New approaches for the design and synthesis of heterocyclic and macrocyclic bioactive peptidomimetics

随着全球范围内微生物对抗生素耐药性的增加，细菌感染的预防和治疗不仅在人类健康方面，而且在兽医和畜牧业方面都变得具有挑战性。控制细菌生长也是食品工业中的一个主要问题，其中食源性疾病的爆发可能导致人类死亡，并且对企业来说非常昂贵和具有破坏性。在此背景下，食品安全、畜牧业、兽医学和人类健康迫切需要新型高效抗菌剂。为了加速发现新的抗微生物剂，设计靶向迄今未开发的细菌机制的化合物以及获得能够进行功能和结构修饰的分子支架已经变得至关重要。在最有前途的策略和支架中，我们对杂环化合物和抗菌肽特别感兴趣。这项研究提案描述了获得用于细菌蛋白结合和操纵的工程化分子支架的新方法，以及创新抗菌剂的开发。第一部分介绍了合成方法的发展，以制备苯并稠合杂环支架的能力，模拟蛋白质二级结构。所提出的方法使用多组分反应来制备具有不同环尺寸和取代模式的多取代杂环。由于其巨大的潜力和灵活性，所提出的方法将获得广泛的官能化苯并稠合杂环化合物。第二部分涉及模拟方法的设计和开发，以利用来自小菌素家族的抗菌肽的有吸引力的结构行为和作用模式。这些抗微生物肽是常规抗微生物肽最有前途的替代品之一，但它们的使用往往受到低产量的限制。在第一个项目中，大环肽将被设计和合成，以模拟小菌素J25的套索拓扑结构，并获得这种有前途的结构。有些微菌素含有一个铁螯合单位，称为铁载体，可以劫持细菌铁运输系统，以达到其目标并杀死细菌。受此策略的启发，第二个项目涉及将铁载体添加到抗菌肽中，以增加效力并扩展其活性谱。开发新的抗菌剂是基础和应用研究中具有挑战性的重要目标。合成方法的发展将为获得新颖和复杂的分子结构提供新的可能性。我们的工作将为肽模拟提供新的方法和分子支架。拟议的研究计划将对有机和药物化学以及食品，兽医和医学微生物学产生重大影响，因为抗菌剂用于食品安全，动物生产，人类健康和兽医学。

With the worldwide increase of microbial resistance to antibiotics, the prevention and treatment of bacterial infections have become challenging not only in human health but also in veterinary medicine and animal husbandry. The control of bacterial growth is also a major concern in the food industry where foodborne illness outbreaks can cause human deaths and be very expensive and damaging for businesses. In this context, new highly effective antimicrobial agents are crucially needed in food safety, animal husbandry, veterinary medicine and human health. To accelerate the discovery of new antimicrobial agents, the design of compounds that target hitherto unexploited bacterial machineries and the access to molecular scaffolds capable of functional and structural modifications have become essential. Among the most promising strategies and scaffolds, we are particularly interested in heterocycles and antimicrobial peptides. This research proposal describes novel approaches to access engineerable molecular scaffolds for bacterial protein binding and manipulation and the development of innovative antimicrobial agents. The first part describes the development of synthetic methodologies to prepare benzo-fused heterocyclic scaffolds with abilities to mimic protein secondary structures. The proposed approach uses a multicomponent reaction to prepare polysubstituted heterocycles with different ring sizes and substitution patterns. With its great potential and flexibility, the proposed approach will give access to a wide array of functionalized benzo-fused heterocyclic compounds. The second part involves the design and development of mimetic approaches to exploit the attractive structural behaviour and mode of action of antimicrobial peptides from the microcin family. These antimicrobial peptides are among the most promising alternatives to conventional but their use is often limited by low production yields. In a first project, macrocyclic peptides will be designed and synthesized to mimic the lasso topology of microcin J25 and give access to this promising structure. Some microcins contain an iron-chelating unit, called siderophore, and can highjack the bacterial iron-transport system to reach their target and kill bacteria. Inspired by this strategy, the second project involves the addition of siderophores to antimicrobial peptides to increase potency and expend their spectra of activity. The development of new antimicrobials is a challenging and important goal in fundamental and applied research. The developed of synthetic approaches will unfold new possibilities to reach novel and complex molecular structures. Our work will give access to new approaches and molecular scaffolds for peptide mimicry. The proposed research program will have a strong impact in organic and medicinal chemistry as well as food, veterinary and medical microbiology since antimicrobials are used in food safety, animal production, human health and veterinary medicine.