From the Spectroscopic Reassessment of Authentic Alkaloid Samples to the Molecular Networking-Guided Discovery of Criophylline-Related Analogues from Callichilia inaequalis .

The molecular network-guided exploration of the alkaloid extract of Callichilia inaequalis stems revealed a cluster attributed tentatively to dimeric monoterpene indole alkaloids of the rare criophylline subtype, initiating the dual study reported herein. A patrimonial-themed portion of this work was aimed at performing a spectroscopic reassessment of criophylline ( 1 ), a monoterpene bisindole alkaloid for which the nature of the inter-monomeric connectivity and configurational assignments have remained dubious. A targeted isolation of the entity annotated as criophylline ( 1 ) was undertaken to strengthen the available analytical evidence. An extensive set of spectroscopic data was acquired from the authentic sample of criophylline ( 1a ) isolated earlier by Cavé and Bruneton. These spectroscopic studies proved the samples to be identical, and the complete structure of criophylline could be assigned, half a century after it was first isolated. The absolute configuration of andrangine ( 2 ) was also ascertained based on a TDDFT-ECD approach from the authentic sample. The forward-looking aspect of this investigation resulted in the characterization of two new criophylline derivatives from C. inaequalis stems, namely, 14'-hydroxycriophylline ( 3 ) and 14'- O -sulfocriophylline ( 4 ). Their structures, including absolute configurations, were elucidated by analysis of NMR and MS spectroscopic data and by ECD analysis. Notably, 14'- O -sulfocriophylline ( 4 ) is the first sulfated monoterpene indole alkaloid to have been reported. The antiplasmodial activity against the chloroquine-resistant strain of Plasmodium falciparum FcB1 was determined for criophylline and its two new analogues.