Sparaco, Rosa (2022) Synthesis of new molecular hybrids of antiglaucoma drugs and H2S donors. [Tesi di dottorato]

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Glaucoma is a group of optic neuropathies consisting of retinal ganglion cells and axonal death with corresponding loss of field vision. Glaucoma is one of the leading causes of irreversible blindness globally. Despite the availability of several drugs for the treatment of glaucoma, researchers are still focused on the development of new therapeutic agents that could provide a better control of the disease. Over the last years, the scientific interest for hydrogen sulfide (H2S) has grown due to the results obtained from studies concerning its biological roles. H2S has been recently identified as a gaseous neurotransmitter implicated in various pathophysiological processes. It has shown a protective effect against damages related to glaucoma. In the first section of this thesis I have described the design, chemical synthesis and characterization of molecular hybrids between drugs for the treatment of glaucoma and H2S releasing moieties. The aim of my PhD project was to synthesize new drugs which combine the action of antiglaucoma agents and H2S released by molecular donors to provide a synergistic heightened therapy. Hybridization is a common strategy in drug design process aimed to obtain novel molecules potentially more effective and less toxic than the parent drugs. By the application of these new antiglaucoma entities, we expect a reduction in the administered dosage as well as adverse side effects may be minimized. Amongst the classes of available drugs for glaucoma therapy, brinzolamide, betaxolol and brimonidine were coupled with different H2S donors such as 4-hydroxybenzothioamide (TBZ), 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), S-ethyl 4-hydroxybenzodithioate (HBTA) and 4-hydroxyphenyl isothiocyanate (HPI). The synthetized molecules were tested for their H2S releasing properties by the research group of Prof. Vincenzo Calderone at the Department of Pharmacy of University of Pisa. The analysis were performed by amperometry to evaluate the release of H2S in the assay buffer, but also in Human Primary Corneal Epithelial Cells (HCEs) to further study the generation of the gas from the tested compounds into the cellular environment. In the second part I have shown the results of my six months traineeship at the R&D laboratories of Genetic S.p.a. Over the course of this experience, I paid attention on the design of ocular formulations containing the molecular hybrids I synthetized at the University of Naples. A recent approach, with the purpose of increasing ocular drug bioavailability, is based on the application of contact lenses as a means to release drugs. In this scenario, I performed a pilot study based on the design of molecular hybrids eluting contact lenses for glaucoma treatment. Finally in the appendix, I have discussed about the research project I was involved in during my experience abroad at the Department of Chemistry of University of Durham (UK), in collaboration with the research group of Prof. Ian Baxendale. I have described the synthesis and the characterization of novel 2-amino-3-benzoyl-thiophene derivatives as potential antileishmanial agents.

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