Marie Laronze-Cochard

In modern medicinal chemistry, the pyridazinone core has emerged as a „versatile“ and privileged scaffold for the design of new therapeutic agents. Over the past decades, numerous pyridazinone derivatives have exhibited significant biological activities across diverse therapeutic areas including antiviral, antimicrobial, cardiovascular, anti-inflammatory, anticancer, and central nervous system disorders. This review discusses the structural diversity, structure-activity relationships (SAR), and pharmacological relevance of pyridazinone-based molecules. Furthermore, it highlights recent advances in hybrid drug design, where the pyridazinone moiety is combined with another pharmacophore to produce synergistic effect that enhance the biological activities of both components towards more than one target. Such hybridization strategy show the potential of pyridazinone scaffold as valuable templates for the development of multifunctional therapeutic agents.

Background: Bioconjugates are promising alternatives for the multiple targeting of any disease. Pyrrole heterocycle is well known with many activities and is a building block of a lot of medical drugs. On the other hand, peptides are short molecules with many advantages such as small size, ability to penetrate the cell membrane and bond-specific receptors, vectorizing potential, etc. Thus, hybrid molecules between peptide and pyrrole moiety could be a promising alternative as an anti-pain tool. Methods: New bioconjugates with a general formula Pyrrole (α-/β-acid)-FELL-OH (NH₂) were synthesized using Fmoc/OtBu peptide synthesis on solid support. HPLC was used to monitor the purity of newly synthesized bioconjugates. Their structures were proven by electrospray ionization mass spectrometry. The Paw Pressure test (Randall–Selitto test) was used to examinate the analgesic activity. Hydrolytic stability of targeted structures was monitored in three model systems with pH 2.0, 7.4 and 9.0, including specific enzymes by means of the HPLC-UV method. Results: The obtained results reveal that all newly synthesized bioconjugates have analgesic activity according to the used test but free pyrrole acids have the best analgesic activity. Conclusions: Although free pyrrole acids showed the best analgesic activity, they are the most unstable for hydrolysis. Combination with peptide structure leads to the hydrolytic stabilization of the bioconjugates, albeit with slightly reduced activity.

Background: The inflammatory process represents a specific response of the organism’s immune system. More often, it is related to the rising pain in the affected area. Independently of its origin, pain represents a complex and multidimensional acute or chronic subjective unpleasant perception. Currently, medical doctors prescribe various analgesics for pain treatment, but unfortunately, many of them have adverse effects or are not strong enough to suppress the pain. Thus, the search for new pain-relieving medical drugs continues. Methods: New tetrapeptide analogs of FELL with a generaanalgesic-Glu-X³-X⁴-Z, where X = Nle, Ile, or Val and Z = NH₂ or COOH, containing different hydrophobic amino acids at positions 3 and 4, were synthesized by means of standard solid-phase peptide synthesis using the Fmoc/OtBu strategy in order to study the influence of structure and hydrophobicity on the analgesic activity. The purity of all compounds was monitored by HPLC, and their structures were proven by ESI-MS. Logp values (partition coefficient in octanol/water) for FELL analogs were calculated. Analgesic activity was examined by the Paw-pressure test (Randall-Selitto test). Results: The obtained results reveal that Leu is the best choice as a hydrophobic amino acid in the FELL structure. Conclusions: The best analgesic activity is found in the parent compound FELL and its C-terminal amide analog.

Osteosarcoma is a rare primary bone cancer that mostly affects children and young adults. Current therapeutic approaches consist of combining surgery and chemotherapy but remain unfortunately insufficient to avoid relapse and metastases. Progress in terms of patient survival has remained the same for 30 years. In this study, novel pyridazinone derivatives have been evaluated as potential anti-osteosarcoma therapeutics because of their anti-type 4 phosphodiesterase activity, which modulates the survival of several other cancer cells. By using five—four human and one murine osteosarcoma—cell lines, we demonstrated differential cytotoxic effects of four pyridazinone scaffold-based compounds (mitochondrial activity and DNA quantification). Proapoptotic (annexin V positive cells and caspase-3 activity), anti-proliferative (EdU integration) and anti-migratory effects (scratch test assay) were also observed. Owing to their cytotoxic activity in in vitro conditions and their ability to limit tumor growth in a murine orthotopic osteosarcoma model, our data suggest that these pyridazinone derivatives might be hit-candidates to develop new therapeutic strategies against osteosarcoma.

Designing nanoprobes in which quantum dots (QDs) are used as photoluminescent labels is an especially promising line of research due to their possible medical applications ranging from disease diagnosis to drug delivery. In spite of the significant progress made in designing such nanoprobes, the properties of their individual components, i.e., photoluminescent QDs, vectorization moieties, and pharmacological agents, still require further optimization to enhance the efficiency of diagnostic or therapeutic procedures. Here, we have developed a method of engineering compact multifunctional nanoprobes based on functional components with optimized properties: bright photoluminescence of CdSe/ZnS (core/shell) QDs, a compact and effective antitumor agent (an acridine derivative), and direct conjugation of the components via electrostatic interaction, which provides a final hydrodynamic diameter of nanoprobes smaller than 15 nm. Due to the possibility of conjugating various biomolecules with hydroxyl and carboxyl moieties to QDs, the method represents a versatile approach to the biomarker-recognizing molecule imaging of the delivery of the active substance as part of compact nanoprobes.