in human cells, highlighting its potential as a lead compound for antiviral drug development.

Herein, we present the first synthesis of hybrid molecules combining the pharmacophores of two natural compounds, schweinfurthin E (SW-E) and the glycosidic moiety of OSW-1. These hybrids were designed leveraging the complementary binding of SW-E and OSW-1 to their biological target. The synthetic process highlights, in particular, one-pot functionalization and glycosylation of an L-arabinose unit using a D-xyloside donor and a CuAAC click reaction involving a polyfunctionalized prenylated stilbene derived from SW-E. The cytotoxicity of the four SW-E and OSW-1 hybrids is also reported, two of them being much more cytotoxic than SW-E on a glioblastoma cancer cell line. Finally, a molecular modeling study is conducted to rationalize the biological results obtained.

Natural products represent a rich source of bioactive compounds, covering a large chemical space. Even if challenging, this diversity can be extended by applying chemical modifications. However, these studies generally require multigram amounts of isolated natural products and face frequent testing failures. To overcome this limitation, we propose a rapid and efficient approach that uses molecular networking (MN) to visualize the new chemical diversity generated by simple chemical modifications of natural extracts. Moreover, the strategy deployed enables the most appropriate reagents to be defined quickly upstream of a reaction on a pure compound, in order to maximize chemical diversity. This methodology was applied to the latex extract of Euphorbia dendroides to follow the reactivity toward a series of Bronsted and Lewis acids of three class of diterpene esters identified in this species: jatrophane, terracinolide, and phorbol. Through the molecular networking interpretation, with the aim to illustrate our approach, BF3 center dot OEt2 was selected for chemical modification on isolated jatrophane esters. Three rearranged compounds (3-5) were obtained, showing that the most appropriate reagents can be selected by MN interpretation.