Guillaume Bernadat

Our research group identified CTN1122, an imidazo[1,2-a]pyrazine derivative, as a promising antileishmanial agent targeting intramacrophage amastigotes of Leishmania major and Leishmania donovani. CTN1122 selectively inhibits Leishmania casein kinase 1 (L-CK1.2) with a favorable safety profile. Docking studies based on a homology model highlighted key pharmacophoric elements: a 4-pyridyl group at C3, crucial for hydrogen bonding with leucine 90 in the ATP-binding site, and a 4-fluorophenyl moiety at C2, fitting into a hydrophobic pocket. In order to validate these findings, 14 analogs were synthesized with targeted modifications on the imidazo[1,2-a]pyrazine core structure. Three probed the C8 position, three evaluated the impact of C2 substitution, six assessed the C3 4-pyridyl group, and two combined changes at C8 and C3. The study confirmed the critical role of C2 and C3 substituents, as their absence significantly reduced L-CK1.2 inhibition and antileishmanial activity. Additionally, the nitrogen's position within the pyridine ring at C3 proved essential: compound 23, with a meta-pyridyl group, was inactive. Notably, compound 30 exhibited the highest antileishmanial in vitro potency (IC₅₀ = 0.20 μM for L. major; 0.16 μM for L. donovani) alongside enhanced L-CK1.2 inhibition (IC₅₀ = 0.384 μM), with no significant mammalian cytotoxicity.

Our research group previously discovered CTN1122, an imidazo[1,2‐a]pyrazine compound with promising antileishmanial activity against intramacrophage amastigotes of Leishmania major and L. donovani strains. CTN1122 effectively targets Leishmania casein kinase 1 (L–CK1.2) and exhibits a favorable safety profile. To further explore its chemical space, we developed a convergent strategy to modify the C2 position of the imidazo[1,2‐a]pyrazine core using Suzuki‐Miyaura coupling of the corresponding triflate intermediate. Among 15 newly synthesized analogs, seven derivatives featuring variously substituted phenyl rings at C2 demonstrated L–CK1.2 inhibition within micromolar to submicromolar ranges and antileishmanial activity in vitro with low cytotoxicity in macrophages. Compounds 7 d and 7 l were particularly potent, with IC₅₀ values of 1.25 μM and 0.92 μM against L. major, and 1.44 μM and 2.34 μM against L. donovani, respectively. They showed IC₅₀ L–CK1.2=0.30 μM and 0.57 μM with enhanced selectivity indices (SI=3.8 and 1.6) over the human CK1ϵ ortholog. Additionally, four C2 analogs and two C5 isomers exhibited notable antiparasitic effects without strongly inhibiting L–CK1.2, indicating a possible alternative mechanism of action. Compound 7 k displayed the highest general activity, with IC₅₀ values of 0.31 μM on L. major and 0.27 μM on L. donovani, coupled with favorable selectivity indexes.

Omic data research projects are still developing today, but analysis suffers from not having a standardized workflow for biostatistics and functional integration steps that we gather here as bioanalysis. To make bioanalysis more reproducible and accessible, we created MOAL (Multi-Omic Analysis at Lab), an R package including a omic() function that automates most classical tasks. We reproduced in one go the results of a published dataset starting from unfiltered available data confirming the capabilities to automate the production of omic bioanalysis using MOAL.

In the context of untargeted metabolomics, molecular networking is a popular and efficient tool which organizes and simplifies mass spectrometry fragmentation data (LC-MS/MS), by clustering ions based on a cosine similarity score. However, the nature of the ion species is rarely taken into account, causing redundancy as a single compound may be present in different forms throughout the network. Taking advantage of the presence of such redundant ions, we developed a new method named MolNotator. Using the different ion species produced by a molecule during ionization (adducts, dimers, trimers, in-source fragments), a predicted molecule node (or neutral node) is created by triangulation, and ultimately computing the associated molecule’s calculated mass. These neutral nodes provide researchers with several advantages. Firstly, each molecule is then represented in its ionization context, connected to all produced ions and indirectly to some coeluted compounds, thereby also highlighting unexpected widely present adduct species. Secondly, the predicted neutrals serve as anchors to merge the complementary positive and negative ionization modes into a single network. Lastly, the dereplication is improved by the use of all available ions connected to the neutral nodes, and the computed molecular masses can be used for exact mass dereplication. MolNotator is available as a Python library and was validated using the lichen database spectra acquired on an Orbitrap, computing neutral molecules for >90% of the 156 molecules in the dataset. By focusing on actual molecules instead of ions, MolNotator greatly facilitates the selection of molecules of interest. Abstract Figure:

Chemokines play critical roles in numerous physiologic and pathologic processes through their action on seven-transmembrane (TM) receptors. The N-terminal domain of chemokines, which is a key determinant of signaling via its binding within a pocket formed by receptors’ TM helices, can be the target of proteolytic processing. An illustrative case of this regulatory mechanism is the natural processing of CXCL12 that generates chemokine variants lacking the first two N-terminal residues. Whereas such truncated variants behave as antagonists of CXCR4, the canonical G protein-coupled receptor of CXCL12, they are agonists of the atypical chemokine receptor 3 (ACKR3/CXCR7), suggesting the implication of different structural determinants in the complexes formed between CXCL12 and its two receptors. Recent analyses have suggested that the CXCL12 N-terminus first engages the TM helices of ACKR3 followed by the receptor N-terminus wrapping around the chemokine core. Here we investigated the first stage of ACKR3-CXCL12 interactions by comparing the activity of substituted or N-terminally truncated variants of CXCL12 toward CXCR4 and ACKR3. We showed that modification of the first two N-terminal residues of the chemokine (K1R or P2G) does not alter the ability of CXCL12 to activate ACKR3. Our results also identified the K1R variant as a G protein-biased agonist of CXCR4. Comparative molecular dynamics simulations of the complexes formed by ACKR3 either with CXCL12 or with the P2G variant identified interactions between the N-terminal 2–4 residues of CXCL12 and a pocket formed by receptor's TM helices 2, 6, and 7 as critical determinants for ACKR3 activation.

Two new cycloartane glycosides, nervisides I–J, were isolated from Nervilia concolor whole plants. Their structures were unambiguously established by interpretation of their HRESIMS and 1D and 2D NMR data. These cycloartanes comprised a stereogenic center at C-24, the R configuration of which was assigned based on DFT-NMR calculations and the subsequent DP4 probability score. These compounds were tested for cytotoxicity against K562 and MCF-7 tumor cell lines, revealing mild cytotoxic activity.

The synthesis of acetoxyendoperoxyacetal derivatives allowed the formation of functionalized 3,5-disubstituted 1,2-dioxolanes through the formation of reactive peroxycarbenium species under Lewis acid mediation. The introduction of a neutral nucleophile such as allylsilane, silane, or silyl enol ether was accomplished with moderate to good yields. The two studied Lewis acids, TiCl₄ and SnCl₄, gave contrasting results. The higher diastereoselectivity toward the trans diastereomer in experiments with TiCl₄ as Lewis acid was explained by a faster degradation of the cis isomer product, leading generally to lower yields. A rationalization of this result was supported by calculations.

A phytochemical investigation of the foliose lichen Parmotrema tsavoense (Krog and Swinscow) Krog and Swinscow (Parmeliaceae) resulted in the isolation of a new trichlorinated xanthone, isodemethylchodatin. The structure elucidation of this new norlichexanthone derivative proved tricky owing to proton deficiency, and to the lack of NMR data of closely related analogues. The structure of this compound was determined based on an integrated interpretation of ¹³C-NMR chemical shifts, MS spectra, and DP4-based computational chemistry was also performed to provide an independent and unambiguous validation of the determined structure. Isodemethylchodatin represents the first chlorinated lichexanthone/norlichexanthone derivative bearing a methoxy group at C-5.

Chiral phosphoric acid catalyzed the formal [4+2]-cycloaddition of 2-benzothiazolimines with enecarbamates to provide benzothiazolopyrimidines with up to 99% yield and >99% ee.

Theionbrunonines A and B (1 and 2), the first examples of monoterpene bisindole alkaloids linked by a thioether bridge, were isolated from the stems of Mostuea brunonis, guided by a molecular networking-based dereplication strategy. Their structures were elucidated by a combination of spectroscopic data and ECD calculations. A plausible biosynthetic pathway for 1 and 2 was postulated. Theionbrunonines A and B (1 and 2) showed moderate antiplasmodial activities in the micromolar range against the strain FcB1 of Plasmodium falciparum and no cytotoxic activity against the MRC-5 cell line at 20 μM.