DESIGN, SYNTHESIS AND BIOLOGICAL PROFILING OF NEW COMPOUNDS: INFECTIOUS AND NEURODEGENERATIVE DISEASES AS TARGETS

The convergence of the COVID-19 pandemic and the rapidly expanding aging population represents a critical intersection fraught with multifaceted social and economic implications. On one front, the emergence of the SARS-CoV-2 virus has precipitated a global health crisis of unprecedented proportions, amplifying preexisting economic vulnerabilities and catalyzing a frenetic pursuit of antiviral therapeutics guided by molecular insights. This dual crisis has underscored the imperative for robust intervention strategies to mitigate the spread of the virus and alleviate its profound socio-economic repercussions. Simultaneously, the demographic landscape is undergoing a profound transformation, as evidenced by a United Nations report revealing a marked escalation in the proportion of elderly individuals within global populations, surging to 15% in 2019 and forecasted to double by 2050. This demographic shift carries profound implications for healthcare systems, social welfare structures, and economic sustainability, particularly given the escalating incidence of neurodegenerative diseases prevalent among the elderly demographic cohort. The escalating prevalence of conditions such as Alzheimer's disease and Parkinson's disease accentuates the pressing need for concerted research efforts aimed at elucidating the underlying mechanisms and advancing therapeutic interventions. Against this backdrop of intersecting crises, my doctoral research endeavors over the past three years have been meticulously focused on the realm of organic chemistry. My primary objective has been the design, synthesis, and characterization of bioactive molecules specifically tailored to target key pathological pathways associated with both COVID-19 infection and neurodegenerative disorders. Through a multidisciplinary approach encompassing molecular modeling, synthetic chemistry, and pharmacological evaluation, my research seeks to unravel the intricate molecular interactions underpinning disease pathogenesis and to pioneer novel therapeutic avenues capable of addressing these formidable challenges at their roots. In doing so, I aspire to contribute meaningfully to the advancement of medical science and the amelioration of human suffering in the face of these converging global crises. During the part of my Ph.D. research thesis, I immersed myself in the captivating realm of proteinopathies, dedicating my efforts to the synthesis and characterization of innovative neuroprotective compounds aimed at combatting the devastating neuropathologies stemming from misfolded proteins. This ambitious endeavor commenced with a meticulous exploration of Proteolysis Targeting Chimera (PROTAC) technology as a promising therapeutic avenue. Within the confines of Chapter 1 of my dissertation, I delved into the intricate design and synthesis of dual-action modulators meticulously engineered to facilitate the degradation of α-Synuclein (αSyn)via the ubiquitin proteasome system, thus holding promise for mitigating αSyn-driven neurodegenerative processes. Subsequently, I embarked on a compelling project detailed in Chapter 2, wherein I endeavored to optimize guanylhydrazone (GH) lead compounds. This endeavor was driven by the aspiration to preserve the binding affinity of these compounds for the retromer complex at the critical Vps35-Vps29 interface, thereby bolstering their potential therapeutic efficacy. Concurrently, I rigorously pursued strategies to minimize off-target effects, particularly concerning interactions with the 5-HT receptor class, thus striving to enhance the safety profile and clinical viability of these neuroprotective agents. In a captivating collaboration spanning continents and academic institutions, the culmination of my doctoral odyssey unfolded in Chapter 3, where I delved into the realm of RNA-targeted small molecules. This fascinating venture materialized through collaborative efforts with esteemed researchers, including Prof. Disney at the Scripps Research Institute of Florida (USA) during an enriching six-month visiting Ph.D. stage. Together, we embarked on a rigorous exploration of the biophysical and in vitro characteristics of a select cohort of GH compounds, previously synthesized within our UniMi research group. Our focus centered on unraveling their potential as binders for G4C2 expanded RNA within the c9orf72 gene, shedding light on novel avenues for therapeutic intervention in debilitating neurodegenerative disorders. Within the dynamic landscape of COVID-19 research, my Ph.D. investigations were dedicated to the meticulous design and development of small molecules meticulously engineered to target two pivotal components crucial to the progression of SARS-CoV-2 infection. In Chapter 4 of my Ph.D. research endeavors, I directed my attention towards indispensable component of the SARS-CoV-2 virion—the outward Spike (S) glycoprotein. This integral protein orchestrates the initial stages of viral infection by mediating the fusion of viral and host cell membranes, thereby facilitating viral entry into host cells. Fully cognizant of the pivotal role played by the S glycoprotein in viral pathogenesis, I endeavored to leverage the principles of medicinal chemistry to synthesize a repertoire of potential therapeutic agents meticulously tailored to disrupt crucial molecular interactions essential for viral entry and subsequent infection. Simultaneously, the focal point of Chapter 5 of my dissertation centered on the SARS-CoV-2 main protease (Mpro), a catalytic enzyme indispensable for the maturation of viral proteins essential for viral replication within host cells. Recognizing the critical role of Mpro in the viral life cycle, I endeavored to harness the power of medicinal chemistry to synthesize a diverse array of putative hits tailored to inhibit this key enzymatic target, thus impeding viral replication and curtailing the spread of infection.