Lead Generation for Infectious Diseases through Rapid Synthesis of Skeletally Diverse Small Molecules Inspired by Artemisinin

Structural modifications of anti-malarial artemisinins have traditionally focused on the lactone (D-ring) as the sole modifiable functional group. Our research group has developed two de novo synthetic processes capable of rapidly synthesizing tetracyclic peroxides with a wide range of skeletal and stereochemical variations. The first approach features the concise synthesis and diversification of structural motifs inspired by highly oxygenated sesquiterpenes recognized for their biological activities against infectious diseases. This divergent synthetic approach, accomplished within five to seven-step sequence, successfully provided appropriately functionalized and skeletally diverse sesqueiterpene-like scaffolds, involving systematic variations of stereochemical relationships at the sp3 ring-junctions. Lead generation for human African sleeping sickness, along with the elucidation of the pharmacophore, provided a proof-of-concept of our synthetic campaign. The second-generation approach focused on the expeditious and customizable access to the anti-malarial pharmacophore by installation of an amino nitrogen at the C6 position, akin to "point mutation". This molecular design presented a completely distinct retrosynthetic disconnection and enabled the most efficient fully synthetic access to the tetracyclic scaffold, achieved in just four steps. This modular catalytic asymmetric synthesis allowed generation of substitutional variations at three sites (N6, C9, and C3). The 6-aza-artemisinins exhibited promising in vivo anti-malarial activities, surpassing the efficacy of artemisinin. These findings overturned the prevailing belief that the cyclohexane moiety (C-ring) of artemisinins merely serves as a structural unit. Instead, it became evident that the piperidine ring, with an unnatural substituent on the N6 nitrogen, played a pivotal functional role within the anti-malarial pharmacophore. These molecular design and modular synthetic strategies have facilitated the rapid and flexible de novo synthesis of sp3-rich pharmacophores relevant to natural products, overcoming limitations associated with semi-synthetic and engineered biosynthetic approaches.