Medicinal Chemistry - Synthesis. Coordinator: Locatelli

Research themes

The research activity is mainly focused to the design, synthesis, evaluation of biological activity and structure-activity relationships of small molecules with a heterocyclic corea and potential therapeutic activity. Particular attention has been given to antiproliferative and cytotoxic activity and, more recently, to antibacterial activity.

The main research topics are: (i) synthesis of tubulin ligands; (ii) synthesis of G-quadruplex ligands; (iii) synthesis of FtsZ inhibitors with antibacterial activity.

From a chemical point of view, the compounds of the first two topics are guanylhydrazones with an imidazothiazole or diimidazopyrimidine nucleus, indolylmethylene-2-indolinones, imidazothiazolylmethylene-2-indolinones, and bis-indoles derivatives. Firstly, the evaluation of anti-proliferative activity is carried out in collaboration with the National Cancer Institute (Bethesda, MD) on a panel of 60 human cancer cell lines. Based on the activity profile, the compounds may be selected for further studies and eventually tested in vivo. In particular, the action on the cell cycle and the possible induction of apoptosis in different tumor lines, as well as the effect on the polymerization of tubulin are studied in collaboration with Dr. Ernest Hamel (National Cancer Institute at Frederick, MD).

G-quadruplexes (G4s) are DNA secondary structures formed by G-rich sequences which have been identified in critical position of human genome, such as telomeres and promoters. Their involvement in numerous events related to tumor development makes the G4s promising targets for the development of selective anticancer agents. The study of new G4s ligands mainly concerns hydrazone derivatives with a diimidazopyrimidine nucleus capable to strongly stabilize these structures, selectively with respect to duplex DNA, and highlighting preferential interactions for parallel G4s. The biophysical studies of binding interactions with telomeric or promoter G4s are carried out in collaboration with Prof. Randazzo (University of Naples Federico II), whereas the effects of G4 binders on cancer cell lines are studied in collaboration with Prof. Capranico (Unibo-FaBiT).

Antimicrobial resistance is currently one of the most serious public health issues, with significant economic and environmental consequences. In this context, developing new antibacterial and antifungal agents is a priority. Isatin and imidazo[2,1b]thiazoles, due to their broad structural and mechanistic diversity, can be considered privileged scaffolds for the discovery of new hybrid candidates with antibacterial and antifungal activity. Molecular docking followed by molecular dynamics (MD) simulations has identified the binding site of the active compound to FtsZ, a key protein in bacterial cell division, and the mechanism of action, i.e. the inhibition of its polymerization. The studies related to biological activity are carried out in collaboration with Prof. Bonvicini (Unibo-FaBiT), and the docking studies in collaboration with Prof. Calvaresi (Unibo-Ciamician).

Lab Members

Alessandra Locatelli, Associate Professor

Rita Morigi, Associate Professor

Daniele Esposito, PhD Student

Internship projects

Internship projects (6) concern the development of research themes.

Main publications

• Morigi R, Locatelli A, Leoni A, Rambaldi M, Bortolozzi R, Mattiuzzo E, Ronca R, Maccarinelli F, Hamel E, Bai R, Brancale A, Viola G.: Synthesis, in vitro and in vivo biological evaluation of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones as new potent anticancer agents. Eur.J.Med.Chem. 166, 514-530 (2019).
• Amato J, Miglietta G, Morigi R, Iaccarino N, Locatelli A, Leoni A, Novellino E, Pagano B, Capranico G, Randazzo A. “Monohydrazone Based G-Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells” J Med Chem. 63(6): 3090-3103 (2020). https://doi.org/10.1021/acs.jmedchem.9b01866
• Marzano S, Miglietta G, Morigi R, Marinello J, Arleo A, Procacci M, Locatelli A, Leoni A, Pagano B, Randazzo A, Amato J, Capranico G. Balancing Affinity, Selectivity, and Cytotoxicity of Hydrazone-Based G-Quadruplex Ligands for Activation of Interferon β Genes in Cancer Cells” J. Med. Chem. 65, 12055 – 12067 (2022) https://doi.org/10.1021/acs.jmedchem.2c00772
• Morigi R, Zalambani C, Farruggia G, Verardi L, Esposito D, Leoni A, Borsetti F, Voltattorni M, Zambonin L, Pincigher L, Calonghi N, Locatelli A: Identification of a new bisindolinone arresting IGROV1 cells proliferation. Eur.J.Med.Chem. 271: 116365(2024). https://doi: 10.1016/j.ejmech.2024.116365. 
• Morigi R, Esposito D, Calvaresi M, Marforio TD, Gentilomi GA, Bonvicini F, Locatelli A: Isatin Bis-Imidazothiazole Hybrids Identified as FtsZ Inhibitors with On-Target Activity Against Staphylococcus aureus. Antibiotics 13(10), 992. (2024). https://doi: 10.3390/antibiotics13100992.