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Campiani Group. Hsp90, HDAC6 and neurodegeneration

margherita.brindisi@unisi.it
www.dbcf.unisi.it/en/department/people/academic-staff/margherita-brindisi
Address
UNIVERSITÀ DI SIENA. DEPARTMENT OF BIOTECHNOLOGY, CHEMISTRY AND PHARMACY. Via A. Moro, 2 53100 Siena
Italy
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Short description of ongoing research projects

HDAC6 inhibitors. This is the most recent research line. However, this activity already led to the discovery of novel chemical scaffold for achieving selective HDAC6 inhibition. The identified compounds demonstrated promising antitumor profile (haematological and brain tumors). Moreover, the most selective inhibitors are currently being explored as potential therapeutic in rare and neurodegenerative diseases. Antimalarial agents. This research activity led to the discovery and development of a series of antimalarials based on different structures: i) quinolylhydrazone-based antimalarials endowed with potent in vitro activity but moderate in vivo activity after i.p. administration; ii) benzoxazines and quinazolines as potential antimalarial agents; iii) endoperoxide-containing antimalarials inspired by the natural compound dihydroplakortin which led to an understanding of the mode of action of this compound and its related analogues and of the structural requirements necessary for an optimal activity; iv) novel inhibitors of Plasmodium falciparum serine protease PfSUB1; v) Simplified synthetic analogue of (+)-epigallocatechin gallate as cytoadherence inhibitors for P. falciparum. Agents for pain treatment. This research activity can be clustered in two main topics: i) extremely potent and selective human and mouse FAAH and MAGL inhibitors were developed and their antalgic potential was demonstrated (in vivo animal studies); also these compounds are being explored for the treatment of neurodegenerative diseases; ii) development of Kainate glutamatergic GluK1 receptor subtype agonists and antagonists as potential pain therapeutics (during this activity and in depth analysis of the developed pyrimidinedione ligands was performed by means of X-ray analysis of the ligands in complex with the receptor binding domain). Antitumor compounds. This research activity led to the development a new class of pro-apoptotic agents endowed with a pyrrolo-1,5-benzoxazepine (PBOX) structure. These compounds, recently co-crystallized in complex with tubulin, have been widely characterized as potent pro-apoptotic agents in different cell lines and are currently used as valuable pharmacological tools for the treatment of ex vivo leukemic cell lines resistant to common anticancer agents. This research activity is paving the way to the design and development of innovative anti-cancer drugs. Compounds active on the CNS. Development of CNS agents covering four main research areas: i) development of benzodiazepine-based (and not) BACE-1 peptidomometic inhibitors as druggable scaffold for obtaining potential anti-Alzheimer’s disease therapeutics; ii) development of potent human cholinesterase reversible inhibitors as potential drugs for the treatment of Alzheimer’s disease; the developed ligands allowed the targeting of key enzyme hot-spots at the active site gorge level of Cholinesterases, more recently, within this activity, some compounds were identified which can also interfere with the aggregation of amyloid beta; iii) development of compounds specifically targeting amyloid plaques as potential diagnostic tools for Alzheimer’s disease; iv) development of atypical antipsychotics endowed with a multireceptor affinity profile able to modulate dopaminergic and serotoninergic systems

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