One-Pot Cascade Annulation-Triggered Synthesis of N-6-Substituted Norcryptotackieine Alkaloids and Evaluation of Their Antileishmanial Activities.

Abstract

Norcryptotackieine or 6H-indolo[2,3-b]quinoline is an indoloquinoline class of alkaloid isolated from Cryptolepis sanguinolenta that is traditionally used for antimalarial therapy. Additional structural tuning can extend the therapeutic potency of these indoloquinolines as antileishmanial drug leads. Synthesis of N-6-functionalized norcryptotackieines suffers from the necessity of complex pre-synthesized starting materials, restricted scope of functionalization, or tedious processes. Consequently, a straightforward synthetic procedure for accessing non-natural N-6-functionalized 6H-indolo[2,3-b]quinolines with potent antileishmanial activities is highly sought-after. Herein, we report a two-step one-pot synthesis of N-6-functionalized norcryptotackieine through a Pd-catalyzed double annulation reaction of commercially available amphipathic amines, 2-iodobenzyl cyanide, and differently functionalized 2-bromobenzaldehydes. The reported procedure allows a broad flexibility of substitution at the N-6 position and access to diversified scaffolds, including two natural products norcryptotackieine and neocryptolepine. Interestingly, 6d showed potent antileishmanial activities by causing disruption in the cytoskeletal structure and apoptotic-mediated death of parasites. Together, our work manifests the shortest route to N-6-substituted norcryptotackieine-derived antileishmanial agents.