Multifunctional isoquinoline-oxazoline ligands of chemical and biological importance.

Multifunctional isoquinoline-oxazolines (MIQOXs) were conceived and synthesized from commercially available chiral amino acids. The multifunctional role of MIQOXs was demonstrated by Pd-catalyzed highly enantioselective addition of arylboronic acids to nitrostyrenes, and by the discovery of novel antifungal candidates.

Late-Stage C-H Functionalization of Nicotinamides for the Expedient Discovery of Novel Antifungal Leads.

Encouraged by the successful flexible modifications of the succinate dehydrogenase inhibitors, antifungal activity guided by the divergent synthesis of nicotinamides of the prevalidated pharmacophore 2-(2-oxazolinyl)aniline was conducted. The work highlighted the first utilization of the late-stage C-H functionalization assisted by the innate pharmacophore for the discovery of promising agrochemicals. New synthetic methodology and antifungal exploration of alkoxylated nicotinamides were accomplished. Fifty-five functionalized nicotinamides of 7 types were rationally designed and efficiently prepared through C-H functionalization, which facilitated the acquirement of four N-para aryloxylated nicotinamides (E3, E13, E19, and E22) as potential antifungal candidates against Botrytis cinerea, with the EC50 values lower than 5 mg/L. In vivo/vitro biotest, molecular docking, and structural analysis reconfirmed the novelty and practical potential of the antifungal candidates E3 and E19. This operationally simple platform will provide various "polar parts" and offer intriguing opportunities for the optimization of the carboxamide fungicides and structure-related pharmaceuticals.

Bioactivity-guided mixed synthesis accelerate the serendipity in lead optimization: Discovery of fungicidal homodrimanyl amides.

The bioactivity-guided mixed synthesis was conceived, in which the designed mix-reactions were run in parallel for simultaneous construction of different kinds of analogs. The valuable ones were protruded by biological screening. This tactic will facilitate more rapid incorporation of bioactive candidates into pesticide chemists' repertoire, exemplified by the optimization of less explored homodrimanes as antifungal ingredients. The discovery of D9 as a potent fungicidal agent can be completed in <2 weeks by one student, with EC50 of 3.33 mg/L and 2.45 mg/L against S. sclerotiorum and B. cinerea, respectively. To confirm the practicability, time-efficiency, and reliability, specific homodrimanes (82 derivatives) were synthesized and elucidated separately and determined for EC50 values. The SAR correlated well with the intentionally mixed synthesis and the potential was further confirmed by the in vivo bioassay. This methodology will foster more efficient exploration of biologically relevant chemical space of natural products in pesticide discovery, and can also be tailored readily for the lead optimization in medicinal chemistry.