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.