The Design, Synthesis And Antifungal Activity Of The Novel Lead Compound

In the past two decades, the incidence of invasive fungal infection has been increasing fastly. Currently, clinical antifungal agents have several limitations, such as comparatively narrow antifungal spectrum, toxicity and side effects, non-optimal pharmacokinetic profiles, and severe resistance. As a result, it is highly desirable to discover novel structures and new mechanism.The first part of this paper aims to design and synthesize a series of novel triazole antifungal agents containing piperidine-oxadiazoleside chains with high activity, low toxicity, broad-spectrum and low chance of resistance. The second part of the paper is based on the carboline antifungal lead compound, which is discovered firstly by our group. Structural optimization was focused on modification of chemical skeleton and improving the water solubility in order to improve the in vivo antifungal activity of the carboline derivatives. The third part is the construction of a pharmacophore model of small molecule inhibitors of (1,3)-β-D-glucan synthase, which provided important information for new inhibitor design.1.Discovery of Highly Potent Triazole Antifungal Agents with Piperidine-oxadiazole Side ChainsDue to increasing incidence and mortality of invasive fungal infections, discovery and development of new generation of antifungal agents represents a challenging task. As we all know, oxadiazole is a drug-like privileged structure in many therapeutic drugs and can be used as a flat, aromatic linker that favors the interaction of C3-side chain with CYP51. Besides, introduction of oxadiazole ring was proven to be an effective strategy to modulate lipophilicity and improve the characteristics of the in vivo metabolic profile. On the basis of our previously reported triazole-benzyloxypiperidinyl lead compound, a series of 25 novel triazole antifungal agents containing piperidine-oxadiazole side chains were rationally designed and synthesized.The target compounds mostly showed excellent inhibitory activity against clinically important fungal pathogens. Particularly, compounds 6g (MICgo= 0.031 μg/mL) and 11b (MIC80=0.016 μg/mL) were highly active against Candida albicans including fluconazole-resistant Candida strains. Moreover, they showed inhibitory activity against hyphal formation with low toxicity. All the results showed they were promising leads for further development.2. Design, Synthesis and Antifungal Activity of Carboline DerivativesIn our previous studies, a series of carboline antifungal agents were designed and synthesized. Among them, C38, a highly active compound, showed potent in vitro activity. Moreover, transmission electron microscopy and GC-MS indicated that it might act by targeting at the fungal cell wall. However, C38 was found with no in vivo activity. In order to enhance the water solubility, a series of amino-based derivatives were synthesized in my work. Besides, structural modification of compound C38 was focused on the variation of the position of N atom in the scaffold, inserting the amide in the scaffold and expanding the ring size. A total number of 18 target compounds were synthesized. Among them,4 compounds showed cell-based antifungal activity. Encouragingly, in Candida-mediated C. elegans model, the serine-derivative B20 showed better water solubility and potent in vivo effect. The results confirmed that the carboline antifungal derivative was likely to be effective in the in vivo model and presented a promising future for the development of novel antifungal agents.3. Ligand-based Pharmacophore Generation:Small Molecule Inhibitor of (1,3)-p-D-Glucan Synthase(1,3)-β-D-Glucan Synthase (GS) inhibitors serve as the most novel series of antifungal agents, represented by Caspofungin. However, GS inhibitors approved for clinical use are macrocyclic hexapeptides, which are used only for parenteral administration. Thus, the discovery and optimization of synthetically convenient and orally bioavailable small molecule GS inhibitors has a promising future. GS crystal structure is yet not known, we thus progress the ligand-based pharmacophore generation. My wrok summarized the reported active ligands, selected the trainingset and constructed the pharmacophore model to guide the design of small molecule inhibitors. After reviewing the literatures, terpenoids, piperazine propyl alcohol, caffeic acid and pyridazinone are currently reported small-molecule GS inhibitors. Considering structural similarity of pyridazinone and piperazine propyl alcohol inhibitorse, they are supposed to bind with the same GS domain. On the basis of the IC50 values and structures of both series, six active molecules were selected from more than 100 molecules as the training set, and then Catalyst Hiphop module was utilized to construct pharmacophore model. Finally, by building decoy set, the model was testified to have strong ability to distinguish between active and inactive inhibitors.