Investigation of chalcone- and flavone-based derivatives as antimicrobial hits: design and synthesis integrating sustainable concepts

This research investigates the synthesis of novel antimicrobial agents, specifically focusing on natural scaffolds and bioisosteric quinolone derivatives, and the application of green chemistry principles in some of their synthetic approaches. The increasing prevalence of antibiotic resistance and the limited availability of drugs for the most severe infections caused by protozoan parasites, necessitate the development of innovative therapeutic strategies, which this study aims to address through sustainable practices in medicinal chemistry. Indeed, this doctoral thesis presents a comprehensive investigation into the design and synthesis of chalcone- and flavone-based derivatives, targeting their potential as novel antimicrobial agents while integrating principles of green chemistry. A significant component of this research involved a six-month internship at S-IN Soluzioni Informatiche, where valuable skills in the application of Design of Experiments (DoE) were acquired. This methodology was applied to the optimization of synthetic pathways, allowing for the systematic evaluation of multiple variables that influence the yield of fundamental synthetic steps for the target compounds, while minimizing waste. Furthermore, the internship provided an opportunity to engage in predictive studies regarding the biodegradability and ecotoxicity of selected final compounds. Utilizing software tools such as EPI Suite, ECOSAR, and VEGA, a preliminary assessment of the environmental fate of some derivatives was conducted. Moreover, various green synthesis techniques were employed, including the utilization of environmentally friendly solvents and reagents, such as Cyrene™ and methyltetrahydrofuran (2-MeTHF) on two different scaffolds. These choices reflect a commitment to reducing the environmental impact associated with traditional synthetic methods, thereby promoting a more sustainable approach to drug development. The biological evaluation of the synthesized compounds was conducted to assess their antibacterial and antiparasitic activities. Regarding the antibacterial properties, I had the opportunity to perform the in vitro assays against a range of Gram-positive and Gram-negative bacterial strains of the compounds synthesized in the frame of this PhD work. Employing Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), and Synergistic Minimum Inhibitory Concentration (SynMIC) assays, the antimicrobial efficacy of the compounds was systematically evaluated. These assays provided critical insights into the potency and spectrum of activity of the chalcone- and flavone-based derivatives. Some compounds showed moderate efficacy against Gram-negative bacteria, but only in the presence of colistin, while others exhibited good activity against Gram-positive bacteria, with compound 20 standing out as particularly effective. On the other hand, regarding activity against Leishmania, some compounds were active towards Leishmania infantum and Leishmania tropica in the promastigote stage, although with poor selectivity index over mammalian macrophages. One of the compounds demonstrated good activity against the previously mentioned strains as well as in the amastigote stage of Leishmania infantum, with moderate cytotoxicity. These findings suggest that the designed compounds are worth further investigation for the discovery of novel hits for infectious diseases. In addition to biological activity, the biodegradability of the synthesized compounds was evaluated in this study. The incorporation of biodegradable linkers, specifically esters and amides, was explored to facilitate environmental degradation upon release. The concept of biodegradability was also applied to the study of the synthesized quinolone compound family. This preliminary study has begun to provide insights into the presence of certain functional groups that have the potential to enhance this property. Overall, this research underscores the importance of integrating green chemistry and sustainability into the drug development process. The combination of optimized synthetic strategies, biological evaluation, and biodegradability considerations contributes to the advancement of effective and environmentally responsible antibacterial and antileishmanial agents. In addition to the antimicrobial studies, a significant focus of the thesis was also directed towards malaria, a pervasive global health challenge. The research aimed to identify and synthesize compounds with potential antiplasmodial activity, thereby contributing to the ongoing efforts to combat this infectious disease. The synthesis of specific derivatives was guided by existing knowledge of structure-activity relationships, which informed the design of compounds that could effectively inhibit the growth of Plasmodium species. Building upon our earlier research on bridged bicyclic 2,3-dioxabicyclo[3,3,1]dioxanes as antimalarial agents, the present study focuses on enhancing both the potency and pharmacokinetic properties of this scaffold through the design of two novel classes of bridged bicyclic endoperoxides, as discussed in the annex section. The incorporation of polar and protonable chains resulted in a significant improvement in potency compared to previously reported derivatives. Furthermore, the introduction of triazine-based substituents opened new studies for the rational development of optimized antimalarial compounds. Both these new endoperoxide classes demonstrated strong inhibitory activity against P. falciparum. In conclusion, this thesis contributed to the understanding of different compounds as promising antimicrobial agents while emphasizing the importance of sustainable practices in their development. The research outcomes not only offer insights into the efficacy of these compounds but also pave the way for future studies aimed at addressing critical health challenges, such as antibiotic resistance, along with the growing resistance to existing therapies for leishmaniasis and malaria. Through the application of innovative methodologies and a commitment to sustainability, this work embodies the principles of modern medicinal chemistry, striving to improve human health while safeguarding the environment.