SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL ANTIPARASITIC AND ANTICANCER AGENTS

Vector-borne parasitic diseases (VBPDs), including human African trypanosomiasis (HAT), leishmaniasis, and malaria, pose a major global health challenge, particularly in tropical and subtropical regions. Climate change is expected to alter their transmission patterns, potentially expanding their impact worldwide. Despite their severe health, economic, and social consequences, available treatments often suffer from toxicity, limited efficacy, and increasing drug resistance. Considering the impact of VBPDs on global health, the first part of the work was focused on design, synthesis and biological evaluation of novel agents for the treatment of VBPDs. The first study explores the potential of nature-inspired hybrids (NIHs), a molecular hybridization approach combining distinct pharmacophores to enhance biological activity and multi-target interactions. The selected bioactive scaffolds include the natural glutamine analog acivicin and its more potent synthetic derivative 3-Br-acivicin, as well as hydroxycinnamic acid derivatives, which have demonstrated antiparasitic properties. These moieties were linked through different molecular connectors to optimize pharmacological properties and evaluated for their activity against Trypanosoma brucei and Leishmania species, with the most potent compound exhibiting micromolar activity. For the second study, we conducted a phenotypic screening of an in-house compound library against Plasmodium falciparum, T. brucei, and two Leishmania species, leading to the identification of promising hit compounds featuring 1,3,4- and 1,2,4-oxadiazole scaffolds linked to a 3-bromo-4,5-dihydroisoxazole (BDHI) core. Structure-activity relationship (SAR) exploration guided the synthesis of novel derivatives, incorporating modifications to enhance potency, drug-like properties, and blood-brain barrier permeability. Our investigations revealed that 1,3,4-oxadiazole derivatives exhibited broad- spectrum antiparasitic activity. In contrast, 1,2,4-oxadiazole derivatives displayed enhanced efficacy against T. brucei and Leishmania. Further scaffold hopping to oxazole-based derivatives led to a new library of potent antimalarial agents showing nanomolar activity.The second part of the thesis was focused on drug discovery for aggressive types of cancers like pancreatic ductal adenocarcinoma (PDAC) and prostate cancer, investigating the antiproliferative effects of the oxadiazoles described in the previous part. Lastly, I moved to a target-based approach, and I selected 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB-3), which plays a key role in oncogenesis. It is a glycolytic regulatory enzyme responsible for glycolytic tumor metabolic reprogramming, and its levels are significantly higher in several types of aggressive cancers. Starting from the structure of a recently identified reversible PFKFB-3 inhibitor, we explored chemical modifications surrounding the proline-based scaffold. These modifications aim to improve solubility, enhance interactions within the enzyme's active site, and potentially engage additional binding pockets. This rational design approach may lead to more effective and selective PFKFB-3 inhibitors with improved therapeutic potential in cancer treatment.

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2025

Author dc:creator

• CORFU, IOANA ALEXANDRA

Contributors dc:contributor

• tutor: P. Conti ; co-tutor: C. Borsari
• I.A. Corfu
• CONTI, PAOLA

• antiparasitic agents
• anticancer agents
• Settore CHEM-07/A - Chimica farmaceutica

Statement dc:rights

• info:eu-repo/semantics/openAccess
• license:Creative commons
• license uri:http://creativecommons.org/licenses/by-sa/4.0/

Language dc:language

eng

Identifier

http://dx.doi.org/10.13130/corfu-ioana-alexandra_phd2025
10.13130/corfu-ioana-alexandra_phd2025

OAI identifier oai:identifier

oai:air.unimi.it:2434/1184595