Design, synthesis, and biological evaluation of new antimicrobials

The rapid emergence of antimicrobial resistance and the limited treatments for parasitic infections underscore an urgent need for the development of new antimicrobial agents. The work presented here describes the design, synthesis and biologically evaluation of small molecules with potential antimicrobial activity, with a focus on inhibitors of Toxoplasma gondii myosin A (TgMyoA). The pathogenicity of T. gondii and related apicomplexan parasites relies on a unique motility mechanism driven by MyoA, an unconventional class XIV myosin, making it an attractive and underexplored therapeutic target. Three complementary strategies were employed: (i) target-based inhibitor development; (ii) bioactive natural product synthesis; (iii) development of modular synthetic routes to access reported antimicrobial compounds. Target-based approaches focussed on the study of new TgMyoA inhibitors. Two hit compounds, CK360 3.1 and UCB-9721 4.1, were investigated through SAR studies. Although enhanced potency was not achieved for CK360 3.1, five analogues (3.21, 3.22, 3.61, 3.62 and 3.66) retained moderate activity, identifying regions tolerant to modification. Compound UCB-9721 4.1 and its novel analogue 4.3 demonstrated potent inhibition of both TgMyoA ATPase activity and T. gondii proliferation in vitro, highlighting their potential as lead compounds. Additionally, a virtual screening campaign identified new inhibitor scaffolds, leading to the successful synthesis of the triazole-based compounds (S)-4.32, (R)-4.32, and (±)-4.32. Chapter 5 focussed on the bioactive natural product synthesis approach. Preliminary studies toward (±)-5.15, an analogue of the neolignan (±)-5.14 from Ocotea cymosa, with reported activity against Plasmodium falciparum, were undertaken. A redesigned synthetic route to the key intermediate (±)-5.18, was developed, improving significantly efficiency and step economy. Finally, a modular synthetic strategy enabled the synthesis of indanol-based compound 1.46, a reported dual antibiotic and antifungal agent, and its analogue 6.8. Compound 6.8 was also prepared from lignin-derived starting materials, highlighting a potentially sustainable approach to antimicrobial synthesis.